EDITORIAL

Early Hippocampal Atrophy Is an Important Signal for

Clinicians but Not Necessarily a Harbinger of
Alzheimer Disease
Peter T. Nelson, MD, PhD, and Gregory A. Jicha, MD, PhD Correspondence

®
Dr. Nelson
Neurology 2023;101:1087-1088. doi:10.1212/WNL.0000000000208071 pnels2@email.uky.edu

Dementia is one of the most formidable health care challenges we face today. Fortunately, there RELATED ARTICLE
is new hope for patients and clinicians because we are on the verge of anti–β-amyloid (Aβ)
Research Article
therapies to slow disease progression in Alzheimer disease (AD). But these new therapies are far
Association of Pathologic
from curative, and many challenges remain related to confounding pathologic processes and
and Volumetric Biomarker
mixed disease states. These challenges are only beginning to be addressed in regard to the use of
Changes With Cognitive
antemortem biomarkers.
Decline in Clinically
Normal Adults: Harvard
In this issue of Neurology®, Hanseeuw et al.1 present new data about how longitudinal changes Aging Brain Study
in cognition and dementia biomarkers are associated with structural brain changes. Their results
Page 1104
underscore that dementia is more complex than a simple attribution to the classic pathobiology
of AD—Aβ plaques and Aβ-driven neurofibrillary tangles. In the study of Hanseeuw et al., 128
participants in their mid-70s (followed longitudinally with normal cognition at baseline) were
serially evaluated using cognitive testing and biomarkers: MRI and molecular PET. A critical
focus of the study was the analysis of hippocampal volume (HV) change, which was correlated
with cognitive status, as expected. An illustrative synoptic pie chart is provided that underscores
the importance of non-AD pathologies in driving HV and cognitive loss. The authors conclude
that HV can be used to help indicate non-Alzheimer pathologies when the HV loss is out of
proportion to observed levels of Aβ/tau biomarkers. This approach is in line with the ongoing
revisions to the National Institute on Aging and the Alzheimer’s Association research criteria for
AD presented for public and scientific comment in July at the Alzheimer Association In-
ternational Conference.

The finding of a complex set of explanations for HV loss highlighted in the article is as expected
because many pathologic insults other than classic Aβ/tau mechanisms can contribute to HV
loss. This understanding is based on several decades of research using clinicopathologic study
paradigms demonstrating that non-AD pathologies can also drive hippocampal atrophy and
amnestic dementia. Importantly, non-AD pathologies often occur in combination. Such mixed
and/or varied pathology is hard to distinguish clinically. As Neurology readers know, the
proportion of amnestic dementia cases with “pure” Aβ/tau pathology corresponds roughly with
the degree of efficacy of the anti-Aβ immunotherapy (;30%).2

With a focus on HV change as a mediator of cognitive decline and dementia, limbic-

predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC)3 as a
driver of amnestic dementia is particularly important.4 LATE-NC (medial temporal lobe-
predominant TDP-43 pathology) is an all-too-prevalent feature of brain aging, often associated
with amnestic impairment and HV loss.3,5 The study of Hanseeuw et al. estimates that 10% of
cases are relatively “pure” LATE-NC, and this comports with prior studies (see e.g., Reference
6). However, it is important to note that many if not most cases with severe Aβ/tau pathology
also have comorbid LATE-NC, and the LATE-NC confers added cognitive impairment.7
In a large study combining autopsy data from community-based cohorts, approximately
50% of cases with severe Aβ/tau pathology had LATE-NC, whereas approximately one-quarter
of cases with no Aβ/tau pathology had LATE-NC (Figure).8 The impact of LATE-NC in cases

From the University of Kentucky, Lexington.

Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial.

Copyright © 2023 American Academy of Neurology 1087

Copyright © 2023 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Figure Frequency of LATE-NC Stratified by AD Severity
(A) LATE-NC was present in the brains of ;50% of persons with severe AD
pathology (operationalized by high level of neuritic amyloid plaques
according to CERAD criteria). (B) In persons with no Aβ neuritic amyloid
plaques, 27% had LATE-NC. Similar synergies are seen between AD pa-
thology and Lewy body pathologies. The data represented in the figure were
derived from Nelson et al.8 Aβ = β-amyloid; AD = Alzheimer disease; CERAD =
Consortium to Establish a Registry for Alzheimer’s disease; LATE-NC = limbic-
predominant age-related TDP-43 encephalopathy neuropathologic change.
with comorbid Aβ/tau pathologies may be extremely
important—perhaps impactful regarding whether the patient
responds to Aβ-oriented immunotherapy. Collectively, these
observations underscore the importance of developing and
validating a disease-specific LATE-NC biomarker.
Another key point that is underscored by both the study of
Hanseeuw et al. and prior autopsy studies is the importance
of primary age-related tauopathy9 and age-related tau
astrogliopathy10—tau pathologies not necessarily associated
with Aβ plaques. Almost a quarter of the HV in the study of
Hanseeuw et al. was associated with nonamyloid tau pathol-
ogy signal. This finding again emphasizes the importance of
pathologic features that are distinct from the Aβ/tau patho-
logic hallmarks, yet remain impactful to the dementia clinical
syndrome, from a patient and public health perspective.
In sum, the data presented by Hanseeuw et al. urgently
highlight the need for tools that might stratify patients into
categories that predict clinical and radiologic progression,
especially at the preclinical stage of disease. Importantly, such
discoveries should enable the clinician to distinguish one
disease from another, in an effort to optimize clinical trials,
1088 Neurology | Volume 101, Number 24 | December 12, 2023
Copyright © 2023 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
and ultimately to guide treatment options in this new era of
antidementia therapies.
Acknowledgment
Thanks to Dr. Karin B. Nelson for editorial input.
Study Funding
This work was supported by the NIH grants R01 AG061111,
R01 AG057187, P30 AG072946, RF1 NS118584, P01
AG078116.
Disclosure
The authors report no relevant disclosures. Go to Neurology.
org/N for full disclosures.
Publication History
Received by Neurology September 11, 2023. Accepted in final form
October 13, 2023.
References
1. Hanseeuw BJ, Jacobs HIL, Schultz AP, et al. Association of pathologic and volumetric
biomarker changes with cognitive decline in clinically normal adults: Harvard Aging
Brain Study. Neurology. 2023;101(24):e2533-e2544.
2. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer
disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):
512-527. doi:10.1001/jama.2023.13239
3. Nelson PT, Dickson DW, Trojanowski JQ, et al. Limbic-predominant age-related
TDP-43 encephalopathy (LATE): consensus working group report. Brain. 2019;
142(6):1503-1527. doi:10.1093/brain/awz099
4. Nelson PT, Schneider JA, Jicha GA, Duong MT, Wolk DA. When Alzheimer’s is
LATE: why does it matter? Ann Neurol. 2023;94(2):211-222. doi:10.1002/ana.26711
5. Dawe RJ, Bennett DA, Schneider JA, Arfanakis K. Neuropathologic correlates of
hippocampal atrophy in the elderly: a clinical, pathologic, postmortem MRI study.
PLoS One. 2011;6(10):e26286. doi:10.1371/journal.pone.0026286
6. Nelson PT. LATE neuropathologic changes with little or no Alzheimer disease is
common and is associated with cognitive impairment but not frontotemporal de-
mentia. J Neuropathol Exp Neurol. 2021;80(7):649-651. doi:10.1093/jnen/nlab050
7. Nelson PT, Abner EL, Schmitt FA, et al. Modeling the association between 43
different clinical and pathological variables and the severity of cognitive impairment in
a large autopsy cohort of elderly persons. Brain Pathol. 2010;20(1):66-79. doi:
10.1111/j.1750-3639.2008.00244.x
8. Nelson PT, Brayne C, Flanagan ME, et al. Frequency of LATE neuropathologic
change across the spectrum of Alzheimer’s disease neuropathology: combined data
from 13 community-based or population-based autopsy cohorts. Acta Neuropathol.
2022;144(1):27-44. doi:10.1007/s00401-022-02444-1
9. Crary JF, Trojanowski JQ, Schneider JA, et al. Primary age-related tauopathy (PART):
a common pathology associated with human aging. Acta Neuropathol. 2014;128(6):
755-766. doi:10.1007/s00401-014-1349-0
10. Kovacs GG, Ferrer I, Grinberg LT, et al. Aging-related tau astrogliopathy (ARTAG):
harmonized evaluation strategy. Acta Neuropathol. 2016;131(1):87-102. doi:10.1007/
s00401-015-1509-x
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