3 Article

Clinical and Translational Imaging
https://doi.org/10.1007/s40336-021-00440-1
SYSTEMATIC REVIEW
Topographical patterns of whole‑brain structural alterations

in association with genetic risk, cerebrospinal fluid, positron
emission tomography biomarkers of Alzheimer’s disease,
and neuropsychological measures
Albert Dayor Piersson1,2 · Mazlyfarina Mohamad1 · Subapriya Suppiah3 · Nor Fadilah Rajab4
Received: 1 April 2021 / Accepted: 7 June 2021

© Italian Association of Nuclear Medicine and Molecular Imaging 2021
Abstract
Purpose This study aimed at investigating the topographical pattern of whole-brain structural alterations in association with
apolipoprotein E ε4 (APOE ε4), cerebrospinal fluid (CSF) [amyloid-beta 42 (Aβ42), and neurofibrillary tau protein], positron
emission tomography (PET) biomarkers [Aβ, tau, and 2-[18F]fluoro-2-deoxy-d-glucose (FDG)], and neuropsychological
measures.
Methods PubMed, Scopus, Ovid, and Cochrane databases were searched. Risk of bias (using a modified Newcastle–Ottawa
Scale) and level of evidence were determined.
Results One hundred and thirty-one studies met the inclusion criteria. APOE ε4 effect is exerted on the whole-brain. Still,
the medial temporal lobe is the most affected, with moderate evidence observed across the lifespan (except late mid-life) and
in the AD continuum. Moderate to strong evidence shows that atrophy of AD-vulnerable regions is associated with reduced
CSF Aβ42, increased Aβ- and tau-PET, and increased CSF tau. No association between gray matter changes and FDG-PET
measures in healthy late mid-life and older adults. Preliminary findings demonstrate a relationship between hippocampal
atrophy and lower episodic memory in early life. Moderate evidence of an association between hippocampal atrophy and
lower episodic memory is observed in late mid-life. In contrast, hippocampal atrophy is associated with reduced episodic
memory and global cognition in older APOE ε4 carriers.
Conclusions Strong evidence suggests that atrophy of the AD vulnerable regions is associated with CSF and PET biomarkers
and cognitive measures. These relationships may be potentially helpful in characterizing the preclinical and clinical stages
of MCI and AD and predicting AD progression.
Keywords Brain · Apolipoprotein · Magnetic resonance imaging · Cerebrospinal fluid · Positron emission tomography ·
Cognitive function · Alzheimer’s disease · Dementia
2
* Mazlyfarina Mohamad Department of Imaging Technology and Sonography,
mazlyfarina@ukm.edu.my School of Allied Health Sciences, University of Cape Coast,
University Post Office, Cape Coast, Ghana
Albert Dayor Piersson
3
p97002@siswa.ukm.edu.my; albert.piersson@ucc.edu.gh; Centre for Diagnostic Nuclear Imaging, Universiti Putra
albert.piersson@gmail.com Malaysia, 43400 UPM Serdang, Selangor, Malaysia
4
Subapriya Suppiah Biomedical Science Programme,
subapriya@upm.edu.my Center for Healthy Aging and Wellness,
Universiti Kebangsaan Malaysia, 50300 Kuala Lumpur,
Nor Fadilah Rajab Malaysia
nfadilah@ukm.edu.my
1
Diagnostic Imaging and Radiotherapy Programme,
Universiti Kebangsaan Malaysia, 50300 Kuala Lumpur,
Malaysia
13
Vol.:(0123456789)
Introduction MTL atrophy [13–15]. Aside from this, it is postulated that

APOE ε4 may confer more significant memory impairment
In clinical practice, the diagnosis of Alzheimer’s disease in demented patients, especially AD [14]. However, APOE
(AD) is based on core clinical criteria. For instance, neu- ε4 is only a genetic risk factor, suggesting that AD can
ropsychological tests are used to complement the diag- occur with or without APOE ε4.
nostic workup of AD. Yet, they are known to be plagued A novel approach would be to combine neuroimaging
by several limitations; a major one is poor test–retest reli- modalities with genomic, AD biomarkers, and neuropsycho-
ability (intraclass correlation coefficients: ~ 0.5–0.8) [1], logical measures. This approach was recently established for
and the inability to ascertain neuronal population and neurometabolites examined with proton magnetic resonance
their function directly. Even more so, the combination spectroscopy (1H-MRS) [16]. It is posited that this approach
of clinical diagnosis with standardized neuropsychologi- may provide greater insight into the mechanisms and underly-
cal tests is limited for use as a standard benchmark for ing neurodegenerative changes in AD. There is also the sug-
diagnosing dementia. Validated AD biomarkers, such as gestion that it may help in the prediction of course, outcome,
brain amyloid-beta (Aβ) deposition, are typically demon- and therapeutic response compared to using either of them
strated as decreased levels of cerebrospinal (CSF) Aβ42 alone. Previous systematic reviews and meta-analysis that
and increased retention of Aβ tracer on positron emis- have examined the effect of APOE ε4 on the brain have mainly
sion tomography (PET) [2]. However, it remains unclear focused on older adults and the MTL [13, 15], neglecting
whether the aggregation of Aβ is sufficient to instigate the other brain structures. Besides, these studies did not account
downstream neuropathological cascade of AD. Biomarkers for the interaction between brain structural alterations and AD
of brain tauopathy include increased tau levels in CSF and biomarkers and neuropsychological measures. Therefore, the
PET [2, 3]; however, increased CSF tau level are not AD current systematic review interrogated the available evidence
specific [2]. Another important validated biomarker of AD on the relations of whole-brain structural alterations examined
is reduced 2-(18F)fluoro-2-deoxy-d-glucose (FDG) uptake with MRI with APOE ε4, validated CSF and PET biomarkers,
on PET. FDG-PET is usually demonstrated in a temporo- and neuropsychological measures across the lifespan.
parietal pattern as hypometabolism, and it is considered to
be related to synaptic dysfunction [2], loss of neuropil, and
functional impairment of neurons [4]. However, the extent Materials and methods
to which FDG-PET can serve as a valuable investigative
tool in the clinical stages of AD remains controversial. Research questions
For instance, one Cochrane review suggested that there is
no robust evidence to support its use in individuals with The current systematic review follows the Preferred
mild cognitive impairment (MCI) [5]. In contrast, another Reporting Items for Systematic reviews and Meta-analyses
review argued that there is sufficient evidence demonstrat- guidelines [17]. Further, this study followed the Patient,
ing that its integration with clinical examinations improves measurement Instrument, Comparison, and Outcome
diagnostic accuracy [6]. This was about identifying those (PICO)-framework, which were applied to generate the fol-
with AD and individuals in the predementia stage [6]. lowing research questions: (1) What is the significant rela-
However, FDG-PET is considered an unspecific marker of tionship between the presence of APOE ε4 allele (O—out-
neurodegeneration [7]. Medial temporal lobe (MTL) atro- come) and whole-brain structural changes (O—outcome)
phy on magnetic resonance imaging (MRI) is a validated measured with MRI (I—instrument) across all age groups
biomarker of AD-related neurodegeneration [2]. Still, it (P—patient)? (2) What is the significant association between
is suggested to occur later compared to PET changes [3], whole-brain changes and CSF biomarkers (O—outcome)?
suggesting that gray matter (GM) or cortical modifica- (3) What is the significant association between whole-brain
tions may be limited in detecting the early structural brain changes (O—outcome) and PET biomarkers (Aβ and tau-
changes in AD before the onset of symptoms. PET and FDG-PET) (I—instrument)? (4) What is the sig-
Although age is recognized as the most significant risk nificant association between whole-brain changes (O—out-
factor for AD [8–11], the risk is increased with the pres- come) and neuropsychological measures (O—outcome)?
ence of apolipoprotein E ε4 (APOE ε4), which is pur-
ported to reduce the age at onset, especially in individu- Sources of information and search approach
als with the homozygous genotype [12]. Strong evidence
suggests that APOE ε4 itself is associated with cerebral The following electronic databases were initially searched
Aβ deposition [13], neurofibrillary tau protein levels [14], till August 19, 2019: PubMed (http://www.ncbi.nlm.nih.
increased cerebral glucose hypometabolism [13, 15], and gov/pubmed/), Scopus (https://www.scopus.com/home.uri),
13
Ovid (http://www.ovid.com/site/index.jsp), and Cochrane duplicates were removed, and the first phase of the screening
(https://www.cochranelibrary.com/search). The search was was performed based on title and abstract. When an abstract
further updated on the 3rd March, 2020 and 23rd Janu- is deemed to provide inadequate information, a retrieval of
ary, 2021. Further, studies included in previous systematic the whole text was undertaken. The next phase involved the
reviews and meta-analysis [13, 15] were reviewed for eligi- retrieval of full-text articles which were evaluated to ensure
bility. The search was further complemented with a search that they meet the inclusion criteria. Consensus was often
of the grey literature. Additionally, cross-referencing of all reached when there is concern regarding the inclusion or
the bibliography of the primary sourced eligible articles was exclusion of an article.
undertaken to identify the articles that fulfilled the inclu-
sion criteria. The following search terms were entered: Data information
(“Apolipoprotein” OR “APOE”) AND (“brain imaging” OR
“magnetic resonance imaging” OR “MRI”) AND (“Tem- The following details were extracted from each included
poral lobe” OR “Hippocampus” OR “Medial Temporal article and presented in Tables 1 and 2. In Table 1, the fol-
Lobe” OR “Parahippocampal gyrus” OR “Amygdala” OR lowing items are listed: (1) authors, (2) magnetic fields, (3)
“ Entorhinal cortex” OR “Parietal lobe” OR “Frontal lobe” MRI parameters, (4) pulse sequences, (5) measurement and
“Occipital lobe” OR “Precuneus” OR “Entorhinal cortex” analysis method, and (6) neuropsychological tools used in
OR “Atrophy”) AND (“Brain size” OR “ Brain volume” the studies. Table 2 shows (1) authors, (2) age and gender
OR “Gray matter volume” OR “Cortical Thickness”) AND of the patient group, (3) age and gender of the control group
(“Cerebrospinal fluid” OR “CSF” OR “amyloid” OR “amy- or healthy cohorts, (4) report of the association between
loid-beta” OR “beta-amyloid” OR “Aβ” OR “amyloid-β” OR APOE ε4 and brain structural alterations, (5) report of the
‘”β-amyloid” OR “Aβ42” OR “tau” OR “p-tau” OR “t-tau”) association between brain structural alterations and PET bio-
AND (“Positron emission tomography” OR “PET”) OR markers, (6) report of the association between brain struc-
(“fluorodeoxyglucose PET” OR “FDG PET” OR “glucose tural alterations and neuropsychological measures, and (7)
metabolism”) AND (“cognitive measures” OR “neuropsy- remarks.
chological testing” OR “neurocognitive measures”).
Risk of bias in individual studies
Study selection
To determine the methodological quality of each eligible
The articles had to fulfill the following inclusion criteria: (1) study, the Newcastle–Ottawa Scale (NOS, http://www.ohri.
healthy subjects without age limit and/ or subjects with AD ca/programs/clinical_epidemiology/oxford.asp) designed
or dementia [including vascular dementia (VaD), demen- purposely for case–control and cohort studies was used
tia with Lewy bodies (DLB), and frontotemporal dementia (Table 3). The NOS is apportioned into three categories:
(FTD)] (P—patient population); (2) all subjects were exam- selection, comparability, and exposure/outcome. The maxi-
ined using structural brain MRI technique (I—instrument); mum score on the NOS is nine points, which represents the
(3) brain was investigated for whole or regional alterations, highest methodological quality. To avoid bias, two reviewers
and measurements made of GM volume (GMv) and/or corti- (A.D.P. and M.M) independently conducted the methodo-
cal thickness (O—outcome); (4) GMv and/or cortical thick- logical quality assessment. After quality assessment, a com-
ness and APOE ε4 included with or without CSF Aβ and parison was made and consensus was reached when differ-
tau, Aβ- and tau-PET, FDG-PET and/or neuropsychological ences occurred in the scores. One point is awarded for each
measures, (5) articles published in English language, and (6) item under the Selection and Exposure/Outcome categories,
full-text available articles. Articles that did not meet each of while two points are awarded for the Comparability category.
the listed criteria were excluded. Regarding the response rate, a subcategory under Exposure
was replaced because it did not fit the assessment criteria
Eligibility criteria for the study. Therefore, this subcategory was replaced with
item 9 to assess for ‘MRI data quality’ [18]. This was to
Assessment for eligibility was undertaken by conducting check whether researchers performed visual inspection of
a screening of all articles obtained in accordance with the ‘MRI data quality’. Overall, the maximum achievable score
listed inclusion and exclusion criteria. More importantly, for of a study was 9 which represented the test methodological
inclusion, studies had to show that the association of APOE quality. The NOS Scale is described in Table 3.
ε4 and structural brain alterations was investigated using Regarding the study design and methodological qual-
MRI. Assessment for eligibility was undertaken by A.D.P, ity, a level of evidence (LOE) was assigned to each
a PhD candidate working on ‘neuroimagenomics’ of MCI/ study, in accordance with the 2005 classification sys-
AD patients. After identifying potentially eligible articles, tem of the Dutch Institute for Healthcare Improvement
13
Table 1 MRI parameters and measurement techniques
Authors Magnet strength (T) TR/TE/TI (ms) FA ST Pulse sequence Measurement and analysis method Neuropsychological testings listed&
13
[19] 3.0 6.16/2.33/450 12° – 3D SPGR Volumetric (SPM) MMSE, Memory Binding Test, and
WAIS
[20] 3.0 or 1.5 – – – 3D T1-weighted; T2*-weighted Volumetric (SPM)
[21] 3.0 4.5/2.2/853 8° 1.2 3D T1-weighted TFE; MP-RAGE Volumetric (FreeSurfer) MMSE, TMT-A and TMT-B, and
CERAD word list test
[22] – – – – 3D T1-weighted Cortical thickening –
[23] 1.5 15/7/- 15° – 3D T1-weighted FFE Manual tracing and semiautomatic MMSE
6000/100/1900 FLAIR
[24] 1.5 – – – – Volumetric MMSE, CDR, RAVLT
[25] 3.0 1950/3.4/- – – 3D MP-RAGE Volumetric and cortical thickening MMSE, AQT-CF, ADAS-cog, and
(FreeSurfer) TMT-A
[26] 1.5 15/5/- 20° 1.5 3D T1-weighted Volumetric and Shape CDR, Text Revision, and Modified
Hachinski Ischemic Scale
[27] 3.0 2300/2.98/900 – 1–1.2 – Volumetric RAVLT, HVLT
[28] 1.5 – – – – Volumetric (FreeSurfer) RAVLT; TMT-A and B, BNT
[29] 3.0 33/5 30° 1.5 3D T1-weighted SPGR Surface (FSL) AVLT, MMSE, HDRS, IADL, and
psychiatric interview
[30] 1.5 4000/15, 105 – 2.5 T2-weighted FSE Visual analysis MMSE
[31] 1.5 10/4/250 12° 1.5–1.8 3D MP-RAGE Volumetric analysis/manual tracing List learning test, HVRT, BNT, copy
a cube test, clock setting test and the
block design subtest of the WAIS,
Luria’s method, TMT-A and B, verbal
fluency, and Wisconsin card sorting
test
[32] 1.5 10/7/300 15° 1.4 3D MP-RAGE Manual tracing MMSE, memory assessment scale, and
CDR
[33] 1.0 11.4/4.4/400 – 1.0 3D MP-RAGE Volumetric analysis/manual tracing CAMCOG, MMSE, and MADRS
[34] 1.5 10/4/300 10° 1.3 3D T1-weighted GRE Volumetric analysis MMSE and IADL
[35] 1.5 33/5 30° 1.5 3D T1- weighted SPGR Volumetric analysis/manual tracing MMSE and HDRS
[36] 1.5 600/30 – 5.0 T1-weighted Volumetric analysis/manual tracing ‘Meaningful test’, Mood test, LGT-3,
Trail and Design recall, WCST, Gat-
terer test, TMT-B, WAIS-R, Complex
reaction time, and Purdue Pegboard
test
[37] 1.5 24/5 45° – 3D SPGR Volumetric analysis/manual tracing MMSE and ADAS-cog
[38] 1.5 2730/3.43/1000 7° – 3D MP-RAGE Volumetric and cortical thickness CVLT-II and WASI
analysis
[39] 0.22 500/30 – 10.0 T1-weighted Manual tracing CDR and Hasegawa Dementia scale
[40] 0.5 500/15 – 5 T1-weighted Volumetric analysis MMSE
Table 1 (continued)
[41] 1.0 11.4/4.4/400 1 3D T1-weighted Visual rating MMSE
[42] 1.5 2000/20 or 100 – 5 CSE Double-Echo Semiautomated segmentation analysis MMSE, DSS, WAIS-R, and BVRT
[43] 1.5 9.7/4 10° 2 3D T1-weighted GRE Voxel-based morphometry (Statistical CDR and other neuropsychological
parametric mapping) testings (not listed)
[44] 1.5 2400/-/1000 8° – 3D MP-RAGE Volumetric and surface-based CDR, WMS-R, and MMSE
analysis
[45] 3.0 – Volumetric and surface analysis Corsi block tapping task
[46] 3.0 2300/2.08 9° – 3D MP-RAGE Voxel-based morphometry MoCA and MMSE
[47] 3.0 3.9/9.5 12° 1 3D SPGR Volumetric analysis (FreeSurfer) MMSE, DRS-2, and RAVLT
3.0 9.6/3.9 12° 1
[48] 1.5 11.9/4.2 15° 1.2 Fast SPGIR Volumetric analysis (FreeSurfer) –
[49] 1.5 9/4 8° – 3D MP-RAGE Volumetric and thickness analysis MMSE, CDR, and WMS-R
[50] 1.5 2400/-/1000 8° – 3D MP-RAGE Volumetric analysis CDR, MMSE, and WMS-R
[51] 1.0 20/5 30° 1.3 3D T1-weighted Volumetric analysis RAVLT, Raven matrices and verbal
11.4/4 8° 1.3 fluency
[52] 1.5 – – 1.2 3D SPGR Volumetric analysis DRS, WMS-R, and CVLT
1.5
[53] 1.5 3500/90 – 5 T2-weighted Visual analysis MMSE, CDR, Modified Hachinski
Ischaemic score
[54] 1.5 – – – 3D MP-RAGE Manual tracing MMSE
[55] 1.5 – – – 3D MP-RAGE Volumetric and thickness analysis CDR and MMSE
3.0 (FreeSurfer)
[56] 3.0 – – – – Volumetric analysis (FreeSurfer) CDR, WMS-R, word list recall imme-
diate and delayed, category fluency
for animals and vegetables, letter flu-
ency, WAIS-R, MMSE, TMT-A and
B, pair binding, correct identification
of intact pairs, new pairs and mixed
pairs, DSS
[57] 1.5 9/2 15° – 3D Fast SPGR Volumetric analysis RAVLT
[58] 7.0 5 to 6 s/49 – – T2-weighted FSE Cortical thickening analysis HVLT-R, BVMT-R, and WMS
[59] 1.5 2730/3.31/1000 7° 1.33 3D MP-RAGE Volumetric and thickness analysis Not listed
[60] 1.5 – – – – Volumetric analysis WMS-R, MMSE, and CDR
[61] 3.0 – – – 3D MP-RAGE Volumetric and thickness analysis NIH Toolbox Cognition Battery
(Flanker Inhibitory Control and
Attention Test, Picture Sequence
Memory Test, and List Sorting Work-
ing Memory Test)
13
Table 1 (continued)
13
[62] 3.0 2500/4.38/1100 8° – 3D MP-RAGE Volumetric analysis (Statistical para- CDR, WMS, BNT, WAIS, TMT-A and
metric mapping) B, Verbal fluency, Free and Cued
Selective Reminding Task, SCWT,
and MMSE
[63] 1.5 – – – – Volumetric and thickness analysis BNT, TMT-A and B, WAIS-R,
(FreeSurfer) RAVLT, WMS-R, MMSE, CDR,
Modified HIS
[64] – – – – – Volumetric and shape analysis MMSE, CDR, and Delayed Logical
Memory Test
[65] 1.5 – – – 3D MP-RAGE Volumetric analysis (FreeSurfer) CDR and MMSE
[66] 1.5 9/4 8° – 3D MP-RAGE Cortical thickening analysis MMSE, CDR, WMS-R
[67] 1.5 – – – – Volumetric and shape analysis CDR and MMSE
[68] 3.0 -/3.7/500 – – 3D SPGR Volumetric and cortical thickness MMSE, BVRT, WMS, Logical
analysis Memory Delayed Recall Portion,
Buschke-Fuld Selective Remind-
ing Test, and Consistent Long Term
Retrieval Section
[67] 3.0 9.5/3.9 12° 1 3D SPGR Volumetric analysis GDS, MMSE, DRS, RAVLT
9.6/3.9 12° 1 3D SPGR
[70] 1.5 – – – 3D MP-RAGE Volumetric and cortical thickness MMSE
analysis (FreeSurfer)
[71] 4.0 1600/4.38/800 – 1.34 3D MP-RAGE Volumetric analysis MMSE
[72] 4.0 3500/0.019 – 2 T2-weighted FSE Volumetric analysis MMSE
[73] 4.0 2300/3/950 7° – 3D MP-RAGE Volumetric analysis (FreeSurfer) MMSE, CVLT, ROCF, Verbal fluency,
8390/70 150° – T2-weighted WAIS, GDS
[74] 3.0 2300/2.93 – 1 3D MP-RAGE Volumetric and cortical thickening Buschke-Fuld selective reminding test,
analysis WMS, CLTR, MMSE, and CDR
[75] 1.5 15/7 15° 1.5 3D FFE Volumetric analysis MMSE, Episodic memory scale (16-
word list)
[76] 1.5 – – – 3D MP-RAGE Voxel-based morphometry (Statistical CDR
Parametric Mapping)
[77] 3.0 1900/3.44 9° 1 3D MP-RAGE Volumetric analysis MMSE, AVLT, ROCF, TMT-A and B,
BNT, SCWT, and SDMT
[78] 1.5 24/7 35° 1.5 3D SPGR Manual tracing MMSE and CVLT
1.5 25/5 35° 1.4 3D SPGR
[79] 3.0 – – – IR-SPGR Volumetric and fraction analysis Not listed (participants were infants)
[80] – – – – – Volumetric and thickness analysis MMSE, RAVLT, TMT-A and B, DSS,
Digit span, Category fluency test,
BNT, CDR, and Digiti symbol
Table 1 (continued)
[81] 1.5 24/2 20° 2 3D SPGR Volumetric and thickness analysis MMSE, WAIS-R, NART, Cognitive
reserve
1.5 24/3 45° 1.5 SPGR
[82] 1.5 90/3.9 8° 1.2 3D MP-RAGE Cortical thickness analysis MMSE
[83] – – – – – Volumetric analysis (FreeSurfer) Stroop task, finger tapping, Digit Sym-
bol, and 15-word list
[84] 1.5 27/9 25° 1.6 3D SPGR Volumetric and manual tracing MMSE
analysis
[85] – – – – 3D MP-RAGE/IR-SPGR Thickness, surface, and volumetric CDR, ADAS-Cog, MMSE, and
analysis (FreeSurfer) RAVLT
[86] 1.5 33/5 30° 1.5 3D SPGR Voxel-based morphometry (Statistical MMSE, HDRS, and AVLT
parametric mapping)
[87] – – – – – Volumetric and thickness analysis MMSE
(FreeSurfer)
[88] 3.0 5200/105 – 3.0 T2-weighted FSE Volumetric and thickness analysis WMS-R, CLTR, ROCF, WMS-III,
CERAD, AAT, NAi, CVLT and FAS
[89] – – – – – Segmentation and surface reconstruc- CDR, MMSE, and Delayed Logical
tion memory test
[90] – – – – FLAIR Volumetric analysis GDS
[91] 1.5 11.2/4.2/450 12° 1 3D SPGR Voxel-based morphometry MMSE, GDS, CDT, WMS-R, CLRT,
BADS, VOSP, BNT, and TMT-A
and B
[92] 1.5 10/4/250 12° 1.5–1.8 3D MP-RAGE Manual tracing MMSE, HIS, CDR, BNT, HVRT, and
shopping list test
[93] 1.5 – – 1.3 FFE Volumetric analysis Not listed
[94] 1.5 28.05/2.64 30° 2.0 FFE Manual measurement and Voxel- MMSE
based morphometry (Statistical
parametric mapping)
[95] 1.5 – – – 3D MP-RAGE Volumetric analysis and thickness CDR, MMSE, WMS-R, ADAS-Cog,
(FreeSurfer) and GDS
[96] 1.5 9.5/2.2/450 7° – 3D SPGR Volumetric, surface, and thickness CVLT, 16-word list, WASI
1.5 2.730/3.39/1000 7° – 3D MP-RAGE analysis (FreeSurfer)
[97] 1.5 9/4 8° – 3D MP-RAGE Volumetric analysis (Semiautomated MMSE, ADAS-Cog, CDR, GDS
tracing)
[98] 1.5 – – – – Volumetric analysis MMSE
[99] 1.5 33/5 30° 1.5 3D SPGR Volumetric analysis (Semiautomated MMSE, AVLT, ROCF, BNT, WAIS-R,
algorithm) COWAT
[100] 1.5 13.8/2.8/400 20° 1.6 Fast 3D SPGR Volumetric analysis (FreeSurfer) Not listed
[101] 1.5 10/4/300 10° – 3D MP-RAGE Manual tracing MMSE, ROCF, WMS, COWAT, CDR
13
Table 1 (continued)
13
[102] 1.5 10/4/250 12° 1.5–1.8 3D MP-RAGE Volumetric analysis (Standard ana- MMSE, BCRS, Webster scale, Ham-
tomical atlas) ilton scale, and modified ischaemic
scale
[103] 3.0 7.92/2.48 – 1 3D MDEFT Volumetric analysis (FSL) MWT-B, BDI, BVRT, CVLT, WMS,
TMT-A and B, and LNS
[104] – – – – – Volumetric analysis (FreeSurfer) CDR and MMSE
[105] 1.5 8.93/3.57 8° 1.5 FFE Volumetric analysis (FreeSurfer) CVLT, MMSE, and 16-word list
[106] 1.5 – – – – Volumetric analysis (FreeSurfer) MMSE and WMS-R
[107] 3.0 – – 1.25 3D MP-RAGE Voxel-based morphometry (DAR- Not listed (participants were young)
TEL, Statistical parametric map-
ping)
[108] 1.5 – – – 3D MP-RAGE Multi-Atlas propagation and segmen- MMSE
tation
[109] 3.0 – – – 3D MP-RAGE Volumetric analysis (FreeSurfer) Not listed (young participants)
[110] – – – – 3D T1 GRE Volumetric analysis (Quarc) CDR, ADAS-Cog, and MMSE
[111] 1.5 10/4/500 – – 3D MP-RAGE Volumetric analysis (FreeSurfer) MMSE
[112] 1.5 9.3 to 20/3.93 to 4.38 15° 1–1.2 FLAIR Volumetric analysis (Statistical para- CDR, MMSE, Delayed verbal recall
1.5 9000–10,000/100–110/2500 5–6 FLAIR metric mapping)
[113] – – – – – Volumetric analysis (FreeSurfer) WMS-R, MMSE, CCI, ECog, GDS,
RAVLT, and MoCA
[114] 1.5 – – – FLAIR Voxel-based morphometry (DAR- CDR
TEL)
[115] – – – – – Cortical thickness (FreeSurfer) MMSE
[116] 1.5/3.0 – – – 3D MP-RAGE Volumetric analysis (FreeSurfer) MMSE, GDS, CDR, and CANTAB
SWM
[117] 1.5 – – – 3D MP-RAGE Volumetric analysis (FreeSurfer) CDR, MMSE, and GDS
[118] 1.5 2300/4/1000 8° – 3D MP-RAGE Volumetric analysis (NeuroQuant) MMSE, TMT-A and B, CDT, MADRS,
RDRS, and BMD
[119] 1.5 22/10 30° – Volumetric analysis RAVLT, After inference test, and
delayed recall
[120] 1.5 1900/3.4 15° 1 3D MP-RAGE Volumetric analysis VLMT and NAI
[121] 1.5 – – – 3D SPGR – MMSE, CDR, GDS, GIDS, and ADLS
[122] – – – – – Volumetric analysis (FreeSurfer) Not listed
[123] Volumetric analysis (FreeSurfer and MMSE, WMS-R, MMSE, and CDR
ITK-SNAP
[124] – – – – 3D MP-RAGE Voxel-based morphometry (Free- ADAS-Cog and RAVLT
Surfer)
Table 1 (continued)
[125] 3.0 2300/2.3 – – 3D T1-weighted Voxel-based morphometry (Free- HADS, DSS, TMT-A and B, Corsi,
Surfer) WMS-R, WCST, Phonemic Verbal
test, BNT, GOF, CERAD, ROCF,
CDR
[126] 3.0 9.5/4.6 20° 1.2 3D TFE Voxel-based morphometry MoCA and AVLT
[127] 3.0 – – – – Visual reading MMSE and CDT
[128] – 8/3.1/600 12° – 3D SPGR Volumetric and cortical thickening WMS-R, CVLT, TMT-A and B, WISC-
analysis R, DKEFS, and DRS
[129] 3.0 2300/2.27 – 1 3D MP-RAGE Volumetric analysis (FSL) MMSE, HADS, DSS, TMT-A and B,
Corsi, 48 Cued recall test, Shapes
test, WCST, Phonemic verbal test,
BNT, ROCF, CERAD, Praxis, ideo-
motor, reflexive, and IADL
[130] – 8/3/450 20° 1 3D SPGR Volumetric and cortical thickening AVLT
analysis (FreeSurfer)
[131] – – – – – Volumetric analysis (Statistical para- MMSE and AVLT
metric mapping)
[132] 1.5 20/2 30° 1.3 – Visual rating CDR and MMSE
1.5 21/20 10° 2.0
[133] – – – – – Segmentation (FAST) Not listed
[134] 1.5 – – – Proton-density, T2-weighted – DDES, HDRS, MADRS, and MMSE
[135] 1.5 5000/20 or 80 – 3.0 Double SE VBM, SPM CVLT, CDR, MMSE, ROCF, BNT,
10/4/300 15 1.5 MP-RAGE TMT-B, DSS, Phonemic fluency, and
semantic fluency
[136] 1.5 – 45 1.6 3D SPGR Manual tracing CDR and MMSE
[137] – – – – MP-RAGE VBM, FreeSurfer RAVLT, ADNI-MEM, TMT-A and
B, category fluency, BNT, MMSE,
CDR, ADAS-Cog, MoCA, FAQ, and
CDT
[138] 1.5 9.7/4.0 12 2.0 – Cortical thickness, volume, manual MMSE and CDR
13.5/7.0 12 1.5 – tracing and automated processing
[139] 1.5 24/5 45 1.5 3D SPGR Cortical thickness, volume, manual Not listed
tracing and automated processing
[140] 1.5 10/4 13 1.8 3D T1-weighted VBM, SPM2 MMSE and CERAD
– – – FLAIR
[141] 1.5 1.5/5.4/650 15 1.5 3D T1-weighted Cortical thickness, FreeSurfer MMSE and RMT
[142] – – – – 3D T1-weighted CAT12, SPM12, Manual tracing and MMSE and CDR
Volumetry
[143] 3.0 1800/2.07/900 12 1.0 MP-RAGE VBM8, SPM8, Volumetry MMSE and ADL
13
Table 1 (continued)
13
[144] 1.5 – – – 3D T1-weighted VBM, SPM8, FreeSurfer MMSE, CERAD, FCSRT, TMT-A and
B, figures recall, figures recognition,
naming test, verbal fluency, phonetic,
and semantic tests
[145] 3.0 6.16/2.33/450 12 – 3D SPGR VBM, SPM12 MBT, TDFR, TFR, TPR, WAIS-IV,
3.0 – – 2.0 T2-weighted DSS, MRV, and GADS
[146] 1.0 20/5 30 1.3 3D T1-weighted SPM99, Manual tracing and VBM MMSE, RAVLT, ROCF, TMT, PSF,
5000/100 90 5.0 FLAIR Token and CDR
[147] 1.5 14/3 20 1.5 3D SPGR Manual tracing, Semiautomated MMSE, WAIS-R, WMS-R
measures
[148] – 2300/2.98/900 9 1.2 MP-RAGE Automated MMSE, CVLT, DKEFS, WTAR, DSS,
– – – – T2-weighted, FLAIR WAIS-III, Stroop task, ROCF, BNT
[149] 1.5 14/3 20 1.5 3D SPGR Manual tracing MMSE, ADAS-Cog, and CDR
[150] 1.0 20/5 30 1.3 3D T1-weighted SPM99, Manual tracing MMSE, BSR, RAVLT, ROCF, PSF,
5000/100 90 5.0 FLAIR Token, and TMT
TR repetition time, TE echo time, TI inversion time, FA flip angle, ST slice thickness, SPGR spoiled gradient recalled echo, IR-SPGR inversion recovery-SPGR, FFE fast field echo, 3D MP-
RAGE three-dimensional magnetization-prepared rapid gradient-echo, FLAIR fluid-attenuated inversion recovery, GRE gradient echo, SE spin echo, MDEFT modified driven equilibrium Fou-
rier transform, TFE turbo field echo, FSL FMRIB Software library, MDD major depressive disorder
&
Neuropsychological testing abbreviations—AAT Aachen Aphasia Test, ADAS-cog Alzheimer’s Disease Assessment Scale-cognitive subscale, ADLS Activities of Daily Living Scale, ADNI-
MEM ADNI composite scores for memory, AQT-CF A Quick Test of cognitive speed—(Color and Form subtest), BADS Behavioral Assessment of the Dysexecutive Syndrome, BCRS brief
cognitive rating scale, BDI Beck Depression Inventory, BMT Behavior and Mood Disturbance, BNT Boston Naming Test, BSRT Babcock Story recall test, BVMT-R Brief Visuospatial Memory
Test–Revised, BVRT Benton Visual Retention Test, CAMCOG Cambridge Cognitive Examination, CANTAB SWM Cambridge Neuropsychological Test Automated Battery Spatial Working
Memory, CCI Cognitive Change Index, CERAD Consortium to Establish a Registry for Alzheimer’s Disease, CDR Clinical Dementia Rating, CDT Clock drawing test, CLTR consistent long-
term retrieval section, COWATControlled Oral Word Association Test, CVLT-II California Verbal Learning Test II, DDES Duke Depression Evaluation Schedule, DKEFS Delis-Kaplan Execu-
tive Function System, DRS-2 Dementia Rating Scale 2, DSS Digit Symbol Substitution test, ECog Everyday Cognition, FAQ Functional Assessment Questionnaire, FAS Controlled oral word
association test, letters F,A,S, FCSRT Free and Cued Selective Reminding test, GADS Goldberg Anxiety and Depression Scale, GDS Geriatric Depression Scale, GlDS Global Deterioration
Scale, GOF Ghent Overlapping Figures, HADS Hospital Anxiety and Depression Scale, HDRS Hamilton Depression Rating Scale, HIS Hachinski Ischaemic Score, HVLT-R Hopkins Verbal
Learning Test, HVRT Heaton Visual Reproduction test, LGT-3 ‘Lern-und Gedachtnistest’, LNT Letter Number Sequencing, MADRS Montgomery Asberg Depression Rating Scale, MBT Mem-
ory Binding Test, MMSE Mini-Mental State Examination, MoCA Montreal Cognitive Assessment, MRVP Matrix Reasoning and Visual Puzzles, MWT-B ‘Mehrfachwahlwortschatztest’, NAI
Nuremberg age inventory, NARTNational Adult Reading Test, PSF Phonological and Semantic fluency, RAVLT Rey auditory verbal learning test, RDRS-2 Rapid Disability Rating Scale-2, RMT
Recognition Memory Test, ROCF Rey–Osterrieth complex figure, SCWTStroop Color-Word Test, SDMT Symbol Digit Modalities Test, TDFR delayed total free recall, TMT-A, B Trail Making
Test (A and B), TPR immediate total paired recall, VLMT Verbal Learning and Memory Test, VOSP Visual Object and Space Perception Test, WASI Wechsler Abbreviated Scale of Intelligence,
WAIS-R Wechsler Adult Intelligence Scale-Revised, WCST Wisconsin Card Sorting test, WISC-R Wechsler Intelligence Scale for Children, WMS-R Wechsler Memory Scale–Revised, WTAR
Wechsler Test of Adult Reading
Table 2 Evidence table of studies included in qualitative synthesis
Authors Patient group (age in years) Control group (age in APOE ε4 and brain struc- Brain structural alterations and CSF biomarkers Brain structural Brain structural alterations Remarks
years) tural alterations (Aβ and tau) alterations and PET and neuropsychological
biomarkers (Aβ and measures
tau) or FDG-PET
[19] None 213 ♂ and 320 ♀ APOE ε4 carriers showed – – Inverse relationship between Participants stratified
(57.58 ± 7.43 years) a reduced GMv in GMv in the caudate and into non-APOE
the right posterior cerebellar crus and scores ε4 and APOE ε4
hippocampus, but in 2 subscales of the zygosity
increased volume in the Wechsler Adult Intelligence C tients had AD
right medial thalamus Scale (Digit-Symbol dy
relative to controls Substitution Test and Digit-

APOE ε4 dose dependent Span Sequencing), but
GMv increase was modulated by APOE ε4
found in the left middle No association found between
occipital cortex and ROIs and episodic memory
in the right superior
frontal cortex
Additive effect of APOE
ε4 on GMv reduction
in the right caudate
nucleus, right precentral
gyrus, and right cer-
ebellar crus
[20] 35 (mean age: > 60 years) 72 (66.6 ± 7.5 years) Increased temporopari- – – Association found between Patients stratified into
MCI etal volume in APOE greater left < right temporo- APOE ε4 zygosity
145 (mean age: > 60 years) ε2 carriers relative to parietal volume asymmetry Cross-sectional study
AD APOE ε4 carriers and language impairment
(p = 0.002)
Association found between
MTL atrophy and more
memory impairment
(p < 0.001) and attention
(p = 0.027) in the patient
group
[21] 12 ♀ and 8 ♂ 8 ♀ and 10 ♂ Lack of associations Lack of associations between CSF biomarkers and – – Cross-sectional study
(66.8 ± 7.4 years) MCI (66.7 ± 6.8 years) SCD; between APOE ε4 hippocampal or amygdala volumetry CSF biomarkers were
10 ♀ and 10 ♂; APOE ε4 carrier status and hip- examined
(62.8 ± 9.6 years) pocampal or amygdala
2. 9 ♀ and 7 ♂; APOE volumetry
ε4- (59.1 ± 8.5 years)
[22] 154 AD (> 60 years) None Association between – – – No information on
increased number of gender distribution
APOE ϵ4 genes and Longitudinal study
faster pace of cortical
atrophy in AD but not
with an earlier atrophy
onset
13
Table 2 (continued)
13
tau) or FDG-PET
[23] None 266 ♀ and 170 ♂ APOE ϵ4 shows an – – At baseline, association found Participants stratified
(70.3 ± 9.1 years) interaction with neuro- between increased MRI into presence or
degeneration scores on score for both neurodegen- absence of APOE ϵ4
MMSE decline eration and microvascular Neurodegeneration
At baseline, no interaction lesions and faster MMSE score include MRI
was found between decline markers of reduced
APOE ϵ4 and baseline hippocampus, and
and neurodegeneration reduced total GM and
scores enlarged ventricles
Longitudinal study
[24] 41.9%♀ and 58.1%♂ 49.1%♀ and 50.9% ♂; MCI and AD APOE ε4 – – In all participants, positive Cross-sectional study
(72.6 ± 7.4 years) aMCI (74.7 ± 5.6) carriers demonstrated correlations were found Data derived from
43.8%♀ and 56.2% ♂ reduced hippocampal between hippocampal ADNI
(74.7 ± 8.0) AD volumes relative to non- volume/intracranial volume
carriers ratio (HpVR) and rey
auditory verbal learning
test (RAVLT) immediate
(p < 0.001) and delayed
(p < 0.001) recall scores.
In diagnosis-stratified
analyses, HCs were found
to demonstrate a positive
correlation between HpVR
and immediate recall
(p = 0.024), but not delayed
recall (p = 0.4). In MCI,
HpVR showed a positive
correlation with immediate
recall (p < 0.001), and
delayed recall (p < 0.001)
scores. In AD dementia,
an association was found
between HpVR immediate
recall (p = 0.016), and
delayed recall scores
(p < 0.001)
Table 2 (continued)
tau) or FDG-PET
[25] 10 ♀ and 9 ♂; None Cortical thinning more – More pronounced – Participants were clas-
(70.1 ± 7.8 years) APOE pronounced in medial effects of tau sified as MCI due to
ε4-; and lateral parietal PET on cortical AD/AD-like dementia
28 ♀ and 18 ♂; regions of non-APOE thickness in non- Tau-PET and CSF
(72.4 ± 6.8 years) APOE ε4 carriers compared to APOE ε4 carriers Aβ42, t-tau, and p-tau
ε4 + APOE ε4 carriers compared to the assessed
APOE ε4 carriers. No correlational

The predominant analysis between
effects of tau CSF biomarkers and
PET on cortical cortical thickness
thickness in the measures
non-carriers were Cross-sectional study
found in all regions
(in the exception
for the entorhinal
cortex/cortex
ratio), while in the
APOE ε4 carriers,
this effect was only
found in the lateral
regions of both
the temporal and
parietal lobes
[26] 20 ♀ and 15 ♂ None Increased atrophy rate of – – – Longitudinal study
(63.81 ± 3.19 years) MCI; the left hippocampus in
8 ♀ and 7 ♂ the MCI and AD APOE
(63.64 ± 3.01 years) AD ε4 carriers compared to
the right hippocampus
of both groups
[27] 14 ♀ and 47 ♂ (75.0 ± 6.0); 33 ♀ and 76 ♂ CN APOE ε4 carriers The CSF Aβ42 positive MCI subjects demonstrated – – Atrophy of the pre-
AD-MCI (75.0 ± 5.0); CN demonstrated decreased increased rate of hippocampal atrophy (p = 0.007) cuneus, appearing
11 ♀ and 22 ♂ (70.0 ± 4.0); 10 ♀ and 18 ♂ cortical thickness in the In the CSF Aβ42 negative controls similar in APOE ε4
PD-MCI (70.0 ± 4.0); CN parahippocampal gyrus (CSFAβ42 > 192 pg/mL), APOE ε4 carriers dem- carriers with AD and
with increasing age onstrated increased cortical thickness in the infe- PD-MCI
Aβ negative APOE ε4 rior parietal (p = 0.002), middle temporal gyrus Longitudinal study
carriers demonstrated (p = 0.005), and precuneus regions (p = 0.01) CSF biomarkers
increased cortical thick- assessed
ness in the inferior pari- Data derived from
etal, middle temporal ADNI
gyrus, and precuneus
regions
aMCI APOE ε4 carriers
demonstrated reduced
cortical thickness in the
middle temporal gyrus,
inferior parietal region,
and the precuneus com-
pared to non-carriers
13
Table 2 (continued)
13
tau) or FDG-PET
[28] 306 ♀ and 324 ♂ MCI 335 ♀ and 367 ♂ In the control, APOE ε4 – – – FDG-PET and Aβ-PET
135 ♀ and 178 ♂ AD allele was associated assessed, but no
with reduced hip- correlational analysis
pocampal volume ratio with GM loss
and hypometabolism in Cross-sectional study
males but not in females Mean age: > 70 years
In MCI, APOE ε4 was Data derived from
associated with reduced ADNI
hippocampal volume Mean age: > 70 years
ratio and hypometabo-
lism and increased Aβ
burden
In AD, APOE ε4 carriers
exhibited reduced hip-
pocampal volume ratio
relative to non-carriers
[29] None 11♂ and 25♀ Evidence of APOE ε4 Participants stratified
(57.2 ± 3.8 years) HT; gene-dose effects on according to the pres-
9♂ and 28 ♀ (58.4 ± 6.8) the left hippocampal ence or absence of
HM; morphology (shape and APOE ε4
15♂ and 29♀ atrophy) Cross-sectional study
(58.6 ± 7.2 years)
[30] None 92 (55 – 85 years) APOE ε4 effect noted – – – Cross-sectional study
on hippocampal sulcal
cavity
[31] 14♂ and 12♀ (mean 6♂ and 10♀ AD APOE ε4 carriers – – In the entire study partici- Cross-sectional study
age: > 65 years) AD (70.2 + 4.7 years) exhibited reduced pants, correlation was found
left frontal lobe, right between hippocampal
hippocampal, and right volumes and scores on
amygdala volumes delayed word recognition
compared to controls (p < 0.001) for the right
hippocampus (p < 0.001)
for the left hippocampus)
and delayed visual memory
(p < 0.0001) for the right
and left hippocampi);
the reduced the volume,
the more impairment in
performance
These relationships were not
significant in the AD group
For executive functions,
correlation was found
between the performance
on trail-making test and
frontal lobes (p < 0.001)
in all participants, but not
significant in those with AD
Table 2 (continued)
tau) or FDG-PET
[32] None 42 (58 – 87 years) No effect of APOE ε4 – – Inverse relationship found Longitudinal study
on atrophy rates of between baseline delayed
entorhinal cortex and list recall (DLR) scores and
hippocampus atrophy rates of entorhinal
cortex (p < 0.01), but no
association found between
annual changes of DLR

scores and atrophy rates of
entorhinal cortex and hip-
pocampus (both at p > 0.3)
[33] 19♂ and 8♀ (75.9 ± 6 14♂ and 12♀ (76.2 ± 6 No effect of APOE ε4 on – – Positive association found Cross-sectional study
7 years) dementia with 5 years) volumetric measures between hippocampal
lewy bodies (DLB); of whole-brain, frontal, volume and MMSE in
9♂ and 16♀ (77.2 ± 6 temporal lobe, hip- demented participants
5 years) AD; pocampal and amygdala (p < 0.01)
15♂ and 9♀ (76.9 ± 6
7 years) Vascular demen-
tia (VaD)
[34] 3♂ and 15♀ (76 ± 5 years) 9♂ and 17♀ FTD APOE ε4 carriers – – – Participants stratified
AD; (69 ± 9 years) had right ventral striatal according to the pres-
6♂ and 2♀ (62 ± 5 years) atrophy ence or absence of
FTD AD APOE ε4 carriers APOE ε4
had greater atrophy of Cross-sectional study
the amygdalae and hip-
pocampi head
[35] None 33 (50 – 62 years) No association found – No association Correlations found between Cross-sectional study
between APOE ε4 and between hippocam- reduced whole hippocam- FDG-PET assessed
hippocampal volume pal volumes and pal volume and lower but no correlational
PCC hypometabo- Long-Term Recall scores analysis with GM loss
lism (p < 0.05) in APOE ε4
homozygote carriers
[36] None 106♂ and 108♀ No association found – – – Cross-sectional study
(60.5 ± 6.0 years) between APOE ε4 and
hippocampal and para-
hippocampal volumes,
and sulcal widening
[37] 26♂ and 29♀ (mean 22♂ and 20♀ APOE ε4 effect observed Significant relationship Patients with AD strati-
age: > 70 years) AD (73.2 ± 6.7 years) on amygdala volume between reduced amygdala fied according to the
volume and lower MMSE presence or absence
score (p < 0.009) in AD of APOE ε4
APOE ε4 positive patients Cross-sectional study
[38] None 110 (53–64 years) No association between – – – Participants stratified
middle-aged; APOE ε4 and total according to the pres-
120 (65–75 years) older- cortical volume ence or absence of
adults APOE ε4
Cross-sectional study
13
Table 2 (continued)
13
tau) or FDG-PET
[39] 34 (mean age: > 80 years) 22 ( 82.0 ± 7.7 years) AD patients with the Patients with AD strati-
AD APOE ε4 demonstrated fied according to the
severe presence or absence
atrophy of the hippocam- of APOE ε4
pus and amygdala (with Cross-sectional study
dilatation of the lateral
ventricular temporal
horn) relative to non-
carriers
[40] 31♂ and 54♀ 9♂ and 11♀ No evidence of APOE ϵ4 – – No association between Left asymmetry implies
(81.04 ± 14.23 years) AD; (76.88 ± 6.48 years) effect on leftward asym- regional temporal lobe right > left in volu-
16♂ and 14♀ metry of hippocampus structures and cognitive metric measures
(84.09 ± 6.79 years) mild and parahippocampal measures Cross-sectional study
ambiguous/MCI gyrus
27♂ and 32♀
(82.22 ± 7.16 years)
“mixed neuropsychiatric
individuals”
[41] 9♂ and 16♀ (77.8 ± 4.4) AD None No evidence of an asso- Cross-sectional study
14♂ and 10♀ ciation between APOE
(76.9 ± 6.7 years) VaD ϵ4 and medial temporal
14♂ and 8♀ lobe atrophy
(77.2 ± 6.3 years) DLB
[42] None 308 (72.5 ± 3.0 years) APOE ε4 carriers – – Reduced brain volume No information on
non-APOE ε4 carriers exhibited reduced total correlated with lower gender distribution
82 (71.9 ± 2.8 years) intracranial (whole- MMSE and Benton Visual Longitudinal study
APOE ε4 carriers brain) volume and Retention Test; this rela-
increased CSF volume tionship was noted to be
significantly impacted by
the carriage of the APOE
ε4 allele
[43] 51 (mean age: > 70 years) 13♂ and 19♀ Homozygous APOE – – – Cross-sectional study
MCI (73 ± 4 years) ε4 carriers showed
more atrophy of the
bilateral amygdala,
right parahippocampal
gyrus, left medial dorsal
thalamic nucleus, and
the bilateral temporopa-
rietal regions relative to
non-carriers
[44] 160♂ and 85♀ 75♂ and 73♀ Correlation found – – Annual hippocampal atrophy Longitudinal study
(74.99 ± 7.17 years) MCI (75.92 ± 4.90 years) between APOE ε4 and correlated with annual Data derived from
49♂ and 48♀ the rate of decreased change in MMSE, global ADNI
(75.77 ± 7.33 years) AD hippocampal volume in CDR and sum-of-boxes
both AD and controls CDR in all participants
APOE ε4 carriers showed and separately within each
faster loss of hippocam- diagnostic group (p < 0.01;
pal tissue compared to p < 0.05)
non-carriers
Table 2 (continued)
tau) or FDG-PET
[45] – 62 (34.47 ± 13.48) No evidence of APOE ε4 – – No association between Participants stratified

effect on hippocampal visuospatial working into mild depressive
volume memory evaluated using disorder (n = 24) and
Reduced mean total Corsi block-tapping task, HC (38). Stratification
intracranial volume and hippocampal volume was also provided for
(whole-brain) in APOE (p = 0.56), but only became homozygous APOE
ε4 homozygotes significant (p = 0.03) after ε4 and non-APOE ε4

removing TIV from the carriers
GLM Cross-sectional study
[46] None 28♂ and 38♀ APOE ɛ4 carriers – – – Multimodal study with
(66.1 ± 4.5 years) demonstrated less grey fMRI
matter in the entorhinal Cross-sectional study
cortex relative to the
non-carriers
[47] None 15 declining APOE ε4 APOE ε4 declining – – – Longitudinal study; Age
carriers group exhibited greater range: 65–85 years
22 declining non-APOE atrophy in the bilateral
ε4 cortical GMvs and
11 APOE ε4 carriers bilateral hippocampi
(cognitively stable) relative to non-carriers
[48] None 212♂ and APOE ε4 status did not – – – Cross-sectional study
172♀(8.49 ± 0.84 years) show an association Participants were
APOE ϵ4 carriers with volumetric sizes assessed for exposure
673♂ and 610♀ of the basal ganglia to high levels of
(8.53 ± 0.88 years) non- including caudate, traffic-related air
APOE ϵ4 carriers putamen, and globus pollution
pallidum
13
Table 2 (continued)
13
tau) or FDG-PET
[49] 73♂ and 46♀ 37♂ and 40♀ In MCI group, APOE No association between baseline CSF biomarker – – Longitudinal study
(74 ± 7.6 years) MCI (75 ± 5.0 years) ε4 carriers exhibited (Aβ42, t-tau, and p-tau) and average regional Data derived from
29♂ and 25♀ independent associa- brain volumes in the CN group ADNI
(74 ± 8.0 years) AD tion with brain tissue Increased baseline CSF t-tau and p-tau (both CSF Aβ42, t-tau, and
volume loss in bilateral p < 0.05) correlated with reduced caudate vol- p-tau were assessed
hippocampus, bilateral umes; but not with rate of volume change in MCI
temporal lobe (i.e., mid- Reduced baseline CSF Aβ42 correlated with
dle temporal, inferior reduced baseline GMvs in lingual (left: p < 0.005;
temporal, temporal right: p < 0.05), pericalcarine (p < 0.05), and post-
pole, fusiform), right central (p < 0.05) cortices in AD
amygdala, right lingual, Lower CSF Aβ42 at baseline (but not t-tau at
left entorhinal, left baseline) correlated with increased rates of
isthmus cingulate, left atrophy pronounced in the left lateral and medial
parahippocampal, and temporal (p < 0.05) cortices, left hippocampus
left precuneus cortices (p < 0.05), right amygdala (p < 0.05), left isthmus
In MCI group, APOE ε4 (p < 0.05), and cingulate (p < 0.05); while CSF
carriers were observed p-tau correlated with increased rates of regional
to show association brain atrophy found to be pronounced in the
with increased rates left temporal lobe (p < 0.005), hippocampus
of cortical thinning in (p < 0.05), and amygdala (p < 0.05) in MCI
temporoparietal cortex, Baseline lower CSF Aβ correlated with lower atro-
precuneus and PCC phy rates in the caudate (left: p < 0.0005; right:
In MCI group, both p < 0.005) and accumbens region (p < 0.005);
CSF tau and APOE while increased CSF t-tau (but not baseline
ε4 showed association p-tau) correlated with reduced rates of atrophy
with increased rates in the right PCC (p < 0.05), isthmus cingulate
of cortical thinning (p < 0.005), and precuneus cortices (p < 0.05),
in the temporal pole, and increased rates of caudate atrophy (p < 0.05)
entorhinal cortex, and in AD
precuneus In CN, reduced baseline CSF Aβ42 correlated with
In the AD group, APOE a cortical thinning in several frontal and temporo-
ε4 carrier status partietal regions across the brain
was associated with No significant association found between baseline
increased rates of brain CSF Aβ42 and average cortical thickness meas-
tissue volume loss in ures in MCI and AD
the bilateral caudate Reduced baseline CSF Aβ42 correlated with
In AD, APOE ε4 showed increased rates of cortical thinning predominantly
an association with more in the left hemisphere (temporal pole, infe-
increased rate of rior temporal, middle temporal, inferior parietal,
volume loss in caudate, paracentral lobule, cingulate, isthmus cingulate,
seen to be independent precuneus, entorhinal, and fusiform) compared to
of t-tau level the right hemisphere (inferior temporal, and mid-
dle temporal cortices) (p < 0.05) in MCI
Increased baseline CSF p-tau correlated with
increased rates of cortical thinning in the left
hemisphere (temporal pole, superior temporal
sulcus, and entorhinal gyrus) and right hemi-
sphere (inferior and middle temporal cortices)
(p < 0.05) in MCI
Increased baseline CSF t-tau correlated with
increased cortical atrophy rates in the left entorhi-
nal gyrus in MCI (p < 0.05)
No correlation between CSF biomarkers and corti-
cal atrophy rates in neither CN nor AD
Table 2 (continued)
tau) or FDG-PET
[50] 330 (74.8 ± 7.5 years) MCI 181 (75.9 ± 5.1 years) Association was found - - Baseline temporal lobe Longitudinal study
165 (75.6 ± 7.6 years) AD between one copy of atrophy correlated with Data derived from
APOE ε4 and increased increased sum-of-boxes ADNI
CSF expansion in CDR scores in MCI and
the Sylvian fissures, AD (but not in CN), with
between inferior frontal significance slightly higher
and superior temporal in MCI compared to AD

lobes Correlation observed between
Association was found reduced volumes at
between increased atro- baseline and the changes
phy of the hippocampal in CDR sum-of-boxes over
and temporal lobe and the following year in all
carriership of an addi- groups (CN: p = 0.01; MCI:
tional APOE ε4 allele p = 0.02; AD: p = 0.01)
Atrophy level correlated
positively with logical
memory test scores for both
immediate and delayed
conditions in all groups (for
immediate—CN = 0.008;
MCI: p = 0.02; AD:
p = .03; for delayed—CN:
p = 0.008; MCI: p = 0.03;
AD: p = 0.01)
[51] None 59♂ and 101♀ Faster age‐related decline – – – Cross-sectional study
(55 ± 11 years) non- and decreased volumes
APOE ϵ4 carriers of the corpus callosum
16♂ and 35♀ and its subregions con-
(53 ± 14 years) APOE nected to the prefrontal,
ϵ4 carriers premotor, motor, senso-
rial, posterior parietal,
temporal, and occipital
cortices
is faster in APOE ϵ4 carri-
ers than noncarriers
[52] 11♂ and 6♀ MCI 22♂ and 30♀ APOE ε4 carriers showed – – At baseline, no association Longitudinal study
(77.3 ± 6.7 years) (76.6 ± 7.0 years) increased rate of hip- found between left hip- 22 APOE ε4 carriers
pocampal atrophy rela- pocampal volumes and and 47 non-ε4
tive to non-carriers performance on Wechsler
Memory Scale-Revised log-
ical memory for Immediate
or Delayed recall in either
of the genotype group, and
all groups (p > 0.21)
At the follow-up, increased
left normalized hip-
pocampal volumes showed
an association with
better Wechsler Memory
Scale-Revised logical
memory Immediate recall
(p = 0.03) and Delayed
recall (p = 0.03) among
13
noncarriers
Table 2 (continued)
13
tau) or FDG-PET
[53] 104 AD (mean None No association between – – – Cross-sectional study

age: > 60 years) APOE ε4 and atrophy
of the frontal, parietal,
temporal, occipital,
basal ganglion, and
cerebellum
[54] 28 AD 10♂ and 20♀ Increased APOE ε4 gene – – – AD patients stratified
(69 ± 8 years) dose on hippocampal into presence or
atrophy (Right < left) absence of APOE ε4;
in AD compared to Cross-sectional study
controls
No effect of APOE ε4
on temporal lobe and
entorhinal cortex
[55] None 189♂ and 308♀ Higher rate of subcortical – – – Longitudinal study
(66.8 ± 10.0 years) atrophy of the hip- Aβ-PET was assessed
pocampus, amyg- but no correlational
dala, putamen, and analysis with GM loss
accumbens in APOE
ɛ4 carriers compared to
non-carriers
[56] None 46♂ and 72♀ No differences between – – – Cross-sectional study;
(37.18 ± 10.54 years) APOE ε4 carriers and 11C Pittsburgh
non-APOE ε4 carriers non-carriers on precu- Compound B PET,
18♂ and 26♀ neal and hippocampal FDG-PET, and CSF
(43.05 ± 11.38 years) volumes Aβ42, p-tau and t-tau
APOE ε4 carriers data included
[57] None 22♂ and 9♀ APOE ε4 carriers showed Longitudinal study

(62.2 ± 6.3 years) non- reduced hippocampal
APOE ε4 carriers volumes relative to non-
23♂ and 2♀ carriers
(59.4 ± 5.7 years)
APOE ε4 carriers
[58] 9♂ and 5♀ (73.2 ± 5.3) 7♂ and 7♀ (68.8 ± 4.7) Association of APOE ε4 Cross-sectional study
aMCI dose-dependent with
5♂ and 6♀ (69.5 ± 9.3) AD increased thinning of
the hippocampal CA1
apical neuropil, or stra-
tum radiatum/stratum
lacunosum-moleculare
Table 2 (continued)
tau) or FDG-PET
[59] 64 Young-Old AD (44%♂; 83 Young-Old (51%♂; No effects of APOE ε4 – – – Participants stratified

77% APOE ε4 carriers); 25% APOE ε4 car- on baseline volumes of according to the pres-
40 Very-Old AD (56%♂; riers); 40 Very-Old bilateral hippocampal ence or absence of
50% APOE ε4 carriers) (54%♂; 28% APOE ε4 formation (includes the APOE ε4
carriers) dentate gyrus, Cornu Longitudinal study;
ammonis fields, subicu- Only men were
lum/ parasubiculum and represented

the fimbria) and cortical Young-old (age range:
thickness measures of 60–75 years)
frontal, temporal, and Very-old (age range:
parietal lobe cortical 80–91 years)
regions and bilateral
cingulate cortical
regions in AD
[60] 243 MCI 145 APOE ε4 carriers dem- – – – Participants stratified
96 AD onstrated reduced hip- according to the
pocampal volume, and presence or absence
APOE ε4 was found of maternal/family
to be associated with history of dementia
reduced hippocampal Longitudinal study
volume at follow-up Mean age: > 70 years
compared with non- Data derived from
carriers ADNI
[61] None 1187 (3 to 20 years) APOE ε4 carriers demon- – – Correlation between increased Cross-sectional study
strated the smallest hip- superior parietal gyral
pocampi, and entorhinal volumes and reduced atten-
cortical thinning of the tion (p = 0.001) or working
left inferior parietal memory score (p < 0.0005)
gyrus and right superior in APOE ε4 carriers
parietal gyrus Association noted between
APOE ε4 carriers dem- heterozygous APOE ε4 car-
onstrated the largest riers with increased cortical
medial orbitofrontal thickening and reduced
cortical areas attention in the right isth-
mus cingulate (p = 0.0002),
temporal pole (p = 0.01);
while homozygous APOE
ε4 carriers with temporal
pole thinning showed an
association with reduced
attention (p = 0.02)
Correlation between reduced
hippocampal volumes and
lower working memory
performance (p = .03),
particularly in homozygous
APOE ε4 carriers
13
Table 2 (continued)
13
tau) or FDG-PET
[62] None 24♂ and 15♀ APOE ε4 allele carriers – – – Cross-sectional study
(73.7 ± 6.2 years) non- showed atrophy of the
ε4 carriers left anterior hippocam-
6♂ and 8♀ pus and amygdala rela-
(72.7 ± 6.2 years) tive to non-carriers
[63] 104 AD 123 No APOE ε4 effects on – – Patient group and
volumetric measures of control group clas-
bilateral hippocampal sified as young-old
(including the dentate and very-old with or
gyrus, CA fields, sub- without APOE ε4;
iculum/parasubiculum Longitudinal study
and fimbria), and corti- Data derived from
cal thickness of frontal, ADNI
parietal lobe cortical Mean
regions, temporal, and age: > age > 70 years
bilateral cingulate corti-
cal regions in the AD
groups
[64] 353 (mean age: 75.06 years) 211 (mean age: APOE ε4 carriers demon- – – – Participants stratified
MCI 76.41 years) strated morphological according to the
160 (mean age: 74.88 years) deformation of the number of samples
AD hippocampus relative recruited in 6-,
to non-carriers in the 12- and 24-months,
entire cohort and the presence or
APOE ε4 carriers dem- absence of APOE ε4.
onstrated increased left Longitudinal study;
hippocampal atrophy Sample size included
relative to the right hip- were that of 6 months
pocampus Data derived from
ADNI
[65] 166♂ and 92♀ 84♂ and 80♀ APOE ε4 carriers demon- – – – Cross-sectional study
(74.48 ± 7.25 years) MCI (76.03 ± 5.22 years) strated increased whole- Data derived from
56♂ and 50♀ brain atrophy in MCI ADNI
(75.11 ± 7.35 years) AD
Table 2 (continued)
tau) or FDG-PET
[66] 73♂ and 46♀ 37♂ and 40♀ APOE ε4 was found to In CN, reduced baseline CSF Aβ42 associated with Longitudinal study
(74 ± 7.6 years) MCI; (75 ± 5.0 years) be associated with cortical thinning in several regions of the frontal Data derived from
29♂ and 25♀ higher rates of cortical and temporo-parietal lobes (p < 0.05) ADNI; CSF Aβ42,
(74 ± 8.0 years) AD thinning in entorhinal No association found between baseline CSF Aβ42 p-tau, and t-tau data
cortex, temporoparietal and cortical thickness measures in MCI and AD included
cortex, temporal pole, In MCI, reduced baseline CSF Aβ42 noted to
PCC, and precuneus in be associated with increased rates of cortical

MCI individuals thinning in extensive areas of the cortex but
significant (p < 0.05) in several regions of the
temporo-parietal lobe
No association between baseline CSF biomarkers
and cortical atrophy rates
Increased baseline CSF p-tau noted to be associ-
ated with increased rates of cortical thinning,
mainly in the temporal cortices (p < 0.05); while
increased baseline CSF t-tau noted to be associ-
ated with increased cortical atrophy rates in the
left entorhinal gyrus in MCI (p < 0.05)
[67] 276 MCI 135 Atrophy of the hip- – – – Patient group and
129 AD pocampi and bilateral control group clas-
amygdala in APOE ε4 sified as young-old
carriers relative to the (< 75 years) and very-
non-carriers, specifi- old (> 80 years) with
cally of the young-old or without APOE ε4
participants Longitudinal study
Reduced hippocampal Data derived from
volume in APOE ε4 ADNI
carriers relative to the
non-carriers in those
with AD
Reduced surface area (or
shape atrophy) of the
right hippocampus, and
bilateral amygdala in
AD-young APOE ε4
carriers relative to AD-
young non-carriers
[68] None 7♂ and 7♀ APOE ε4 carriers – – – Cross-sectional study
(57.7 ± 9.6 years) demonstrated lower
APOE ε4 carriers cortical thickness in the
8♂ and 8♀ entorhinal cortex and
(57.3 ± 7.8 years) non- subiculum relative to
APOE ε4 carriers non-carriers
13
Table 2 (continued)
13
tau) or FDG-PET
[69] None 7♂ and 23♀ APOE ε4 carriers – – – Longitudinal study

(73.94 ± 5.38) non- exhibited greater rate
APOE ε4 carriers of atrophy in total GM,
14♂ and 28♀ right hippocampal sub-
(73.02 ± 4.98) APOE fields (CA 1–4, dentate
ε4 carriers gyrus, presubiculum/
subiculum and fimbria),
bilateral hippocampi,
parahippocampal gyrus,
bilateral lingual gyri,
and right lateral orbito-
frontal cortex relative to
the non-carriers
[70] None 184 (mean: 79.9 years) APOE ε4 effect observed – – – Longitudinal study
on atrophy of hip- Data derived from
pocampus, amygdala, ADNI
entorhinal cortex and
cerebral cortex
[71] None 22♂ and 50♀ (19 to Older APOE ε4 with – – – Participants stratified
77 years) higher blood pressure according to the
exhibited reduced presence or absence
lateral prefrontal cortex of APOE ε4, Cross-
volumes sectional study
[72] 12♂ and 6♀ 55♂ and 64♀ Association between AD – – – Participants stratified
(69.1 ± 9.6 years) AD; (53.4 ± 17.2 years) APOE ε4 and volume according to the
14♂ and 6♀ loss in CA3-dentate presence or absence
(73.5 ± 7.1 years) aMCI gyrus relative to non- of APOE ε4; Cross-
APOE ε4 carriers in sectional study
HCs and AD
[73] (67.5 ± 9.3 years) AD 81 (60.8 ± 13.6 years) Reduced CA3 and DG – – – Control group stratified
in AD with APOE ε4 as young and old age
relative to AD without adults with or without
APOE ε4 APOE ε4, Cross-
APOE ε4 effect observed sectional study
on CA3-dentate gyrus
demonstrating reduced
volumes only in the
entire control popula-
tion, older controls,
a subgroup of older sub-
jects, and AD subjects
Table 2 (continued)
tau) or FDG-PET
[74] None 4♂ and 12♀ Lower cortical thickening – – – Longitudinal study

(60.1 ± 7.1 years) non- in the subiculum and APOE ε4 carriers
APOE ε4 carriers entorhinal cortex of demonstrated MTL
6♂ and 10♀ APOE ε4 carriers rela- volume loss and
(61.7 ± 11.5 years) tive to non-carriers whole-brain volume
APOE ε4 carriers Reduced cortical loss over of 2.8% and
thickening across the 0.2% respectively

medial temporal lobe over the 2 year period,
sub-regions (cornu while non-carriers
ammonis fields 1, 2, demonstrated 1.1%
and 3, dentate gyrus, and 0.1% volume loss
subiculum, entorhinal respectively, but were
cortex, perirhinal not significant
cortex, parahippocam- Global cortical thick-
pal cortex, and fusiform ness reduced signifi-
gyrus) combined in cantly more in APOE
APOE ε4 carriers rela- ε4 carriers by 4% in
tive to non-carriers 2 years (p = 0.01)
[75] None 424 (60 – 87 years) No evidence of APOE – – Significant positive correla- Participants
effect on hippocampal tion between hippocampal stratified according to
volume volume and episodic TOMM40 genotype
memory (free recall) per- and presence or
formance in APOE ε4 car- absence of APOE ε4
riers (p = 0.026) driven by allele; Cross-sectional
the presence of TOMM40 study
“risk” alleles in APOE
ε4 carriers (rs2075650:
p = 0.012; rs11556505:
p = 0.013) compared with
the “non-risk” carriers
of TOMM40 (p = 0.042;
p = 0.338) carrying APOE
ε4 but not significant in
non-carriers
[76] 48 MCI (mean None APOE ε4 carriers – – – Longitudinal study
age: > 70 years) exhibited GMv loss of Data derived from
47 MCI-AD (mean the temporal lobe, hip- ADNI
age: > 70 years) pocampi, parietal lobe, CSF Aβ level assessed
right caudate nucleus, but no correlational
and insulae in MCI to analysis with GM loss
AD group
APOE ε4 carriers who
were MCI stable
exhibited lower GMv of
the temporal lobes and
bilateral insular
13
Table 2 (continued)
13
tau) or FDG-PET
[77] None 836 (65.2 ± 7.5 years) APOE ε4 carriers dem- – – Positive correlation between Participants stratified
onstrated reduced GM right inferior temporal into 4 groups accord-
of the right fusiform gyrus GMv with MMSE ing to rs405509 T
gyrus, right inferior (p < 0.001) and Symbol allele and APOE ε4
temporal gyrus, left Digit Modalities Test allele. Cross-sectional
middle and superior (SDMT) (p = 0.024) study
frontal gyrus, right Right fusiform gyrus GMv
angular gyrus, and left correlated with MMSE
cingulate gyrus and (p = 0.016) and SDMT
precuneus relative to (p = 0.003). These were
non-carriers mediated by APOE ε4
interaction
[78] None 5♂ and 6♀ APOE ε4 exhibited – – – Longitudinal study
(67.0 ± 5.2 years) non- greater annual atrophy
APOE ε4 carriers rates in the temporal
7♂ and 9♀ lobes and hippocampus
(65.0 ± 4.5 years) (right > left)
APOE ε4 carriers
[79] None 60 APOE ε4 carriers APOE ε4 carriers exhib- – – – All participants were
102 non-APOE ε4 ited GMv reduction of infants with age
carriers PCC, medial cingulate range between 2- to
cortex, precuneus, 25-month-old, cross-
lateral temporal, and sectional study
medial occipitotemporal
regions relative to non-
carriers
[80] 38♂ and 29♀ None APOE ε4 carriers – – Hippocampal volume All participants were
(74.9 ± 9.2 years) APOE demonstrated reduced (p < 0.01) and MTL AD patients, Cross-
ε4 carriers hippocampal volume (p < 0.05) correlated with sectional data
13♂ and 11♀ relative to non-carriers poor performance on Data derived from
(74.3 ± 7.3 years) non- APOE ε4 carriers episodic memory (delayed ADNI
APOE ε4 carriers demonstrated reduced recall, recognition memory) CSF Aβ and t-tau
cortical thickness of the in APOE ε4 carriers assessed but no corre-
superior parietal lobule, Non-MTL regions correlated lational analysis with
precuneus, angular with poor performance on GM loss
gyrus, and superior Trails A (p < 0.05), Trails B
frontal gyrus relative to (p < 0.05), backward digit
non-carriers span (p < 0.05), and Boston
APOE ε4 carriers dem- naming test (p < 0.05) in
onstrated more cortical noncarriers
thinning of the superior Positive correlation between
and midline parietal poor performance on Bos-
and dorsolateral frontal ton naming test and inferior
regions, in addition frontal sulcus (p < 0.01);
to medial temporal, while Trails A (p < 0.01),
caudal temporal, lateral Trails B (p < 0.001), and
temporal regions, and Auditory Verbal Learn-
occipital regions rela- ing Test (trial 1 recall)
tive to the non-carriers (p < 0.01) correlated
Non-carriers exhibited positively with the angular
greater frontoparietal gyrus in noncarriers
atrophy
Table 2 (continued)
tau) or FDG-PET
[81] None 148♂ and 201♀ No associations between – – No associations between Longitudinal study
(57.3 ± 10.4 years) APOEε4 and rate of baseline cognitive reserve Cognitive reserve com-
atrophy of entorhinal score and rate of atrophy posite score encom-
cortex and hippocampus of the MRI measures passed baseline scores
Left amygdala showed (p > 0.30) on the: National
an interaction between Baseline MRI measures Adult Reading Test,
atrophy rate and APOE correlated with cognitive Wechsler Adult

ε4 genotype in asso- reserve score in the left and Intelligence Scale—
ciation with symptom bilateral entorhinal cortex Revised vocabulary
onset volume (both p < 0.05), subtest, and years of
found to be more pro- education
nounced in those with low
cognitive reserve with con-
comitant reduced entorhinal
volume (p < 0.03)
[82] None 75♂ and 84♀ (mean Increased cortical thick- Participants stratified
age: > 70 years) ness of the left superior according to APOE
temporal and left ɛ4 genotypes
dorsolateral prefrontal Data derived from
region in APOE ε2 car- ADNI
riers relative to APOE CSF Aβ42, t-tau and
ε4 carriers p-tau levels assessed,
but no information on
correlational analysis
with cortical thicken-
ing measures
[83] None 54 (30.1 ± 9.3 years) No impact of APOE ε4 – – – Cross-sectionl study
APOE ε4 carriers on volumes of bilateral (Professional fighters,
139 (31.1 ± 9.4 years) hippocampus, bilateral cross-sectional study,
non-APOE ε4 carriers thalamus, and bilateral no information on
caudate gender distribution)
[84] 88 AD (mean None No association found – – – Cross-sectional study
age: > 70 years) between the APOE ε4
dose and hippocampal
volume in this cohort
13
Table 2 (continued)
13
tau) or FDG-PET
[85] 165♂ and 132♀ 123♂ and 128♀ Among CN and early – Significant relation- – Multimodal study with
(71.53 ± 7.43 years) Early (75.47 ± 6.54) MCI participants, there ship between PET PET included
MCI was association between Aβ load and corti- Cross-sectional study
111♂ and 85♀ APOE ε4 allele and cal thinning in AD- Data derived from
(73.83 ± 8.06 years) Late increased cortical thick- vulnerable regions, ADNI
MCI ening in the entorhinal and temporo-
94♂ and 86♀ cortex, parahippocam- parietal regions
(74.94 ± 7.81 years) AD pal gyrus, inferior (most significant
temporal gyrus, and effects noted in the
temporal pole relative to following cortical
the non-carriers regions—inferior
Late MCI and AD par- temporal gyrus,
ticipants who are APOE inferior parietal
ε4 carriers exhibited lobule, precuneus,
reduced cortical thick- average cortical
ness relative to the thickness for all
non-carriers regions, and the
supramarginal
gyrus [for all
p < 0.00]), in the
exception of the
temporal pole
and frontal lobe
regions (superior
and rostral middle
frontal gyrus), all
controlled for the
effect of APOE ε4.
[86] None 27 APOEε4 homozy- Increased APOE-ε4 dose – Correlations noted – Multimodal study with
gotes found to be associated between the FDG-PET included,
36 APOE ε4 heterozy- with reduced GMv in reduced total and longitudinal cohort
gotes inferior frontal, parietal, regional cerebral study
67 non-APOE ε4 carriers anterior cingulate, tem- glucose metabo- Mean age: > 55 years
poral, parahippocam- lism on FDG-PET
pus, and hippocampus and reduced GMv
in AD-affected
regions, but
not significant
(p = 0.05)
Table 2 (continued)
tau) or FDG-PET
[87] 237 (mean age = 79.9 years) None Association found – – – Longitudinal study
MCI between APOE ε4 Data derived from
allele and accelerated ADNI
rates of atrophy of the Age-related hippocam-
amygdala, cerebral pal volume loss at
cortex, entorhinal an average of 23.57
cortex, fusiform gyrus, mm3/year

hippocampus, inferior
parietal cortex, inferior
temporal cortex, middle
temporal cortex, para-
hippocampal cortex,
precuneus cortex,
superior parietal cortex,
temporal pole cortex,
and transverse temporal
cortex
[88] 28 (mean age: > 72 years) 26 (mean age: > 55 years) APOE ε4 carriers exhib- – – No correlation between Cross-sectional study
AD middle-age individu- ited thinner entorhinal cortical thickness measures
als; cortex of the left and neuropsychological test
23 ( mean hemisphere relative to performance
age: > 65 years) older the right hemisphere
individuals
[89] 167 (mean age: > 70 years) 204 (mean Accelerated hippocampal – – – Cross-sectional study
AD; age: > 70 years) atrophy (left > right) Data derived from
354 (mean age: > 70 years) more salient in APOE ADNI
MCI ε4 homozygotes relative
to heterozygotes
[90] None 1280♂ and 1845♀ APOE ε4 carriers – – – Longitudinal study
(76.3 ± 5.4 years) non- demonstrated reduced
APOE ε4 carriers GMvs compared to
505♂ and 673♀ non-carriers
(75.7 ± 5.3 years)
APOE ε4 carriers
[91] 95 MCI (mean 15♂ and 34♀ Increased atrophy of – – No correlation between cog- Cross-sectional study
age > 70 years) (71.6 ± 4.26) GM in hippocampus, nitive measures and GMv
parahippocampal gyrus, changes
and thalamus in MCI
homozygous-APOE
ε4 relative to MCI
heterozygous-APOE ε4
and MCI non-APOE ε4
controls
More marked GM atrophy
of bilateral middle
frontal gyrus in MCI
non-APOE ε4 relative
to MCI heterozygous-
APOE ε4 and MCI
homozygous-APOE ε4
groups
13
Table 2 (continued)
13
tau) or FDG-PET
[92] 5♂ and 6♀ 11♂ and 20♀ APOE ε4 is associated – – – Cross-sectional study

(69.1 ± 7.1 years) APOE (72.2 ± 3.9 years) with atrophy of the Patient group are classi-
ε4 – entorhinal cortex in fied as AD
10♂ and 6♀ early AD
(70.4 ± 9.9 years) APOE
ε4 +
[93] None 23♂ and 9♀ No effect of APOE ε4 on – – – Cross-sectional study
(45.97 ± 7.5 years) reduced hippocampal
non-APOE ε4 allele volume
carriers
11♂ and 9♀
(47.55 ± 11.1 years)
APOE ε4 allele car-
riers
[94] None 177♂ and 154♀ No association between – – – Longitudinal study
(62.6 ± 1.4 years) APOE ε4 allele
and atrophy of the
hippocampus and
amygdala
[95] 74♂ and 143♀ 97♂ and 118♀ Association found – – – Longitudinal study
(75.3 ± 7.4 years) MCI-nc (75.9 ± 5.5 years) between APOE ε4 allele Data derived from
55♂ and 85♀ (74.6 ± 6.8) and reduced volumes ADNI
years) MCI-c of the hippocampus
81♂ and 87♀ and amygdala, reduced
(75.5 ± 7.7 years) AD thickness of entorhinal
cortex, parahippocam-
pal gyrus cortex, and
temporal lobe cortex
[96] None 170 (46 – 77 years) No associations between – – Positive Cross-sectional study
hippocampal volumes correlation found between
and APOE ε4 allele California Verbal Learning
Test-II scores and total
hippocampus volumes
(p < 0.0001)
[97] 140♂ and 86♀ 66♂ and 61♀ Association found Overall, correlation found between rates of hip- – Correlation found between Longitudinal study
(75.0 ± 7.1 years) MCI (76.3 ± 5.1 years) between increased rates pocampal GM loss and reduced CSF Aβ42 ADAS-cog and rates of hip- Data derived from
51♂ and 45♀ of hippocampal atrophy (p < 0.01), mainly driven by MCI pocampal GM loss in AD ADNI
(75.8 ± 6.6 years) AD and APOE ε4 allele No correlation between CSF Aβ42 and MRI meas- and MCI (p = 0.0005) CSF Aβ42, t-tau, and
in AD ures in AD (p = 0.01) and CN (p = 0.5) Correlation found between p-tau assessed
CSF t-tau (p = 0.058) and p-tau showed no signifi- rates of MMSE change CSF Aβ42 contributed
cant correlation with hippocampal GM loss rates and rates of hippocampal more (~ 1.5 times) to
GM loss in AD and MCI rates of hippocampal
(p = 0.04) GM loss than APOE
[98] 510♂ and 826♀ Associations between – – Association found between Longitudinal study
(72.0 ± 4.0 years) reduced hippocampal longitudinal GMv changes 20.1% reported as expe-
volume and subjective and episodic memory riencing subjective
memory impairment (verbal fluency and visual memory complaints at
at follow-up, found to memory) (< 0. 001) 4 year follow-up
be stronger in APOE
ε4 allele
Table 2 (continued)
tau) or FDG-PET
[99] None 28♂ and 48♀ Association found – – – Cross-sectional study

(56.5 ± 4.7 years) between APOE ε4 and FDG-PET assessed
15♂ and 27♀ reduced hippocampal but no correlational
(55.9 ± 4.0 years) HT volume analysis with GM
APOE ε4 changes
10♂ and 21♀
(55.5 ± 5.1 years) HM

APOE ε4
[100] None 1806♂ and 2156♀ No association found – – – Cross-sectional study
(60.1 ± 8.50 years) between APOE ε4 and
cerebral or cerebellar
volume
[101] 28 AD 10♂ and 20♀ Progressive reduction of – – Hippocampal and entorhinal Cross-sectional study
(69 ± 8 years) volumes of the temporal cortex volumes (but not
lobe regions volumes frontal and temporal lobes)
(i.e. entorhinal cortex correlated with CDR and
and hippocampus) from disease duration (p < 0.05)
controls to AD patients (but not MMSE score)
with increasing APOE in AD
ε4 gene-dose
Increased frontal lobe
volume with increasing
APOE ε4 gene dose in
AD patients
[102] 30♂ and 28♀; AD 14♂ and 20♀ AD homozygous APOE – – Lower MMSE score cor- Cross-sectional study
ε4 allele carriers related with reduced amyg- Mean age: > 60 years
demonstrated atrophy dala volume (p = 0.03) but SPECT data included
of the hippocampus and not with left (p = 0.07) and
amygdala relative to right (p = 0.06)hippocampal
control group volumes
No association between ε4
allele and frontal lobe
[103] None 13♂ and 9♀ Lower hippocampal – – – Cross-sectional study
(26.86 ± 5.28 years) volume (right < left) in
APOE ε4 carriers healthy young APOE
13♂ and 9♀ ε4 carriers compared to
(26.73 ± 4.00 years) non-carriers
non-APOE ε4 carriers
[104] 58♂ and 42♀ ( 54♂ and 50♀ No association found – – – Cross-sectional study
75.1 ± 7.8 years) AD (75.9 ± 5.1 years) between APOE ε4 allele Data derived from
and cortical thickness ADNI
of entorhinal cortex, CSF Aβ42, t-tau, and
temporopolar cortex, p-tau assessed, but no
lateral temporal cortex, direct correlational
inferior parietal cortex analysis with cortical
and sulcus, PCC, and thickness measures
inferior frontal cortex
13
Table 2 (continued)
13
tau) or FDG-PET
[105] None 314 (44 – 48 years) No association between – – – Longitudinal study

313 (64 – 68 years) APOE ε4 and bilateral
entorhinal cortex, bilat-
eral middle and superior
temporal region, and
bilateral inferior and
temporal poles
[106] 321 mild MCI; 198 Evidence of significant – – – Cross-sectional study
143 AD dose-dependent interac- Data derived from
tions between APOE ADNI
ε4 and the diagnoses of Mean age: > 70 years
MCI and AD resulting
in reduced hippocam-
pal volumes in both
groups (AD < MCI)
relative to the lack of
effect of APOE ε4 on
hippocampal volume of
HC group
[107] None 33♂ and 24♀ APOE ε4 carriers – – – Cross-sectional study
(21.8 ± 4.0 years) demonstrated increased
right entorhinal cortex
volume relative to non-
carriers
[108] 81♂ and 67♀ 90♂ and 77♀ Increased hippocampal – – – Longitudinal study
(75.0 ± 7.6 years) AD; (76.0 ± 5.1 years) atrophy rates in APOE Data derived from
307 MCI ε4 carrier AD, MCI- ADNI
progressors and MCI-
stable relative to APOE
ε4 non-carriers
[109] None 2,842 No evidence of dose- – – – Cross-sectional study
dependent effect of Mean age:
APOE ε4 alleles or 14.44 ± 0.41 years
APOE ε2 alleles on
either hippocampal vol-
ume and hippocampal
asymmetry
[110] 273 MCI 188 Significant effects of – – – Longitudinal study
110 MCI-converter APOE ε4 found on Data derived from
105 AD structures of the medial ADNI
temporal lobe (i.e. Mean age: > 70 years
entorhinal cortex and CSF Aβ42, t-tau, and p-
hippocampus), inferior tau were assessed, but
parietal cortex, in addi- no direct correlational
tion to additive effect analysis with GM loss
of APOE ε4 on annual
atrophy rate
[111] None 343♂ and 312♀ APOE ε4 allele showed – – – Longitudinal study
no effect on hippocam- Mean age: 55–76 years
pal volumes
Table 2 (continued)
tau) or FDG-PET
[112] 57♂ and 63♀ ( No association was found – – In both APOE sub-groups, Longitudinal study
70.4 ± 6.4 years) AD between APOE ε4 allele correlation found between
APOE ε4 carriers and decreased right hip- performance on the
28♂ and 35♀ pocampus volume TMT A and GMv in the
(70.4 ± 8.7 years) AD No association was found parietal (p < 0.05) and
APOE ε4 non-carriers between non-carriers temporal regions (p < 0.01
status of APOE ε4 and or p < 0.001); APOE ε4

reduced volume of the carriers also demonstrated
right superior frontal effects in frontal cortex
gyrus relative to carriers (p < 0.01)
[113] 305 early MCI 104 SMC; Reduced hippocampal – – – Cross-sectional study
185 volume in early MCI Data derived from
APOE ε4 carriers and ADNI
noncarriers relative to Mean age: > 70 years
CN APOE ε4 noncar- CSF Aβ42, t-tau, and
riers and SMCI APOE p-tau, Aβ-PET and
ε4 carriers. Reduced FDG-PET were
hippocampal volume assessed, but no
was found in early MCI correlational analysis
noncarriers of APOE ε4 with GM loss
relative to CN APOE ε4
carriers
[114] None 142 (39 – 83 years) Reduced left cuneal vol- – – – Longitudinal study
ume found to be associ-
ated with APOE ε4
[115] None 90♂ and 78♀ Relative to the non-carri- – – – Cross-sectional study
(73.4 ± 6.02 years) ers, male APOE ε4 car- Data derived from
MRI data riers exhibited increased ADNI
166♂ and 162♀ cortical thickness in CSF Aβ42, t-tau and
(74.5 ± 5.57 years) the left hemisphere, p-tau, and FDG-PET
FDG-PET data dorsolateral frontal were assessed, but no
136♂ and 138♀ region, temporoparietal, direct correlational
(74.4 ± 5.97 years) occipital and precuneus analysis with GM loss
CSF data regions; and in the
right hemisphere in the
occipital and parietal
regions
APOE-by-gender interac-
tion in the dorsolateral
frontal and temporopa-
rietal regions
13
Table 2 (continued)
13
tau) or FDG-PET
[116] 365 AD 2281 Reduced hippocampal AD APOE ϵ4 and CSF Aβ positive participants – – Cross-sectional study
522 MCI volume was found in demonstrated more hippocampal atrophy com- Data derived from
APOE ϵ4 carriers rela- pared to CN APOE ϵ4/Aβ positivity or APOE ϵ4 ADNI and other
tive to APOE ϵ3 carri- only participants cohort studies
ers; APOE ϵ3 carriers (AddNeuroMed,
and APOE ϵ2 carriers AIBL, BRC-AD,
exhibited intermediate SNAC-K, IMAGEN)
volumes and the largest ADNI (age:
volumes, respectively 55–70 years); AIBL
AD and MCI APOE (at least 60 years);
ϵ4 carriers demon- BRC-AD (mean
strated more reduced age: > 70 years);
hippocampal volumes SNAC-K (mean
relative to APOE ϵ2 age: > 60 years);
carriers with the highest IMAGEN: (mean age:
hippocampal volumes 14.4 years)
Participants with both Aβ PET level assessed
Aβ + and APOE ϵ4
showed the lowest
hippocampal volumes
relative to Aβ- APOE
ϵ4 carriers
[117] 15♂ and 60♀ 111♂ and 117♀ Higher average severity CSF Aβ positive MCI and AD individuals demon- – Correlation found between Longitudinal study
(74.5 ± 7.4 years) MCI- (75.9 ± 5.0 years) index (SI) and a faster strated rapid increase of severity index compared severity index and lower Data derived from
stable increase of SI of to their counterpart CSF Aβ negative individuals score on MMSE in at ADNI
27♂ and 43♀ mediotemporal region baseline (p = 0.001), and Level of CSF Aβ
(74.3 ± 6.9 years) MCI- in APOE ε4 positive stronger at follow-up at a assessed
progressed MCI relative to APOE 3-year, 2-year, and 1-year The severity index pro-
95♂ and 100♀ ε4 negative MCI period (all at p < 0.001) vide a summary of the
(75.5 ± 7.5 years) AD in MCI patterns of structural
brain alterations as a
single score for each
participant
[118] 18♂ and 115♀ 14♂ and 11♀ Association was found – – – Longitudinal study
(74.5 ± 7.5 years) MCI (70.0 ± 9.1 years) between APOE ε4 and
SMC; reduced hippocampal
36♂ and 22♀ volume
(70.6 ± 6.7 years)
[119] None 64♂ and 56♀ Increased GM of hip- – – – Cross-sectional study
(23.83 ± 4.32 years) pocampus, middle
Behavioural sample temporal gyrus, and
19♂ and 18♀ precuneus in APOE
(25.00 ± 4.26 years) ε2 allele relative to
MRI subsample APOE ε3 and APOE ε4
carriers
[120] None 1472 (22–90 years) No evidence of an – – – Longitudinal study
association between
APOE ε4 and volumes
of the lateral and medial
frontal region, lateral
temporal and hippocam-
pus
Table 2 (continued)
tau) or FDG-PET
[121] 34♂ and 46♀ (69.2 ± 5.1y 46♂ and 44♀ MCI-AD and MCI-MCI Longitudinal study
ears) MCI-AD (75.2 ± 6.8 years) groups who were APOE
44♂ and 48♀ ε4 carriers showed
(72.8 ± 6.2 years) MCI- reduced hippocampal
MCI volume relative to that
of the control group
[122] 280♂ and 284♀ 746♂ and 1021♀ An association was Longitudinal study
(75.5 ± 7.1 years) AD (75.3 ± 5.9 years) older found between APOE Data derived from
648♂ and 492♀ adults ε4 and lower volumes ADNI and other
(75.8 ± 6.7 years) MCI 467♂ and 765♀ of the amygdala and cohort studies
(22.9 ± 3.3 years) hippocampus in AD and Younger adults included
young adults MCI but not in healthy (age: 16–30 years)
older group
No such associations
noted in the young
adults
[123] 540♂ and 390♀ (55 – None Significantly reduced left Cross-sectional study
90 years for males; 55 – hippocampal volumes Data derived from
96 years for females) MCI in females relative to ADNI and other
males with 1 APOE cohort studies
ε4 allele
Significantly reduced
right hippocampal in
females relative to
males with 0, 1, or 2
APOE ε4 alleles
Significant reduction in
bilateral amygdala for
females with 0, 1, and
2 APOE ε4 alleles rela-
tive to men
[124] 302 MCI 125 ♂ and 131 ♀ In MCI with suspected MCI Aβ positive participants demonstrated smaller – – Cross-sectional study
220 Late MCI (75.5 ± 6.7 years) non–AD pathophysiol- left middle temporal gyrus compared to their Data derived from
ogy, association was counterparts with Aβ negativity ADNI
found between APOE CSF Aβ42, t-tau, and
ε4 and reduced p-tau, Aβ-PET, and
GMv (left middle tempo- FDG-PET assessed
ral region)
[125] None 43 (74.1 ± 3.8 years; 22 Lower GM concentration – – – Longitudinal study
sCON and 21 dCON) of PCC and amygdala
APOE ε2 in APOE ε4 relative to
274 (74.1 ± 4.1 years; APOE ε2 and APOE ε3
132 sCON and 142 Increased GM concentra-
dCON) APOE ε3 tion of parietal lobe in
65 (73.6 ± 4.1 years; 27 APOE ε4 and APOE ε3
sCON and 38 dCON) carriers
APOE ε4
13
Table 2 (continued)
13
tau) or FDG-PET
[126] None 12 ♂ and 20 ♀ APOE ε4 carriers dem- – – – Cross-sectional mul-

(27.5 ± 5.0 years) onstrated reduced GMv timodal (task-based
APOE ε4 + in the bilateral anterior fMRI included) study
16 ♂ and 24 ♀ and middle cingulate
(28.1 ± 5.3 years) gyri
APOE ε4 –
[127] None 300 ♂ and 195 ♀ AD APOE ε4 carriers Cross-sectional study
(70.14 ± 15.0 years) demonstrate increased
APOE ε4 + incidence of brain
1363 ♂ and 975 ♀ atrophy and severe brain
(70.9 ± 14.8 years) atrophy
APOE ε4 –
[128] None 26 ♂ and 50 ♀ An interaction was – – Increased cortical thickening Longitudinal study
(72.98 ± 6.03 years) found between APOE in the caudal anterior cingu-
APOE ε4 + and right caudal late cortex noted to be asso-
13 ♂ and 28 ♀ anterior cingulate ciated with poor memory in
(74.02 ± 6.62 years) cortex (cACC) cortical APOE ε4 carriers (p = 0.03)
APOE ε4 – thickness on memory but not in non-carriers
performance, such that
increased CT in the
right cACC showed
association with worse
memory in APOE ε4
carriers relative to the
non-carriers
[129] None 148 ♂ and 232 ♀ No association between – – GM densities in the hip- Cross sectional study;
(74.2 ± 4.1 years) APOE ε4 and GMvs pocampus (p = 0.02) and Aβ PET included
of hippocampus and amygdala (p = 0.014) but no correlational
amygdala correlated positively with analysis reported
continuous cognitive score
(p = 0.02) but not for mesial
temporal and parietal gyrus
[130] None 77 ♂ and 195 ♀ Inclusion of APOE locus Cross-sectional study;
(24.8 ± 6.9 years) T1 with polygenic risk DTI included
data scores (PRSs) dem-
34 ♂ and 53 ♀ onstrated significant
(23.9 ± 4.4 years) association between AD
Tractography data PRSs and reduced left
hippocampal volume
[131] None 47–86 years (26 APOE Cortical thickness and – – – Cross-sectional study;
ε4 HMs; 48 HTs; 90 hippocampal volumes Aβ and tau PET
NCs) did not show any asso- assessed, but no
ciation with APOE ε4 correlational analysis
in entire age range with GM loss
[132] None 20–84 years No evidence of an asso- – – – Cross-sectional study
(50.2 ± 14.7 years) ciation between APOE
ε4 and medial temporal
atrophy nor posterior
atrophy severity
Table 2 (continued)
tau) or FDG-PET
[133] None 2916 ♂ and 3124 ♀ No evidence of an asso- – – – Cross-sectional study

(61.66 ± 7.03 years) ciation between APOE
APOE ε4 – ε4 and volumes of
941 ♂ and 1206 ♀ bilateral hippocampus,
(61.19 ± 7.04 years) total GM
APOE ε4 +
[134] - 45 (68.96 ± 1.02 years) Association found – – No association between Longitudinal study
between right hip- hippocampal volume and 9 APOE ε4 carriers
pocampal atrophy and MMSE score 36 non-APOE ε4
APOE ε4 carriers
Depressed participants
[135] 24♂ and 27 ♀ AD; 24♂ and 32♀ Atrophy of GM regions – – – Mean age: 50 years
21♂ and 10 ♀ bvFTD (bilateral parietal cor-
tex, right hippocampus,
precuneus, and middle
frontal gyrus) in AD
APOE ε4 carriers
Atrophy of GM regions
(bilateral medial, dor-
solateral, orbital frontal
cortex, anterior insula,
and cingulate cortex)
found in bvFTD APOE
ε4 carriers
[136] 62 AD 125 No association between – – – No information on
hippocampal atrophy gender
and APOE ε4 Mean age: > 70 years
[137] 99♂ and 79♀ Prodromal – APOE ε4 carriers – – Subcortical volumes of the Mean age: > 70 years
AD demonstrated thinner bilateral hippocampus and CSF Aβ42, t-Tau, and
cortical thickening in left amygdala, in addition to p-Tau, Aβ-PET,
the bilateral entorhinal, the mean cortical thickness and FDG-PET were
and reduced subcorti- of bilateral entorhinal corre- assessed but no corre-
cal volume of the left lated with global cognition lational analysis with
amygdala, bilateral and memory measures GM loss
hippocampus and left
ventral dorsal column
[138] 68 (72.5 ± 4.8 years) stable 26 (73.8 ± 4.4 years) No association between – – Association found between Longitudinal study
MCI; 30 (70.8 ± 6.3 years) APOE ε4 and cortical reduced MMSE score corti- 46% male HC, 40%
progressive MCI, 21 thickening in the cal thinning in large regions male stable MCI,
(75.2 ± 4.2 years) AD groups of the right hemisphere of 43% male progressive
the frontal and temporal MCI, and 33% male
cortices (p < 0.05) in AD AD
No association between corti-
cal thickening measures and
CDR-sum-of-boxes scores
in both
Groups
13
Table 2 (continued)
13
tau) or FDG-PET
[139] – 32♂ and 33♀ APOE ε4 APOE ε4 carriers demon- – – – Cross-sectional study
carriers; 16♂ and 13♀ strated cortical thinning Age: ≤ 21 years (chil-
noncarriers; 84♂ and in the left entorhinal dren and adolescents)
59♀ APOE ε3 carriers cortex
Increased cortical thick-
ness in the entorhinal
cortex moving from
the most thinned cortex
in APOE ε4 carriers,
via an intermediate,
thickness for APOE
ε3 homozygotes, with
APOE ε2 carriers
demonstrating the thick-
est cortex, with same
effect seen for small
regions of the MTL and
posterior-medial and
orbitofrontal cortex
[140] 15♂ and 27♀ noncarriers – Single APOE ε4 dem- – – – Cross-sectional study
(71.48 ± 5.19 years); onstrated reduced GM All patients had MCI
12♂ and 15♀ heterozy- density in the right
gous APOE ε4 carriers inferior frontal gyrus
(72.19 ± 4.90 years); Homozygous APOE
5♂ and 9♀ ( ε4 demonstrated GM
69.63 ± 3.48 years) reduction in the left
homozygous APOE ε4 hippocampus, parahip-
carriers pocampal gyrus, and
amygdala
Homozygous APOE ε4
carriers showed reduced
GM density in the left
entorhinal cortex
[141] 6♂ and 3♀ 12♂ and 11♀ APOE ε4 homozygotes – – – Cross-sectional study
(68.5 ± 8.3 years) APOE (69.7 ± 7.2 years) demonstrated cortical All patients had AD
ε4 non-carriers; 6♂ and thinning mainly in a
17♀ (70.7 ± 7.2 years) frontotemporal (MTL
APOE ε4 het- atrophy of entorhinal
erozygotes; 3♂ and 3♀ cortex) topography
(67.5 ± 3.2 years) APOE in AD
ε4 homozygotes APOE ε4 homozygotes
demonstrated more
anterior and MTL pat-
tern of cortical thinning
compared to the APOE
ε4 heterozygotes who
showed more posterior
distribution
Table 2 (continued)
tau) or FDG-PET
[142] 19♂ and 15♀ APOE ε4 – APOE ε4 carriers dem- – PET-measured tau – Cross-sectional study
carriers; 13♂ and 10♀ onstrated atrophy in the deposition associ- Mean age: > 70 years
noncarriers PCC, medial temporal, ated with GM CSF Aβ42, t-tau, and p-
inferior temporal, superior volume tau and tau-PET were
temporal, amygdala, of the measured
inferior, middle, and temporal, entorhinal Participants had AD
superior occipital, pre- cortex, parahip-

cuneus, supplementary pocampal regions,
motor area amygdala, parietal,
and superior frontal lobe posterior precu-
neus, and occipital
regions
[143] – 6♂ and 7♀ APOE ε4 carriers dem- – – – Cross-sectional study
(66.36 ± 6.34 years) onstrated atrophy in the Participants were
APOE ε4 carri- inferior temporal gyrus, classified as having
ers; 6♂ and 7♀ middle frontal gyrus, subjective memory
(66.18 ± 7.83 years) inferior parietal lobule, impairment
noncarriers anterior cingulum, and,
and precentral gyrus
[144] 45%♀ (73.7 ± 4.9 years) – MCI APOE ε4 carriers – – – Cross-sectional study
stable MCI; demonstrated atrophy in Microtubule-associated
38%♀ (72.5 ± 4.8 years) the hippocampus, ros- protein tau was
progressive MCI tral amygdala, superior assessed
and middle temporal
gyrus, inferior and
superior frontal gyrus,
inferior parietal
lobule, supramarginal
gyrus, supplementary
motor area, pre- and
postcentral gyri, and the
left fusiform gyrus
[145] – 190♂ and 425♀ Homozygous APOE ε4 – – – Cross-sectional study
(56.6 ± 6.8 years) carriers demonstrated Control group included
Insomnia; more atrophy in the participants with
475♂ and 593♀ right hippocampus, left insomnia and those
(55.4 ± (6.5 years) middle temporal, left without insomina
fusiform, left angular, Atrophy in APOE ε4
bilateral superior fron- carriers noted in the
tal, bilateral postcentral presence of insomnia
gyri, and thalami com-
pared to heterozygous
APOE ε4 carriers
[146] 15 (71.8 ± 9.8 years) 8♂ and 21♀ APOE ε4 carriers dem- – – – Cross-sectional study
APOE ε4 carriers and (69.7 ± 8.7 years) onstrated more atrophy All patients had AD
14 (68.6 ± 8.7 years) in the whole bilateral
noncarriers temporal lobes, occipi-
tal lobes, retrosplenial
and posterior cingulate
region
13
Table 2 (continued)
13
tau) or FDG-PET
[147] 46♂ and 144♀ – Association found – – – Cross-sectional study
(72.7 ± 9.7 years) APOE between APOE ε4 and All participants had AD
ε3 homozygous; 46♂ and atrophy in the hip- FDG-PET was assessed
157♀ (73.3 ± 6.7 years) pocampus, amygdala, but no correlational
heterozygous APOE and whole-brain analysis with GM loss
ε4 carriers; 46♂
69.5 ± 6.0 years) homozy-
gous APOE ε4 carriers
[148] 29♂ and 28♀ (75.5 89♂ and 88♀ MCI carriers of a least – Inverse correlation Positive correlation noted Cross-sectional study.
7.5 ± years) MCI; 23♂ (71.6 ± 7.4 years) one APOE ε4 demon- found between between hippocampal Aβ-PET assessed
and 30♀ (72.6 ± 8.9 years) HC; 42♂ and 39♀ strated greater neocortical PiB atrophy and decline in
AD (72.0 ± 7.5 years) atrophy of the hip- binding and hip- memory in MCI (CVLT-II
HC without memory pocampus pocampal volume long delay) (p = 0.04)
complaint; 47♂ and in MCI (p = 0.006), and MMSE in healthy control
49♀ (71.2 ± 7.4 years) but ( p = 0.01), but not in AD
Subjective memory weakly in healthy Correlation found between
complaints controls (p = 0.01), global GM volume and
but no such MMSE in AD (p = 0.008)
relationship exists
in AD
Neocortical PiB
correlated inversely
with global GMv
in the healthy con-
trols (p < 0.0001)
but not in MCI
Correlation noted
between neocorti-
cal PiB binding
and global
GMv in AD
[149] 4♂ and 13♀ – APOE ε4 carriers demon- – – – Longitudinal study
(71.1 ± 6.4 years) APOE strated increased rate of All patients had AD
ε4 carriers; 6♂ and 32♀ hippocampal atrophy,
(72.4 ± 5.5 years) noncar- with severity in rate
riers seen with homozygosity
[150] 2♂ and 12♀ 10♂ and 18♀ AD APOE ε4 carriers – – No association between Cross-sectional study
(71.7 ± 8.2 years) APOE (70.8 ± 8.1 years) demonstrated hip- hippocampal volume and Patients had AD
ε4 carriers; 6♂ and 8♀ pocampal atrophy cognitive decline (MMSE
(71.2 ± 9.5 years) carriers and memory [verbal and
visual]) in AD
AD Alzheimer’s disease, GMvs gray matter volumes, SCD subjective cognitive decline, aMCI amnestic mild cognitive impairment, EMCI early mild cognitive impairment, LMCI late mild cogni-
tive impairment, PD Parkinson’s disease, FTD frontotemporal dementia, VaD vascular dementia, DLB dementia with Lewy bodies, DMN default mode network, TIV total intracranial volume,
PPR pulse pressure, KIBRA Kidney and brain expressed protein, PRSs polygenic risk scores, sCON stable cognitive function, dCON deteriorating cognitive function, ADNI Alzheimer’s Disease
Neuroimaging Initiative, AIBL Australian, Imaging, Biomarkers and Lifestyles, BRC-AD Biomedical Research Centre for Dementia, SNAC-K Swedish National study on aging and care in Kung-
scholmen, IMAGEN Neuroimaging-Genetics, ♂ male, ♀ female
(CBO) (http://w ww.c bo.n l/D ownlo ads/6 32/b ijlage_A. 139, 143, 145]. Meanwhile, 14 studies involved patients
pdf) (Table 4). Following the clustering of studies with with MCI and/or AD without healthy controls [22, 53, 76,
comparable methods or results, the strength of conclusion 80, 84, 87, 123, 137, 140, 142, 144, 146, 147, 149], and
was determined (Table 5) based on the CBO classifica- three studies involved patients with AD and other types
tion, which accounted for the study designs as well as the of dementia (behavioral variant FTD, DLB, and vascular
risk of bias. dementia) compared with healthy controls [33, 34, 135].
One study included patients with AD and other types of
dementia (DLB and vascular dementia) without healthy
Results controls [41], while another involved patients with MCI
and AD and Parkinson’s disease compared with healthy
Study selection controls [27]. Finally, 52 studies involved patients with
MCI and/ or AD compared with healthy controls.
Briefly, the initial search yielded a total of 817 studies.
After eliminating duplicates, 492 studies remained. Fur- Summary of studies that included AD validated CSF
ther exclusion of studies based on titles and abstracts led and PET biomarkers
to 256 articles remaining. After assessing the full-text
articles, a total of 125 articles were removed, leaving a Studies that included CSF biomarkers A total number of 19
total of 131 studies which were included in the current studies investigated the levels of CSF biomarkers [21, 25,
study (Fig. 1). 27, 49, 56, 66, 76, 80, 82, 97, 104, 110, 113, 115–117, 124,
137, 142].
Study characteristics Studies that included PET biomarkers A total of 14 studies

explored the measurement of cortical Aβ and/or tau load
MRI parameters, pulse sequences, measurement methods, using Aβ- and/ or tau-PET biomarkers [25, 28, 55, 56, 85,
and neuropsychological tests 113, 116, 124, 129, 131, 137, 142, 148]. Among these stud-
ies, five used [11C] Pittsburgh Compound B [55, 56, 116,
Briefly, from Table 1, for the studies that documented 131, 148], seven studies used [18F] AV-45 (florbetapir) [28,
the MRI parameters, the magnetic field strengths ranged 85, 113, 116, 124, 129, 137], while three studies explored
between 0.22 and 7.0 T, while the repetition time (TR) the use of [18F]-AV-1451 (flortaucipir) [25, 131, 142]. On
and echo time (TE) varied between 2.73 to 10,000 ms and the other hand, nine studies assessed brain glucose metabo-
2.0 to 30,153 ms, respectively. Other parameters such as lism levels using FDG-PET [28, 35, 56, 86, 99, 113, 115,
flip angle (FA) and slice thickness (ST) varied between 137, 147].
7° to 15° and 1 to 10 mm, respectively. While few studies
acquired T 2-weighted imaging [30, 53, 58, 72, 73, 88], Summary of studies that included neuropsychological
most studies acquired 3D T 1-weighted imaging using testing measures
gradient echo pulse sequence. Further, a few studies used
manual tracing [32, 39, 54, 78, 92, 101, 136, 139, 142, In the exception of 11 studies [22, 48, 59, 79, 93, 100, 107,
146, 147, 149, 150], and visual analysis [41, 53, 132], 109, 122, 133, 139], all studies included a wide range of
while most studies performed volumetric measures using neuropsychological testing measures.
semi- or fully automated software. A wide range of neu-
ropsychological tests were conducted; however, the mini- Risk of bias and level of evidence
mental state examination (MMSE) was the most common.
Table 3 shows the results of the methodological quality
assessment. The LOE is graded as follows: −, score not ful-
Characteristics of included case–control and cohort studies filled; + , score fulfilled; /, answer is unclear. Methodologi-
cal quality varied from poor to good, between 3 of 9 and
A total of 61 studies involved only healthy cohorts [19, 8 of 9. Most studies lost points on ‘selection of controls’,
23, 29, 30, 32, 35, 36, 38, 42, 45–48, 51, 55–57, 61, 62, and ‘definition of controls’, and ‘MRI data quality’. This
68–71, 74, 75, 77–79, 81–83, 86, 90, 93, 94, 96, 98–100, was mainly because authors did not provide the required
103, 105, 107, 109, 111, 114, 115, 119, 120, 125–134, information or the information was inadequate. Most eligible
13
Table 3 Methodological quality Study 1 2 3 4 5 6 7 8 9 Total score LOE

of included studies
[19] + + + + + + + + − 8/9 B
[20] + + − + + + + + − 7/9 B
[21] + + − + + + + + − 7/9 B
[22] + + − − + + + − − 5/9 B
[23] + − + + + + + + + 8/9 B
[24] + / − + + + / / / 4/9 B
[25] + / + − + + + − + 6/9 B
[26] + − / + + + + + + 7/9 B
[27] + + + + + − + + + 8/9 B
[28] + + + + + + + + − 8/9 B
[29] + + + + + + / − + 7/9 B
[30] + + / + − + + / + 6/9 B
[31] + + − + + + + / − 6/9 B
[32] + / + + + + + / + 7/9 B
[33] + + + + + + + − − 7/9 B
[34] + + + + + + + / − 7/9 B
[35] + + + + + + + / − 7/9 B
[36] + + + + + + + / − 7/9 B
[37] + + + + + + + + / 8/9 B
[38] + + + + + + + / − 7/9 B
[39] + + − + + + + / − 6/9 B
[40] + + + + + − + + − 7/9 B
[41] + / + + + + + / − 6/9 B
[42] + / + + + + + / + 7/9 B
[43] + + / + + + + + + 8/9 B
[44] + + / + + + / + + 7/9 B
[45] + / + + + + + + / 7/9 B
[46] + / + + + + + / + 7/9 B
[47] + / + + + + + + + 8/9 B
[48] + / + + + + + / + 7/9 B
[49] + + / + + + + / + 7/9 B
[50] + + / + + + + + + 8/9 B
[51] + + / + + + + / + 7/9 B
[52] + / + + − − + + + 6/9 B
[53] + / − + + + + / − 5/9 B
[54] + + − + + − + + − 6/9 B
[55] + / + + + − + + + 7/9 B
[56] + / + + + − + + + 7/9 B
[57] + / + + + − + / − 5/9 B
[58] + + + + + − + + + 8/9 B
[59] + / + + + − + / + 6/9 B
[60] + + / + + + + + + 8/9 B
[61] + / + + + − + / + 6/9 B
[62] + / + + + + + / + 7/9 B
[63] + / + + + + + + + 8/9 B
[64] + + / + + + + + + 8/9
[65] + + / + + + + / + 7/9 B
[66] + + / + + + + + + 8/9 B
[67] + + / + + + + + + 8/9 B
[68] + / + + − − + / − 4/9 B
[69] + / + + + + + + + 8/9 B
13
Table 3 (continued) Study 1 2 3 4 5 6 7 8 9 Total score LOE
[70] + / + + + + + + + 8/9 B
[71] + / + + + + + / + 7/9 B
[72] + + − + + + + / − 6/9 B
[73] + + / + + + + + + 8/9 B
[74] + / + + / − + + + 6/9 B
[75] + / + + + + + / − 6/9 B
[76] + / / + + + + + + 7/9 B
[77] + / + + + + + / + 7/9 B
[78] + / + + + + + + + 8/9 B
[79] + / + + + / + / + 6/9 B
[80] + + / + + + + / + 7/9 B
[81] + / + + + + + + − 7/9 B
[82] + / + + + + + / + 7/9 B
[83] + / + + + + + / + 7/9 B
[84] + / + + + + + / − 6/9 B
[85] + + / + + + + + + 8/9 B
[86] + / + + + + + / + 7/9 B
[87] + + − + + / + / + 6/9 B
[88] + + / + + / + + − 6/9 B
[89] + + / + / / + / + 5/9 B
[90] + + / + + − + + − 6/9 B
[91] + + − + − − + + + 6/9 B
[92] + + / + − − / + − 4/9 B
[93] + − − − + + / / − 3/9 B
[94] + + − − + + + − + 6/9 B
[95] + + / + + + + + + 8/9 B
[96] + / / + + − / / + 4/9 B
[97] + + + + + − / + + 7/9 B
[98] + + + + + + / / / 6/9 B
[99] + / − − + + + / / 4/9 B
[100] + + + + + + + / + 8/9 B
[101] + + − + + − / + / 5/9 B
[102] + + / + + + / / / 5/9 B
[103] + + / + + + / / + 6/9 B
[104] + + / + + + / + + 7/9 B
[105] + + + + + − + / + 7/9 B
[106] + + / + + − / / + 5/9 B
[107] + + / + / / − − − 3/9 B
[108] + + − − + + / / + 5/9 B
[109] + − − + − − − − + 3/9 B
[110] + + − − + + / / + 5/9 B
[111] + + + + + + + / + 8/9 B
[112] + + + + − − + + + 7/9 B
[113] + + − + + + / / − 5/9 B
[114] + + + + + + + / − 7/9 B
[115] + / − + + + − / − 4/9 B
[116] + + − + + + − / + 6/9 B
[117] + / − + + − − + + 5/9 B
[118] + + + + + + / + − 7/9 B
[119] + − − + + + + / − 5/9 B
[120] + + + + + + + + + 9/9 B
13
Table 3 (continued) Study 1 2 3 4 5 6 7 8 9 Total score LOE
[121] + + − + + − + + − 6/9 B
[122] + + − + + + − − + 6/9 B
[123] + / + + + + + / + 7/9 B
[124] + + − + + + − − + 6/9 B
[125] + + + + + + + + + 9/9 B
[126] + / + + + + + / − 6/9 B
[127] + + − + + − + + − 6/9 B
[128] + + + + + + + / + 8/9 B
[129] + + + + + + + / − 7/9 B
[130] + / + + − − + / + 5/9 B
[131] + + + + + + + / − 7/9 B
[132] + / / / + + + / + 5/9 B
[133] + / / / + + + + + 6/9 B
[134] + / + + − − + + − 5 B
[135] + + − + + + + + + 8 B
[136] + + − + / / + + + 6 B
[137] + + − + + + / / + 6 B
[138] + + − + + + + + + 8 B
[139] + + + + + − / / + 6 B
[140] + / + + + + + + / 7 B
[141] + + − + + + + + + 8 B
[142] + / + + + + + / + 7 B
[143] + / + + + + + / + 7 B
[144] + + / + + + + / + 7 B
[145] + / + + + − + + + 7 B
[146] + + − + + − + + + 7 B
[147] + / + + + − + / + 6 B
[148] + + + + + − + + + 8 B
[149] + / + + + + + + + 8 B
[150] + + − + + − + + + 7 B
LOE level of evidence, − score not fulfilled, + score fulfilled, / answer is not clear
NOS Scale: (Items 1 to 4 classified under Selection category). 1 = Is the case definition adequate?; 2 = Rep-
resentativeness of the cases; 3 = Selection of controls; 4 = Definition of controls; (Items 5 and 6 under
Comparability category) 5 = Study controls for age or sex; 6 = Study controls for any additional factor;
(Items 7, 8, and modified 9 under Exposure category) 7 = Ascertainment of exposure; 8 = Same method of
ascertainment for cases and controls; 9 = Visual inspection of the MRI data quality
Table 4 LOE, according to Intervention

the 2005 classification system
of the Dutch Institute for A1 Systematic review of at least 2 independent from each other conducted studies of evidence level A2
Healthcare Improvement CBO
A2 Randomized double-blinded comparative clinical research of good quality and efficient size
(www.cbo.nl)
B Comparative research, but not with al characteristics as mentioned for A2. This includes also
patient-control research and cohort research
C Not comparative research
D Opinion of experts
studies matched participants for age and gender. A few stud- All studies in the review were assigned an LOE B due to
ies controlled for additional factors (e.g. APOE ε4). the inclusion of only case–control and cohort type of studies.
13
Table 5 Strength of conclusion Conclusion based on

(modified table)
1 Research of evidence level A1 or at least 2 independent conducted studies of evidence level A2
2 1 research of evidence level A2 or at least 2 independent conducted studies of evidence level B
3 1 research of evidence level B or C
4 Opinion of experts or inconclusive or inconsistent results between various studies
Fig. 1 PRISMA flowchart of Additional records identified through

Records identified through database
the study selection process other sources
searching: Pubmed (n = 693); Ovid (n =
48); Scopus (n = 42); Cochrane (n = 0) (n = 34)
Records after duplicates removed

(n = 492)
Records screened on titles and abstracts

(n = 492) Records excluded
(n = 236)
Full-texts articles excluded (n =

Full-text articles assessed for eligibility
125)
(n = 256)
Reasons:
Populaons (n = 50)
Outcome (n = 46)
Studies included in qualitative
synthesis Design (n = 29)
(n = 131)
Syntheses of results APOE ε4 and brain alterations
Overall, the temporal lobe was the most commonly inves- Figure 2 shows the summary of the effect of APOE ε4 on the
tigated region followed by the frontal lobe, and parietal frontal, parietal, temporal, and occipital lobe structures, and
lobe, while the occipital lobe was the least studied. Several the subcortical GM regions in a voxel-wise map.
GM volume and cortical thickening regions and their sub-
structures were also investigated. The summary of these Frontal lobe In conclusion, moderate evidence shows
findings from Table 2 are, therefore, presented below. The reduced middle frontal gyrus size among APOE ε4 carriers
regional structures found to be strongly associated with (strength of conclusion 2). Some evidence showed cortical
APOE ε4, CSF, and PET biomarkers, and neuropsycho- thinning in the lateral frontal, left rostral midfrontal, right
logical measures are presented in the voxel maps shown caudal midfrontal, and superior frontal gyrus in APOE ε4
in the Figures. carriers (strength of conclusion 3). Additionally, there is
13
Fig. 2 Reduced level of CSF Aβ42 is shown to be significantly associated with GM atrophy in the MTL (A), parietal (B), temporal (C), and tem-
poroparietal (D) regions in MCI (strength of conclusion 2)
some evidence of increased cortical thickening of the lat- regarding the direction of change of cortical thickness in the
eral medial orbitofrontal cortical region (strength of conclu- precuneus, and inferior parietal region in APOE ε4 carri-
sion 3). Further, moderate evidence showed that there is no ers (strength of conclusion 4), these regions were altered.
association or APOE ε4 effect on the frontal lobe (strength However, moderate evidence showed a reduced precuneal
of conclusion 2); however, there were alterations of specific and right angular gyrus GMv in APOE ε4 carriers (strength
frontal lobe regions. of conclusion 2).
Parietal lobe In conclusion, there is evidence that APOE ε4 Temporal lobe Hippocampus In conclusion, moderate
carriers show cortical thinning in several parietal substruc- evidence shows that the hippocampal volume is not only
tures including the medial lateral parietal and left parietal reduced in APOE ε4 carriers but also associated with APOE
gyrus (strength of conclusion 3), and moderate evidence ε4 (strength of conclusion 2). Furthermore, there is moder-
for cortical thinning of the superior parietal gyrus (strength ate evidence of reduced cortical thickness or GMv of some
of conclusion 2). Although inconclusive evidence exists hippocampal subfields (cornu ammonis [CA]1–3, dentate
13
gyrus, and subiculum) (strength of conclusion 2). Some evi- APOE ε4 is associated with an increased rate of cortical
dence shows that APOE ε4 dose effect is associated with thinning in temporoparietal cortex and that APOE ε4 does
cortical thinning of the hippocampal subregions (strength not exert an effect on temporal lobe volume (strength of
of conclusion 3). However, there is moderate evidence that conclusion 2). There is also some evidence that APOE ε4
increased APOE ε4 dose effect is observed on hippocam- is associated with lower cortical thickening of the temporal
pal atrophy (strength of conclusion 2), but no association lobe cortex and reduced GMv in the fusiform gyrus and
between APOE ε4 dose effect and hippocampal atrophy temporal pole cortex (strength of conclusion 3).
(strength of conclusion 2). There is moderate evidence of
decreased cortical thickness in the hippocampal subregions Occipital lobe In conclusion, although there is evidence of
(strength of conclusion 2), and some evidence of the lack increased GMv (middle occipital cortex) or cortical thick-
of APOE ε4 effect on hippocampal thickness (strength of ness (right hemisphere) in the occipital lobe in APOE ε4
conclusion 3). carriers, only the bilateral lingual gyri were found to dem-
Amygdala In conclusion, there is moderate evidence of onstrate atrophy (strength of conclusion 3). This is reflected
reduced amygdala volumes in older individuals with MCI in the differences in the association between APOE ε4 and
and AD compared to HCs (strength of conclusion 2). How- occipital lobe or its regions.
ever, there is inconclusive evidence regarding the effect of
APOE ε4 on amygdala volumes or its atrophy, and sym- Other cortical gray matter regions In conclusion, it is clear
metrical differences in demented and non-demented older that there is some evidence that APOE ε4 carriers showed
adults (strength of conclusion 4). decreased GMv in the insula and several regions of the cin-
Entorhinal cortex In conclusion, moderate evidence gulate cortex (strength of conclusion 3). Further, some evi-
shows that APOE ε4 carriers demonstrate cortical thinning dence shows that APOE ε4 is related to reduced GMv in
in the entorhinal cortex (strength of conclusion 2). There the anterior cingulate cortex (ACC), and the cerebral cortex
is indistinct evidence regarding the effect of APOE ε4 and (strength of conclusion 3). In addition, there is some evi-
likewise the association between APOE ε4 and entorhinal dence that APOE ε4 is related to increased cortical thick-
size reduction (strength of conclusion 4). ness in the right caudal ACC (strength of conclusion 3).
Parahippocampal gyrus In conclusion, moderate evi- Also, there is some evidence that APOE ε4 does not affect
dence shows that APOE ε4 carriers demonstrate reduced the cortical thickness of bilateral cingulate cortices in AD
cortical thickening, increased atrophy, or increased rate of patients (strength of conclusion 3). However, there is some
atrophy in the parahippocampal gyrus (strength of conclu- evidence of additive effect of APOE ε4 on reduced GMv in
sion 2). Further, moderate evidence shows no APOE ε4 the right cerebellar crus (strength of conclusion 3). There
effect on parahippocampal gyrus (strength of conclusion is moderate evidence of reduced GMv and lower cortical
2). Additionally, moderate evidence shows that APOE ε4 thickening in the posterior cingulate cortex (PCC) in APOE
is associated with reduced volume and increased rate of ε4 carriers (strength of conclusion 2). There is some evi-
atrophy of the parahippocampal gyrus (strength of conclu- dence that APOE ε4 exerts an effect on cerebral cortex atro-
sion 2). phy (strength of conclusion 3). However, there is a lack of
Other temporal lobe regions of interest An interesting association between APOE ε4 and cerebral volume (strength
point to highlight is the report of increased cortical thick- of conclusion 2), and cerebellar GMv reduction (strength of
ness in APOE ε2 carriers relative to APOE ε4 carriers [20, conclusion 3).
119], suggesting that APOE ε2 may offer some protective
role against dementia in both young adults and older age Other subcortical gray matter regions In summary, based
group. on the findings shown in Table 2, APOE ε4 may have mini-
In conclusion, there is reasonable evidence that APOE ε4 mal to no effect on the size of the thalamus from young to
carriers demonstrate reduced GMv in the middle temporal middle age, while in older adults, it may exert more nega-
lobe, temporal pole, and in general, the whole temporal lobe tive effect (strength of conclusion 3). that older adult APOE
(strength of conclusion 2). Further, some evidence shows ε4 carriers with MCI exhibit increased GM atrophy of the
that APOE ε4 carriers demonstrate reduced cortical thin- thalamus (strength of conclusion 3). There is some evidence
ning in the middle temporal gyrus, and medial and tem- of an increased rate of subcortical atrophy of the putamen
poral regions; and GMv reduction or rate of reduction in and loss of GM in the right caudate nucleus in APOE ɛ4
the fusiform, temporoparietal and occipitotemporal regions carriers (strength of conclusion 3). Inconclusive evidence
(strength of conclusion 3). Conversely, some evidence shows exists regarding the association between APOE ɛ4 carriers
that male APOE ε4 carriers demonstrate increased corti- and basal ganglia GMv (strength of conclusion 4). Some
cal thickening in the temporoparietal regions (strength of evidence shows subcortical atrophy in the accumbens, right
conclusion 3). Furthermore, there is moderate evidence that
13
Fig. 3 Increased tau-PET is associated with GM atrophy in the temporoparietal lobes (A), MTL (B), and the occipital lobe (C) in MCI and AD
(strength of conclusion 2), whereas increased Aβ-PET is associated with GM atrophy in the MTL (MCI > > AD) (strength of conclusion 2)
ventral striatum, and sulcal widening among APOE ε4 car- relationship was found between GM changes and FDG-PET
riers (strength of conclusion 3). in healthy older adults (strength of conclusion 3).
Brain alterations and CSF biomarkers (Aβ42, t‑tau, Brain alterations and neuropsychological measures
and p‑tau)
In total, 36 studies assessed the relationship between brain
In summary (Fig. 2), it is difficult to establish the direction alterations and cognitive measures [19, 20, 23, 24, 31–33,
of the relationship between CSF Aβ42 and brain changes in 35, 37, 40, 42, 44, 45, 50, 52, 61, 75, 77, 80, 81, 88, 91,
healthy older adults (strength of conclusion 4), but there is 96–98, 101, 102, 112, 117, 128, 129, 134, 137, 138, 148,
some evidence that CSF tau is not related to GMv in healthy 150].
older adults (strength of conclusion 3). There is substantial Conclusively from Table 2 (Fig. 4), for healthy cohort
evidence that reduced CSF Aβ42 is associated with GM studies, preliminary findings show that there is some evi-
atrophy as well as its rate of atrophy in the MTL and other dence of a relationship between MTL lobe atrophy, pre-
temporoparietal regions in patients with MCI (strength of dominantly the hippocampus, and lower episodic memory
conclusion 2). Further, there is moderate evidence that both in early life (3–20 years) but not in early mid-life (strength of
increased CSF tau levels correlated with MTL and caudate conclusion 3). However, there is moderate evidence that hip-
atrophy; however, each tau measure correlated differentially pocampal atrophy is associated with lower episodic memory
with specific regions of the temporal cortices in patients not only in healthy late mid-life (i.e., ~ 45–65 years), but also
with MCI (strength of conclusion 2). Contrarily, there is in older adults with APOE ε4 allele (strength of conclu-
inconsistent evidence regarding the association between sion 2). Some evidence shows lower GMv is associated with
CSF Aβ42 and regional brain alterations in AD (strength of lower global cognition in healthy older adults (strength of
conclusion 4). However, there is strong evidence of reduced conclusion 3); however, inconclusive evidence remains for
CSF Aβ42 and lower brain measures in patients with AD an association between GMv and episodic memory (strength
(strength of conclusion 2). Furthermore, there is some evi- of conclusion 4), even though strong evidence shows that
dence that increased CSF t-tau is associated with the parietal both GMv and episodic memory were reduced (strength of
lobe regions (PCC and precuneus), as well as the isthmus conclusion 2). There is more strong evidence for an associa-
cingulate and caudate in AD (strength of conclusion 3). tion between hippocampal atrophy (than temporal lobe atro-
phy) and reduced global cognitive function in healthy older
Brain alter ations, Aβ‑ and tau‑PET, and FDG‑PET adults (strength of conclusion 2). Interestingly, changes in
subcortical regions (i.e., ACC, caudate, cerebellar crus, tem-
In conclusion (Fig. 3), there is moderate evidence that tau- poral pole, and parietal lobe) were also found to be differen-
PET is associated with GMv changes most strongly in the tially associated with lower performance in specific cogni-
temporoparietal lobes, and with the involvement of the MTL tive domains which includes executive function, episodic
and occipital regions (strength of conclusion 2). There is memory, and attention in early life, late mid-life, and older
also moderate evidence demonstrating that alterations in the age (strength of conclusion 3).
brain GM are inversely associated with Aβ-PET in AD vul- For studies that compared demented patients with healthy
nerable regions (especially the MTL), which is stronger for controls, there is cumulative evidence that hippocampal
MCI than AD (strength of conclusion 2). Furthermore, no atrophy (including the amygdala and entorhinal cortex) is
13
Fig. 4 GM atrophy in the MTL (i.e., hippocampus) is associated with conclusion 2); (3)lower global cognition in healthy older adults (C)
the following: (1) lower episodic memory in young age (3–20 years (strength of conclusion 2); and (4) lower episodic memory and global
of age) (A) (strength of conclusion 3); (2) lower episodic memory in cognition in demented adults (D) (strength of conclusion 2)
healthy middle-to-older age and APOE ε4 carriers (B) (strength of
strongly associated with both reduced episodic memory and tissues, anthropometric measures, genetic and environmental
global cognitive function, as well as increased dementia influences on brain development.
severity at baseline and over time (strength of conclusion Furthermore, the varied methods of analysis (manual ver-
2). Further, there is inconclusive evidence for an associa- sus semi- or full-automated) and the software used among
tion between reduced GMv and global cognitive function the selected studies can affect the results. Together, these
(strength of conclusion 4). However, some evidence shows factors can affect the final MRI signal intensity and ulti-
that atrophy of the frontal, temporal, and parietal lobe was mately the morphometric measures, leading to a few of the
associated with lower global cognition, episodic memory, discordant findings reported. The disproportionate distribu-
and dementia severity (strength of conclusion 3). Although tion of sample size and sex, age range or average age, and
conflicting evidence was found for the relation between differences in cognitive measuring tools used may have also
the frontal lobe and executive function, moderate evidence affected the relationships between the variables of interest.
shows that there is atrophy of the frontal lobe and lower Nonetheless, the results are striking in that there is much
performance in executive function in AD (strength of con- consistency in the association between structural alterations
clusion 2). with APOE ε4 status, CSF and PET biomarkers, and neu-
ropsychological measures.
Discussion Brain alterations in relation with APOE ε4 status
MR-based brain morphometry is a valuable imaging bio- Several studies reported neuroplastic changes in the cor-
marker. Its use is well-established for identifying early and tical areas of GM, and several subcortical regions. These
late changes in a wide range of neurodegenerative disor- changes were predominant in APOE ε4 allele carriers rela-
ders. However, pooling brain MRI studies that focused on a tive to noncarriers. These changes manifested as reduced
specific neurodegenerative disease comes with several chal- GMvs or cortical thinning, suggested as reflecting synaptic
lenges. The use of different scanners can be associated with pruning size alterations and the number of glia or neuronal
several confounding factors, leading to various morpho- size [151, 152]. We found that GMv reduction in the middle
metric measures. For instance, low field strength scanners frontal gyrus may provide better insight into the underlying
(i.e., < 1.5 T) have proven valuable for brain morphometric pathophysiological changes in APOE ε4 carriers, instead of
measures in the past, but they have limited capabilities for changes in the right lateral orbitofrontal cortex or lateral pre-
optimum differentiation of GM and WM. Alternatively, frontal cortex. Cortical thinning in the frontal lobe subcorti-
the increasing availability of 3.0 T or higher allows one to cal structures and increased cortical thickening in the lateral
acquire quality brain images with excellent contrast and spa- medial orbitofrontal region in APOE ε4 carriers may be of
tial resolution. Yet, they have their limitations as well. The clinical significance. These subcortical structures include
vast differences in acquisition parameters (TR, TE, FA, and the lateral frontal, left rostral midfrontal, right caudal mid-
ST) can also lead to morphometric differences. Even indi- frontal, and superior frontal gyrus. Overall, it appears that
viduals within the same age group may demonstrate mor- cortical thickness measurements of the frontal lobe subcorti-
phometric differences. Presumably, this can be due to sub- cal structures may better demonstrate neuroplastic changes
tle differences in the cellular organization within the brain compared to GMv measurements.
13
Decreased volumes in specific parietal lobe subtructures, The occipital lobe is the least studied, possibly because
i.e., right angular gyrus and precuneus may provide valu- visual symptoms are uncommon and that this region is not
able details about structural changes in APOE ε4 carriers. usually affected until relatively late in the neocortical stages
We noted that the cortical thinning in the superior parietal of AD [161]. From the findings, it seems plausible to suggest
gyrus appears better to reflect the effect of APOE carrier that the whole occipital lobe may better provide insight into
status with neurodegeneration. The National Institute of structural changes among APOE ε4 carriers compared to its
Aging-Alzheimer’s Association guidelines recommends that subcortical regions. The PCC may be an essential structure
the presence of cortical thinning or GMv loss in the lateral to earmark for analysis during the pathophysiological pro-
and medial parietal gyri is a marker of AD-pathophysiology cess of AD or in healthy individuals with APOE ε4, as there
[2]. We did find substantial evidence to support medial and was moderate evidence that this region showed cortical thin-
lateral parietal lobe atrophy in the APOE ε4 carriers. There ning. Other plausible areas with some evidence of reduced
are consistent reports of precuneal GMv reduction and its GMv and/ or association with APOE ε4 status include the
association with APOE ε4. The PCC/precuneus has been insula, ACC, cerebral cortex, and cerebellar crus, particu-
the main focus of several studies investigating cognitively larly in older adults. Some evidence also showed that brain
normal individuals and/or AD. This region is one of the key regions associated with delusions (such as the putamen,
regions that demonstrate cortical thinning [153], hypome- thalamus, and caudate nucleus) [162] demonstrated GM
tabolism [154], lower levels of N-acetyl aspartate/creatine, atrophy in older APOE ε4 carriers. The accumbens, exhib-
elevated myoinositol/Cr [155, 156], functional disruptions ited GM atrophy in older APOE ε4 carriers. The accumbens
[157, 158], and histopathologic changes [159] in the early is a critical component of the ventral striatum thought to
course of AD. Thus, the precuneal GMv may better provide play a role in mediating processes associated with motiva-
insight into neuronal injury compared to cortical thickness tion and emotion, and the interface between the limbic and
measures. the motor systems [163]. Another interesting finding is the
Strong evidence shows that APOE ε4 carriers demon- increased cortical thickness in APOE ε2 carriers compared
strate reduced cortical thickening or increased GMv reduc- to the APOE ε4 carriers, suggesting that APOE ε2 may offer
tion in the MTL regions. The MTL is widely known to play some protective role against dementia in both young adults
significant roles in memory. Besides, the MTL is implicated and older adults.
in the neural correlates of AD. This outcome also firmly
holds for APOE ε4 healthy older adults and those with Brain alterations in relation with CSF and PET
dementia, especially in AD, and it is consistent with previ- biomarkers
ous systematic reviews and meta-analysis [13–15]. Note that
the MTL is also the most studied region, which could also Overall, while preliminary evidence suggests that GMv may
partly be the reason for this vital evidence. be preserved in cognitively normal older adults, it is hard
Interestingly, in healthy young APOE ε4 carriers to conclude the exact direction of changes in CSF Aβ42
(< 21 years of age), there is moderate evidence for hip- level and cortical thickening changes in these individuals.
pocampal and entorhinal cortical thinning. In addition, Regardless of these diverse changes in direction, there is
there is some evidence of GMv reduction in the PCC/pre- some evidence of CSF Aβ42 and cortical thickness changes
cuneus, medial cingulate cortex, lateral temporal, and medial in cognitively normal older adults and specific brain regions
occipitotemporal regions in this age group. In comparison, in which such changes are more pronounced. Further, there
slightly overlapping and beyond this age to ~ 35 years, there is evidence that CSF tau is not related to GMv in cognitively
is inconclusive evidence to suggest an association between normal older adults. On the other hand, there is substantial
APOE ε4 and regional brain changes, especially the MTL evidence that reduced CSF Aβ42 is associated with GM
due to increased, decreased, and unaltered GM structures. atrophy and its rate of atrophy in the MTL and other tempo-
On the other hand, moderate evidence suggests the lack of an roparietal regions in patients with MCI. APOE ε4 genotype
association between APOE ε4 and cortical or GM changes largely drove the relationship between lower levels of CSF
in late mid-life (averagely 44–64 years of age). Therefore, Aβ42 and GM atrophy and its rate of atrophy which involved
these findings do not wholly embrace the antagonistic pleiot- more extensive regions including the MTL and other tempo-
ropy hypothesis suggested by Han and Bondi [160], particu- roparietal areas in patients with MCI.
larly in early life, where it is hypothesized that APOE ε4 is Further, it is plausible to suggest that these regions are a
advantageous. There are mixed reports on the effect or asso- significant hub for amyloid deposition in the AD continuum,
ciation between APOE ε4 and amygdala, entorhinal cortex, consistent with the neuropathological staging of topographic
and parahippocampal gyrus. This suggests their limitation distribution of amyloid plaque as determined by Braak
as potential AD biomarkers compared to the hippocampus. and Braak [159]. A significant highlight is that it remains
13
inconclusive to pinpoint the exact relationship between CSF with MCI or AD, there is ample evidence from studies that
Aβ42 and GM changes in AD. This may suggest that the did not meet our inclusion criteria that there is a significant
combination of these variables may not provide a robust association between lower FDG-PET and reduced MTL
representation of the level of amyloid deposition, severity, volume in the AD continuum [4, 167]. This relationship
or AD progression. Indeed, Braak and Braak [159] have also is postulated to demonstrate that lower FDG-PET is either
asserted that neuritic plaques may not help differentiate the predictive or drives brain atrophy [4], suggesting that it may
neuropathological staging of AD. Comparatively, we found be potentially helpful in characterizing brain changes in the
moderate evidence for the relationship between CSF tau lev- early stages of AD.
els (p-tau and t-tau) and MTL and temporoparietal atrophy
in MCI. In contrast, for AD, some evidence showed that Brain alterations in relation
there is a relationship between only CSF t-tau and parietal with neuropsychological measures
lobe atrophy (i.e., PCC and precuneus), including the isth-
mus and caudate. These findings suggest that the two neu- Preliminary findings demonstrate a relationship between
ropathological hallmarks of AD drive neurodegeneration. MTL atrophy (predominantly the hippocampus) and lower
It is postulated that the combination of MRI and PET episodic memory in early life (< 21 years) of APOE ε4 car-
imaging can improve the diagnostic accuracy of AD. MRI/ riers, but not in early mid-life. These early life trajectories
PET combination is characterized by an inherent high-spa- also involved higher behavioral problem scores related to
tial-resolution, and high-contrast anatomical imaging that traffic-related air pollution exposures [48]. Recent system-
complements absolute quantitative tracer uptake obtained atic reviews suggest that plausible targets of air pollution are
with PET [173]. Besides, it is well acknowledged that PET/ not only limited to cortical GM alterations but also involve
MRI can provide the differential diagnosis of AD by provid- alterations of the cerebral white matter, basal ganglia, and
ing neuroimaging biomarkers of neuronal injury and Aβ, disruption in resting-state functional connectivity in early
tau, and metabolism in a multimodal framework [174]. Our life [168, 169]. These are posited to be related to cogni-
study revealed exciting findings regarding the relationship tive decline in older children and older adults [168, 170].
between MRI and PET biomarkers. We found moderate evi- We also noted moderate evidence regarding the association
dence demonstrating an inverse relationship between GM between hippocampal atrophy and lower episodic memory
brain changes and Aβ-PET in AD vulnerable regions, par- in cognitively healthy individuals in the late mid-life stage
ticularly for the MTL, which is more substantial for MCI (i.e., ~ 45–65 years). An association was established between
than AD. These findings agree with the topography found the hippocampal atrophy and cognitive decline (reduced
for the relationship between CSF Aβ42 and GM changes episodic memory and global cognition) in older adults
as earlier indicated; hence, we can postulate an agreement (i.e., ≥ 65 years of age) carrying the APOE ε4 genotype.
between CSF Aβ42 and Aβ-PET. This is supported in previ- This may give credence to the hypothesis that the risk of
ous studies [164, 165], including a recent study that reported dementia, AD, in particular, is characterized by a clinically
that their concordance was predictive of clinical progression silent period in late mid-life or perhaps even at a younger
in patients with MCI [166]. However, controversy remains age. There is some evidence that lower GMv is associated
regarding whether CSF Aβ precedes fibrillar Aβ or vice with reduced global cognition in healthy older adults. In
versa in the AD continuum [175, 176]. Notwithstanding, contrast, it remains inconclusive to suggest an association
there is the suggestion that there are two alternative path- between GMv and episodic memory even though there was
ways (“CSF-first” vs. “PET-first”) toward established Aβ substantial evidence of an independent reduction in both
pathology, characterized by different genetic profiles and GMv and episodic memory. Therefore, it is plausible to sug-
rates of Aβ accumulation [177]. gest that late mid-life and older adulthood carriage of the
Further, we found moderate evidence for the relation- APOE ε4 genotype have overlapping but distinct changes
ship between tau-PET and GMv changes, mainly confined in cognitive trajectories concerning the hippocampal neu-
to the temporoparietal lobes but also including the MTL ronal injury. Increased and decreased cortical thickness and
and occipital regions. This further strengthens the evidence increased GM in subcortical regions were differentially asso-
that tau pathology drives neurodegeneration. Recent stud- ciated with lower performance in specific cognitive domains
ies have also confirmed that tau pathology is a major driver in early life, late mid-life, and older adulthood. These brain
of local neurodegeneration [178, 179] and highlighted the regions include the ACC, caudate, cerebellar crus, temporal
relevance of tau-PET as a precision medicine tool to help the pole, and parietal lobe, while the cognitive domains affected
prediction of an individual’s progression [179]. We found were the executive function, attention, and the least, epi-
no relationship between GM changes and FDG-PET in both sodic memory. These GM and cortical changes appear to
healthy late mid-life and older adults. Although we found be related to the decline in cognitive composite reported
none of the studies examined this relationship in patients in the preclinical stages of AD [171, 172]. Some evidence
13
also shows that atrophy of the frontal, temporal, and parietal the correlational findings; an alternative approach may be
lobe was associated with lower global cognition, episodic to test the hypothesis of this study by focusing only on stud-
memory, and dementia severity. Further, although we found ies of longitudinal design. In addition, some studies used a
conflicting evidence regarding the relationship between the relatively small sample size, and across studies, the sample
frontal lobe and executive function, there was moderate size varied widely, so there is the possibility that some were
evidence of frontal lobe atrophy and lower performance in underpowered. These reasons prevented the creation of reli-
executive function in AD. able meta-analytic summary estimates. Therefore, we are
unable to establish the magnitude of effect sizes. Thus, it
Strengths and limitations is essential to exercise caution in the interpretation of the
aforementioned correlational findings. Some studies also
To the best of our knowledge, the current systematic review failed to provide a clear stratification of the age group of
is the first to summarize the evidence regarding GM and/or participants. This made it difficult to establish hard evidence
cortical changes in relation to APOE ε4, validated AD bio- regarding the relationship between some of the variables,
markers, and neuropsychological measures across the lifes- for example, the relationship between brain alterations and
pan with a focus on the changes in the whole-brain. While neuropsychological measures in early mid-life. Finally, the
we revealed significant findings that have improved our wide range of different neuropsychological scales used may
understanding of the mechanism underlying the interplay have affected the direction of the associations observed and
between various variables, it is also important to highlight the regional brain structures interrogated.
this study’s limitations. It is important to note that we did not
consider non-English studies that might have improved this
study’s quality. Further, some studies included other MRI Conclusion and future directions
sequences that provided additional crucial information to
what was inferred besides volumetric or cortical thickening We, therefore, establish that the deleterious effect of APOE
measures, i.e., the use of T2-, T2*-, diffusion-, and FLAIR ε4 is not only limited to the MTL or temporal lobe. APOE ε4
(FLuid Attenuated Inversion Recovery)-weighted sequences. effect is exerted on the whole-brain manifesting as reduced
Although these sequences are well-established diagnostic GMv or cortical thinning in several GM and cortical and
markers commonly used in the clinical practice of brain substructures of the frontal, parietal, and occipital lobe.
MRI, their measures were not extracted from the included These structures demonstrate differential ability to elicit bet-
studies to separately evaluate their diagnostic performance ter details regarding individual brain regions or individual
in the early stage and advanced stage of the disease. Besides, lobar changes. At present, it is hard to establish whether
we did not consider other advanced MRI techniques. These early young and mid-life carriers of the APOE ε4 genotype
include functional MRI, diffusion tensor imaging, electro- would develop AD in later life. Therefore, this remains an
encephalography, magnetoencephalography, and functional open question. There is strong evidence that reduced levels
near-infrared spectroscopy. Other biomarkers from other of CSF Aβ42, increased Aβ- and tau-PET, and increased
fluid media, i.e., blood, urine, saliva, and tears, were also CSF tau (p-tau and t-tau) are significantly associated with
not considered. atrophy of AD vulnerable regions. These relationships may
The methodology was largely heterogeneous, con- be potentially helpful in characterizing the preclinical and
sidering the use of different MRI equipment, magnetic particularly the clinical stage of MCI, and to some extent,
field strengths, MRI scanning protocols and parameters, by combining CSF t-tau and parietal lobe atrophy for AD.
sequences, types, radiomics, pre- and postprocessing While we found no support for the combination of brain
software, and algorithms (i.e., manual vs. semi- and full MRI and FDG-PET biomarkers in healthy late life and older
automated methods) across studies. Besides, compared to adults, further studies may be required to interrogate their
the large number of works analyzed, the literature data on combination in the AD continuum. There is a strong effect of
the correlation between morphometry and CSF/PET are APOE ε4 on the MTL structures, especially the hippocam-
somewhat limited. Only 19 studies used CSF and, among pus in relation to lower episodic memory observed in early
these, only 8 (~ 42%) did a correlation analysis between life, late mid-life, and older with similar observation in the
morphometry and CSF. Similarly, out of the 14 studies MCI and AD. This relationship may serve as an endpoint for
that used Aβ- and/ or tau-PET, only 4 (~ 29%) correlated prognosticating the occurrence of AD-related neurodegen-
morphometry with these biomarkers. For the nine studies eration. Besides, their combination may be helpful in clinical
that used FDG-PET, only two (~ 22%) performed a cor- trials targeting neuroplasticity in AD. However, further stud-
relational analysis. Most of the studies included were also ies may be required to validate these findings, particularly
of cross-sectional design, which may decrease the value of
13
considering the influence of environmental factors in early Alzheimer’s disease dementia and other dementias in people with
life and the increasing risks of developing AD in later life. mild cognitive impairment (MCI). Cochrane Database Syst Rev
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have been explored mainly on the White population. Data (2015) A Cochrane review on brain [18F]FDG PET in dementia:
limitations and future perspectives. Eur J Nucl Med Mol Imaging
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represented ethnic groups. Therefore, it would be essential 7. Botha H, Mantyh WG, Murray ME, Knopman DS, Przybelski
to target this population and investigate the trajectory of AD SA, Wiste HJ, Graff-Radford J, Josephs KA, Schwarz CG, Kre-
pathology trajectory and how they change over time across mers WK, Boeve BF, Petersen RC, Machulda MM, Parisi JE,
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the lifespan. tau-negative amnestic dementia resembles that of autopsy-proven
hippocampal sclerosis. Brain 141(4):1201–1217
8. Meramat A, Rajab NF, Shahar S, Sharif R (2015) Cognitive
Author contributions Conception and study design (ADP), data col- impairment, genomic instability and trace elements. J Nutr
lection (ADP), interpretation of results (ADP, MM, and SS); drafting Health Aging 19(1):48–57
the manuscript work (ADP), revising manuscript (ADP, MM, SS, and 9. Hussin NM, Shahar S, Yahya HM, Din NC, Singh D, Omar MA
NFR); approval of final version to be published and agreement to be (2019) Incidence and predictors of mild cognitive impairment
accountable for the integrity and accuracy of all aspects of the work (MCI) within a multi-ethnic Asian populace: a community-based
(ADP, MM, SS, and NFR). longitudinal study. BMC Public Health 19(1):1159
10. Rivan NFM, Shahar S, Rajab NF, Singh DKA, Che Din N,
Funding None. Mahadzir H, Mohamed Sakian NI, Ishak WS, Abd Rahman
MH, Mohammed Z, You YX (2020) Incidence and predictors of
cognitive frailty among older adults: a community-based longi-
Declarations tudinal study. Int J Environ Res Public Health 17(5):1547
11. Shahar S, Lee LK, Rajab N, Lim CL, Harun NA, Noh MF, Mian-
Conflict of interest The authors declare that they have no conflict of Then S, Jamal R (2013) Association between vitamin A, vitamin
interest. E and apolipoprotein E status with mild cognitive impairment
among elderly people in low-cost residential areas. Nutr Neurosci
Ethical approval All procedures performed in studies involving human 16(1):6–12
participants were in accordance with the ethical standards of the insti- 12. American Psychiatric Association (2013) Diagnostic and statis-
tutional and/or national research committee and with the 1964 Helsinki tical manual of mental disorders (DSM–5), 5th edn. American
declaration and its later amendments or comparable ethical standards. Psychiatric Publishing, Washington, DC
13. Liu Y, Yu JT, Wang HF, Han PR, Tan CC, Wang C, Meng XF,
Informed consent Informed consent was obtained from all individual Risacher SL, Saykin AJ, Tan L (2015) APOE genotype and neu-
participants included in the studies reviewed in this paper. roimaging markers of Alzheimer’s disease: systematic review
and meta-analysis. J Neurol Neurosurg Psychiatry 86(2):127–134
14. Emrani S, Arain HA, DeMarshall C, Nuriel T (2020) APOE4
is associated with cognitive and pathological heterogeneity in
patients with Alzheimer’s disease: a systematic review. Alzhei-
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Clinical and Translational Imaging

Topographical patterns of whole‑brain structural alterations

Received: 1 April 2021 / Accepted: 7 June 2021

Introduction MTL atrophy [13–15]. Aside from this, it is postulated that

relative to controls Substitution Test and Digit-

APOE ε4 carriers. No correlational

annual changes of DLR

[45] – 62 (34.47 ± 13.48) No evidence of APOE ε4 – – No association between Participants stratified

ε4 homozygotes significant (p = 0.03) after ε4 and non-APOE ε4

and superior temporal in MCI compared to AD

[53] 104 AD (mean None No association between – – – Cross-sectional study

[57] None 22♂ and 9♀ APOE ε4 carriers showed Longitudinal study

[59] 64 Young-Old AD (44%♂; 83 Young-Old (51%♂; No effects of APOE ε4 – – – Participants stratified

lum/ parasubiculum and represented

PCC, and precuneus in be associated with increased rates of cortical

[69] None 7♂ and 23♀ APOE ε4 carriers – – – Longitudinal study

[74] None 4♂ and 12♀ Lower cortical thickening – – – Longitudinal study

thickening across the 0.2% respectively

atrophy rate and APOE correlated with cognitive Wechsler Adult

cortex, fusiform gyrus, ­mm3/year

[92] 5♂ and 6♀ 11♂ and 20♀ APOE ε4 is associated – – – Cross-sectional study

[99] None 28♂ and 48♀ Association found – – – Cross-sectional study

(55.5 ± 5.1 years) HM

[105] None 314 (44 – 48 years) No association between – – – Longitudinal study

status of APOE ε4 and or p < 0.001); APOE ε4

[126] None 12 ♂ and 20 ♀ APOE ε4 carriers dem- – – – Cross-sectional mul-

[133] None 2916 ♂ and 3124 ♀ No evidence of an asso- – – – Cross-sectional study

superior occipital, pre- cortex, parahip-

Study characteristics Studies that included PET biomarkers A total of 14 studies

Table 3 Methodological quality Study 1 2 3 4 5 6 7 8 9 Total score LOE

Table 3 (continued) Study 1 2 3 4 5 6 7 8 9 Total score LOE

Table 3 (continued) Study 1 2 3 4 5 6 7 8 9 Total score LOE

Table 4 LOE, according to Intervention

Table 5 Strength of conclusion Conclusion based on

Fig. 1 PRISMA flowchart of Additional records identified through

Records after duplicates removed

Records screened on titles and abstracts

Full-texts articles excluded (n =

Syntheses of results APOE ε4 and brain alterations

Discussion Brain alterations in relation with APOE ε4 status

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cortex, fusiform gyrus, mm3/year