Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring

Impact of COVID-19 on Functional, Cognitive, Neuropsychiatric, and Health-Related

Outcomes in Patients with Dementia: A Systematic Review
--Manuscript Draft--

Manuscript Number: DADM-D-23-00258

Article Type: Review Article

Keywords: Mild Cognitive Impairment, Dementia, mortality rate, SARS-CoV-2, COVID-19

Corresponding Author: Lucia Crivelli

Foundation for the Fight against Childhood Neurological Diseases
Argentina, ARGENTINA

First Author: Lucia Crivelli

Order of Authors: Lucia Crivelli

Andrea Munblit Winkler

Greta Keller

Simone Beretta

Ismael Calandri

Wouter De Groote

Arianna Fornari

Jennifer Frontera

Miia Kivipelto

Ana Sabsil Lopez-Rocha

Francesca Mangialasche

Daniel Munblit

Katie Palmer

Alla Guekht

Ricardo Francisco Allegri

Abstract: Background: This systematic review analyzes the impact of SARS-CoV-2 on dementia
patients’ functional, cognitive, neuropsychiatric, and overall health outcomes. It
hypothesizes that dementia patients infected experience more pronounced
deterioration compared to those uninfected. Methods: Research from 01/03/2020 to
07/10/2023 was conducted using Medline, Web of Science, and Embase databases,
adhering to PRISMA guidelines and the PICO framework. The study aimed to
determine if SARS-CoV-2 infection is associated with worse outcomes in dementia
patients. The protocol is registered in PROSPERO (CRD42022352481), and bias was
evaluated using the Newcastle-Ottawa Scale. Results: Among 198 studies reviewed,
only two met criteria. Chen et al. (2023) identified higher mortality in SARS-CoV-2-
infected dementia patients, while Merla et al. (2023) observed faster cognitive decline
in infected individuals with increased hospital admissions. Conclusion: Limited data
suggest higher mortality and cognitive decline in COVID-19-infected dementia patients,
underscoring the need for extensive research in this area.

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Cover Letter

November 18th, 2023

Editorial Department of The Journal of The Alzheimer's Association

Dear Editor-in-Chief, Dr. Wilcock,

I am a member of the Neurology and COVID-19 Global Forum at the World Health
Organization (WHO). Previously, we had the privilege of publishing a paper in your
esteemed journal. This paper not only garnered significant attention but also received
numerous citations, establishing itself as a precedent in the field (doi:
10.1002/alz.12644).

Today, I am submitting the manuscript entitled “Impact of COVID-19 on Functional,

Cognitive, Neuropsychiatric, and Health-Related Outcomes in Patients with Dementia:
A Systematic Review” for consideration for publication in the Journal of the
Alzheimer's Association. I declare that this manuscript has not been previously
published nor is it being considered for publication elsewhere.

This is a systematic literature review of remarkable relevance in the scientific field as it

allows us to compare the longitudinal outcomes of patients with dementia who
contracted SARS-CoV-2 with those who did not. The results suggest that patients with
dementia infected with SARS-CoV-2 face increased mortality risks and more severe
cognitive decline compared to those uninfected. Furthermore, due to the limited
number of studies with follow-up and a comparison group, it also indicates that future
research must focus on the long-term cognitive impact of COVID-19 on dementia, the
role of SARS-CoV-2 variants on disease progression, and how prior vaccination affects
mortality risk in these patients. Prospective longitudinal studies with longer follow-ups
are needed.

The material described in the manuscript is the original work of the authors and has
not been previously published, nor is it under simultaneous consideration by any other
journal. All the authors mentioned have contributed significantly to the manuscript
and consent to have their names appear in it. There are no conflicts of interest to
disclose.

Author's name: Lucía Crivelli

Full address: Montañeses 2325
Telephone: (+54911) 57773200
Fax: (+54911) 57773200

Email:
Lucía Crivelli: lcrivelli@fleni.org.ar
Manuscript (clean)

Title: Impact of COVID-19 on Functional, Cognitive, Neuropsychiatric, and Health-

Related Outcomes in Patients with Dementia: A Systematic Review.

Authors: Crivelli, L¹*; Winkler, A*2,3,4 ; Keller, G¹; Beretta, S5; Calandri, I¹, De Groote, W6; Fornari,
A7; Frontera, J8; Kivipelto, M9,10,11,12,13, Lopez-Rocha, A14; Mangialasche, F9,15, Munblit, D16,17,18;
Palmer, K9,10,; Guekht, A19, Allegri, R¹.

¹Department of Cognitive Neurology, Fleni, Montañeses 2325 (C1428AQK), Buenos Aires, Argentina.
² Department of Neurology, Center for Global Health, School of Medicine, 685 West Baltimore Street Baltimore,
MD 21201-1509, USA.
3
Department of Community Medicine and Global Health, Institute of Health and Society, Faculty of Medicine,
University of Oslo, Postboks 1130 Blindern, 0318, Oslo,Norway
4
Department of Global Health and Social Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA
02115, Boston, MA, USA
5
Department of Neurology, Fondazione IRCCS San Gerardo dei Tintori Monza, University of Milano Bicocca,
Via G. B. Pergolesi, 33, 20900 Monza MB, Italia
6
WHO Rehabilitation Programme, Avenue Appia 20, 1211 Geneva, Switzerland
7
Neurology, Public Health and Disability Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via
Giovanni Celoria, 11, 20133 Milano MI, Italia
8
NYU School of Medicine, 550 First Avenue New York, USA.
9
Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and
Society, Karolinska Institutet, 171 77 Stockholm, Sweden.
10
FINGERS Brain Health Institute, 22, 112 19 Stockholm, Sweden
11
Medical Unit Aging, Karolinska University Hospital, 171 77 Stockholm, Sweden
12
Ageing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College London, St Dunstan's
Road, London, United Kingdom
13
Institute of Public Health and Clinical Nutrition and Institute of Clinical Medicine, Neurology, University of
Eastern Finland,Yliopistonrinne 3, Kuopio, Finland
14
Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences
and Society, 171 77 Stockholm, Karolinska Institutet, Sweden
15
Theme Inflammation and Aging, Medical Unit Aging, Karolinska University Hospital, 171 77 Stockholm,
Sweden
16
Care for Long Term Conditions Division, Florence Nightingale Faculty of Nursing, Midwifery and Palliative
Care, King's College London, James Clerk Maxwell Building 57 Waterloo Road. London, United Kingdom
17
Department of Paediatrics and Paediatric Infectious Diseases, Institute of Child’s Health, Sechenov First
Moscow State Medical University (Sechenov University), 119991, Moscow, Trubetskaya street, Russia
18
Research and Clinical Center for Neuropsychiatry, Ulitsa Ostrovityanova, 1 (117997), Moscow, Russia
19
Moscow Research and Clinical Center for Neuropsychiatry; Pirogov Russian National Research Medical
University, Ulitsa Ostrovityanova, 1 (117997), Moscow, Russia

Correspondence: Crivelli, Fleni, Montañeses 2325 (C1428AQK), Buenos Aires, Argentina. E-mail:
lcrivelli@fleni.org.ar

*Crivelli and Winkler are join as first author

1
ABSTRACT:

BACKGROUND: This systematic review analyzes the impact of SARS-CoV-2 on dementia

patients’ functional, cognitive, neuropsychiatric, and overall health outcomes. It hypothesizes

that dementia patients infected experience more pronounced deterioration compared to those

uninfected.

METHODS: Research from 01/03/2020 to 07/10/2023 was conducted using Medline, Web of

Science, and Embase databases, adhering to PRISMA guidelines and the PICO framework.

The study aimed to determine if SARS-CoV-2 infection is associated with worse outcomes in

dementia patients. The protocol is registered in PROSPERO (CRD42022352481), and bias was

evaluated using the Newcastle-Ottawa Scale.

RESULTS: Among 198 studies reviewed, only two met criteria. Chen et al. (2023) identified

higher mortality in SARS-CoV-2-infected dementia patients, while Merla et al. (2023)

observed faster cognitive decline in infected individuals with increased hospital admissions.

CONCLUSION: Limited data suggest higher mortality and cognitive decline in COVID-19-

infected dementia patients, underscoring the need for extensive research in this area.

KEYWORDS: Mild Cognitive Impairment, Dementia, mortality rate, SARS-CoV-2, COVID-

19

2
1. INTRODUCTION:

In 2020, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread

across the globe. Clinical manifestations of coronavirus disease 2019 (COVID-19) exhibit a

broad spectrum, from mild to severe. Various studies have highlighted an array of sequels,

some linked to the initial clinical presentation severity 1,2, while others were unrelated 3.

In 2023, the World Health Organization (WHO) estimated a general COVID-19 mortality rate

of approximately 0.70% (WHO, 2023). Several risk factors, including advanced age, male sex,

pre-existing comorbidities, pre existing neurological diseases4; immunization status,

racial/ethnic disparities in healthcare access, prior exposure to SARS-CoV-2, and occupation

as a healthcare worker, increase the risk of severe disease and mortality5. Some factors, such

as older age, inherently pose a greater risk due to weakened immune responses, heightened

prevalence of comorbidities6, and aging-related chronic pro-inflammatory immune states7.

Despite numerous studies on COVID-19's cognitive impacts, targeted research on individuals

with pre-existing cognitive impairment remains scarce8. It is vital to discern COVID-19's

repercussions on this population, as they may confront distinct challenges, accelerated

cognitive decline, and exacerbated health outcomes.

Individuals with cognitive impairment, especially those with dementia, have an increased

vulnerability to upper respiratory infections, both viral (e.g., influenza) and bacterial (e.g.,

community-acquired pneumonia)9,10. This susceptibility, theorized to result from impaired

personal hygiene and self-care stemming from cognitive decline, influences short- and long-

term mortality rates11, 12 . Significant post-infection cognitive declines have been observed,

3
lasting up to six months13 . Therefore, studying COVID-19's impact on those with antecedent

cognitive impairments—covering cognitive and neuropsychiatric outcomes, along with

mortality risk—is critical.

Although COVID-19 is no longer considered a Public Health Emergency of International

Concern (PHEIC), according to WHO, it still poses profound global health implications. Given

the potential for its indefinite presence and mutation propensity, proactive measures, such as

the WHO-Europe's transition plan for COVID-19, are essential. It is equally crucial to

persistently study COVID-19's effects on patients with dementia, providing insights to tailor

treatment and care strategies. Hence, health systems should brace for this enduring and

unpredictable adversary. Sustained research endeavors, informed by the pandemic's lessons,

are needed to aptly address future health crises and dementia patients' specific concerns.

While there have been preliminary investigations into the longitudinal outcomes of patients

with MCI and dementia about COVID-19 infection, a thorough examination of the available

data has not been conducted. This systematic review aims to assess the existing evidence on

the cognitive and functional decline in patients with MCI and dementia, contrasting those who

contracted SARS-CoV-2 with those who remained uninfected.

4
2. METHODS:

The study protocol was registered in the International Prospective Register of Systematic

Reviews (PROSPERO: registration number CRD42022352481). This systematic review was

reported following the Preferred Reporting Items for Systematic Reviews (PRISMA)

recommendations14. This systematic review was developed by the WHO’s Neurology and

COVID-19 Global Forum working group. The interdisciplinary group includes experts from

four continents and comprises neurologists, geriatricians, neuropsychologists, psychiatrists,

and epidemiologists.

2.1 Eligibility Criteria

The PICO (Population, Intervention/issue of interest, Comparison, and Outcome) question was

formulated as follows: In patients with dementia, is there an association between SARS-CoV-

2 infection and worse longitudinally measured outcomes (including functional, cognitive,

neuropsychiatric and health-related ) compared to patients of equivalent dementia severity who

remained uninfected?” The study population includes patients with previous medical diagnoses

of dementia (mild to severe). The intervention/exposure includes being infected with SARS-

CoV-2 (confirmed by real-time polymerase chain reaction (RT-PCR) test / nasopharyngeal

swabs). The comparison group consists of patients with the same dementia severity as the

patient group but without SARS-CoV-2 infection. Outcomes included functional, cognitive,

neuropsychiatric, and health-related measures (either before infection or during the acute phase

of COVID-19 and after recovery). The study design required a longitudinal follow-up.

5
2.2 Search strategy

A systematic literature search was performed in October 2023 in Medline, Web of Science, and

Embase. The systematic literature review's literature search and study selection process

included articles published between 01/03/2020 and 07/10/2023. The Supplementary material

presents the search strategies (see Appendix A).

2.3 Study inclusion and exclusion criteria

The inclusion criteria were as follows: a) articles with patients with all types of dementia who

had SARS-CoV-2 infection or not, b) published as of 2020, c) with longitudinal follow-up of

outcomes, d) original reports such as case-control or cohort studies. The exclusion criteria were

a) duplicate articles, b) unrelated ones, c) systematic reviews, d) case series with less than 5

cases, and 6) abstracts only. There were no restrictions regarding the study’s language.

Two reviewers (LC, GK) independently screened the titles and abstracts according to the

eligibility criteria. Disagreements were discussed with a third reviewer (IC) and subsequently

resolved via consensus (see Figure 1).

2.4 Data extraction and synthesis

The following data categories were collected when available: study design, sample size,

country, patient demographics, population setting, time of assessment related to SARS-CoV-2

infection, comorbidity, outcome measures, and COVID-19 disease severity. One of the

6
reviewers performed the data extraction, and the other reviewer assessed the accuracy of the

extracted data (see Table 1).

2.5 Risk of Bias Assessment

Two reviewers independently rated the quality of included studies using the Newcastle-Ottawa

Scale (NOS) (see Table 2). The quality of case-control and cohort studies was assessed by

judging three categories: the selection of the study groups, the comparability of the groups, and

the ascertainment of either the exposure or outcome of interest for case-control or cohort

studies, respectively.

3. RESULTS:

3.1 Overview of the included studies

3.1.1 Study Selection

After removing the duplicates, a total of 1.670 records were identified from the databases (see

Figure 1). Screening titles and abstracts excluded a total of 1.472 studies. Other studies were

also left out after reading the full text because their aims were unrelated (n=186) to those

selected for this review.

3.1.2 Study Characteristics

The remaining 12 studies are described in Table 1; only 2 matched all the PICO criteria and

were included. The remaining ten also aimed to investigate the impact of COVID-19 on

patients with dementia but were excluded as they did not meet the complete PICO

requirements; this is why they are discussed as supplementary studies. Of these supplementary

7
studies, nine did not have a control group15,16,17,18,19,20,21,22,23, while others did not include a

longitudinal follow up 15,16, 17, 18, 19, 22, 23, 24.

3.2 Results of individual studies

Only two studies met the eligibility criteria Chen [25] and Merla [26]. Both studies investigated

different outcomes. When comparing dementia patients with and without SARS-CoV-2

infection, Chen [25] found differences in the risk of death, while Merla [26] observed

differences in cognitive outcomes and hospitalization rates.

The study by Chen [25] evaluated the longer-term effects of the SARS-CoV-2 infection on

patients with dementia, drawing data from a retrospective study. One hundred and sixty-five

dementia patients who had survived their SARS-CoV-2 infection during their hospital

admissions were compared to 1325 dementia patients who had been hospitalized but had not

contracted the virus. A comprehensive analysis included socio-demographic information,

clinical data, and other investigative results. The findings showed a significant disparity

between the two groups. Patients with both dementia and SARS-CoV-2 infection demonstrated

a significantly elevated risk of death, with an adjusted hazard ratio (aHR) of 4.44 (95%

confidence interval [CI] 3.13–6.30). This was done by comparing survival trajectories in people

with dementia with or without SARS-CoV-2 (COVID-19). This increased mortality risk

persisted for up to 125 days post-recovery but did not extend beyond this period.

Common clinical factors associated with increased mortality in COVID-19 cases—such as

inflammation, hypernatremia, liver dysfunction, and low albumin—were also observed to

increase mortality risk in dementia patients. Further analysis revealed a two-fold increased risk

of death in dementia patients who were prescribed antipsychotics (aHR = 3.06, 95%CI 1.40–

8
6.69) and benzodiazepines (aHR = 3.00, 95%CI 1.28–7.03). Based on these findings, the

researchers developed a model predicting post-acute COVID-19 mortality in these patients for

the initial 120 days after recovery, achieving an accuracy rate of 87.2%. This model can

potentially guide targeted follow-up or interventions for those at the highest risk. In conclusion,

the study underscores that patients with dementia continue to face a significantly elevated risk

of death, even after recovering from the acute phase of the illness.

Merla [26] compared two groups of dementia patients: those infected with SARS-CoV-2

(N=31) and those not infected (N=80). The primary objective was to investigate the presence

of cognitive decline, defined as a five-point loss on the Mini-Mental State Examination

(MMSE), and the deterioration of basic and instrumental activities of daily living (BADL and

IADL, respectively). Results indicated that cognitive decline was approximately 3.5 times

more prevalent in the SARS-CoV-2 infected group (weighted hazard ratio 3.56, (95% CI 1.50–

8.59), p = 0.004). On average, the MMSE score declined by 1.7 points/year regardless of

COVID-19 status. However, the rate of decline was twice as fast in the COVID-19 group (3.3

vs. 1.7 points/year, p < 0.050). On average, BADL and IADL indices decreased by less than 1

point/year, irrespective of SARS-CoV-2 infection. Another notable finding was the higher

incidence of new institutionalizations among COVID-19 patients compared to those without

the infection(45% versus 20%, p = 0.016).

3. 3 Risk of Bias Assessment Results

In summary, when using the Agency for Health Research and Quality (AHRQ) threshold

standards, both of the included studies were good.

9
3. 4 Supplementary studies

Several studies only met parts of the PICO requirements. Some of these studies either lacked

longitudinal follow-up or did not have the required comparison group (see "Reasons for

Exclusion" in Table 1). However, these studies are still noteworthy for discussion as they

present COVID-19-related outcomes in patients with dementia.

The study by Dubey [21] included the follow-up data of 14 patients with different dementia

types (four with Alzheimer’s disease, five with vascular dementia, three with Parkinson’s

disease dementia, and two with the behavioral variant of frontotemporal dementia) who were

studied at baseline before SARS-CoV-2 infection and one year after the disease. Interestingly,

the researchers found that regardless of the type of dementia, the severity of COVID-19, the

presence of vascular risk factors, or the need for oxygen or ventilator support, patients

experienced a significant progression of dementia and periventricular white matter

hyperintensities and increased global cortical atrophy. This progression was characterized by

an added decline in cognitive abilities, primarily of the subcortical variety, and a pronounced

increase or new onset of white matter lesions.

Two other studies, which need to be considered carefully, met most of the PICO criteria but

lacked a comparison group. In their cohort study, Cascini [24] evaluated the incidence of

SARS-CoV-2 infection and associated mortality within a cohort of dementia patients using

administrative databases coupled with the SARS-CoV-2 infection surveillance system. Patients

diagnosed with dementia aged ≥65 (n=31,2019) were monitored throughout the pandemic, and

7% contracted the infection. The comparative analysis between infected (N=2,548) and

uninfected patients (N=35,181) indicated that people with dementia had a significantly higher

risk of both infection (60% increased risk) and death 31.0 per 100 (95 CI%: 28.8–33.6),

compared to the overall elderly cohort. The standardized mortality ratio (SMR) was reported

10
at 2.32 (95% CI 2.05–2.65) for males and 2.82 (95% CI 2.55–3.11) for females. The study

noted a pronounced prevalence of comorbidities and antipsychotic medication use, both of

which emerged as key risk factors for infection and subsequent mortality within 60 days of

diagnosis. Additionally, the severity of clinical symptoms at diagnosis and male gender were

associated with an increased probability of COVID-19-induced mortality. The study highlights

the need for careful and individualized monitoring of dementia patients to mitigate the impact

of COVID-19 in this vulnerable group.

The case-control study by Beobide Telleria [22] studied the correlation between demographic,

clinical, and pharmacological risk factors and the incidence of SARS-CoV-2 infection in a

sample of elderly residents (n=436). The study further investigated the variables influencing

COVID-19 mortality. Their findings revealed that advanced dementia was linked to a reduced

risk of infection with an odds ratio (OR) of 0.65 (95% CI 0.43–0.97). In contrast, a COPD

diagnosis and the consumption of antipsychotic medication yielded ORs of 7.8 (95% CI 1.9-

31.3) and 3.1 (95% CI 1.0-9.0), respectively, which were associated with an increased mortality

risk.

Matias-Guiu [23] examined the incidence and mortality among dementia patients, with

Alzheimer's Disease (AD) (n=147) 72.1%, and with Frontotemporal Dementia (FTD)

hospitalized with a confirmed COVID-19 diagnosis. The study found an increased mortality

risk for patients with AD compared to those with FTD (χ2 = 3.22, p = 0.119). These differences

may be due to age differences between groups, and genetic factors like APOE 4 and

comorbidities like hypertension, which is more frequent in AD than FTD, could also contribute

to explaining these differences. In addition to AD, living at a care home was the most relevant

factor associated with the risk of death, and clinical stage and age were less significant.

11
The study of Hu [20] included 96,275 participants of the UK Biobank who had available SARS-

CoV-2 test results. Of these, 2,617 had a clinical diagnosis of neurodegenerative diseases in

the UK Biobank inpatient hospital data before the outbreak of COVID-19, while the remaining

participants constituted the reference group. Data indicated that individuals with prior

neurodegenerative diseases were at an increased risk for COVID-19. This increased risk

included not only contracting the infection, with an OR of 2.47 (95%CI 2.25–2.71) but also

requiring hospitalization due to COVID-19 2.18 (95%CI 1.94–2.45) and higher mortality of

3.67 (95%CI 3.11–4.34) from the disease.

In addition, across various investigations 15, 16, 17, 18, 19 , the role of dementia as a comorbidity in

COVID-19 patients has been consistently studied. Covino [17] noted an increased risk of death

in COVID-19 patients over 80 years, specifically identifying severe dementia and particular

clinical risk factors independently contributing to this increased mortality. Lozano Montoya

[15] supported these results by demonstrating an association between dementia and increased

in-hospital mortality among their study cohort, emphasizing the role of delirium and a high

Pneumonia Severity Score in this outcome. Lucijanic [16] provided a longer-term perspective,

revealing that dementia patients exhibited a significant mortality risk even post-hospital

discharge, with a hazard ratio of 4.32 (95%CI 3.23-5.77) in a 12-month follow-up period after

discharge. Further corroborating these findings, Vlachogainnis [19] indicated that among their

patient sample, dementia was the sole comorbidity associated with both early and late mortality

in unadjusted analyses; after accounting for age and sex confounders, the significance persisted

specifically for late mortality. In summary, these studies underline the amplified vulnerability

of dementia patients during a SARS-CoV-2 infection, not only during hospitalization but also

in the subsequent recovery period.

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4. DISCUSSION:

This review analyzes the existing literature regarding the impact of COVID-19 on patients

affected with dementia compared to an appropriate control group, including functional,

cognitive, neuropsychiatric, and health-related outcomes. After extensive search, only two
25,26
studies met the eligibility criteria. Although this may be attributed to highly specific

research questions and corresponding restrictive search strategies, the results of the studies that

we identified are insightful and show the urgent need for more longitudinal studies, preferably

with an appropriate control group, in order to explore the effects of SARS-CoV-2 infection in

patients with dementia.

From Chen [25], it becomes clear that dementia patients who contract SARS-CoV-2 remain at

an increased risk of death, even after recovering from the acute phase of the disease. Such

sustained vulnerability emphasizes the long-term consequences of the virus on this susceptible

population. This observation agrees with other studies, such as Cascini [24] and Hu [20], which

have also identified increased mortality risks and a greater likelihood of infection among

dementia patients. The specific reasons for this population’s increased vulnerability to infection

remain unknown. Still, a potential explanation could be an imbalanced immune system that

often plays a role at the onset of neurodegenerative diseases with changes in the immune

reactions27, 28, 29, 30

. Furthermore, chronic inflammation, a frequent characteristic of

neurodegenerative diseases, might also amplify the risk of infection with SARS-CoV-2

Stephenson [31]; Subhramanyam [32]. Moreover, Chen [25], highlighted the added risks

associated with specific medications, namely antipsychotics and benzodiazepines. These

findings resonate with the observations made by Cascini [24] and Beobide Telleria [23],

strengthening the understanding of pharmacological implications in these patients.

13
The study by Merla [26] emphasizes the substantial cognitive repercussions of COVID-19 on

dementia patients, with a marked acceleration in cognitive decline, as evidenced by the MMSE

scores. This, together with the notable increase in new institutionalizations, indicates the far-

reaching consequences of SARS-CoV-2 on dementia patients' quality of life and healthcare

needs. This study is supported by the results of Dubey [21], who also found rapid progression

of dementia post-SARS-CoV-2 infection, irrespective of the dementia type. The acceleration

of cognitive decline following a SARS-CoV-2 infection is a crucial insight. It not only affects

the patient’s quality of life and functionality but also places additional strains on healthcare

systems and caregivers. Therefore, medical and social care strategies and infrastructure must

be adapted to accelerated cognitive decline in patients with dementia and SARS-CoV-2

infection.

Our review has strengths but also some obvious weaknesses. Its strengths lie with its adherence

to the PRISMA guidelines and the deliberate selection of the PICO strategy to pinpoint studies

with stringent design and inclusion criteria. That way, we were able to pick up high-quality

studies with strong evidence, but at the same time had to put a restriction on other seemingly

well-designed pre-selected studies. However, we did not discard those studies that did not fit

100% our eligibility criteria but included them into the manuscript (see Results and Table 1),

at the same time putting their results into perspective regarding the design used. For example,

although not entirely fulfilling our eligibility criteria the UK Biobank study, despite it not being

focused on patients with dementia, is a strong study comparing their results with a robust

control group and sending a clear message of increased risk of infection with SARS-CoV-2,
20
hospitalization, and mortality in patients with overall neurodegenerative diseases . We

described several of the studies that did not fit our eligibility criteria in the Result section and

14
used them in the Discussion section in support of the two studies by Chen [25] and Merla [26]

that entirely satisfied our eligibility criteria.

In summary, in the context of SARS-CoV-2 infection, the role of dementia as a comorbid

condition has gained substantial attention. Several studies identified dementia as a significant

predictor of increased mortality and revealed that even post-discharge dementia patients

exhibited a markedly higher mortality risk; collectively, these findings underscore the

imperative for clinicians to consider dementia as a significant comorbidity when managing

SARS-CoV-2 patients, necessitating specialized care strategies and vigilant post-infection

follow-up. The lack of evidence underscores the urgent need for systematic case/control studies

on the cognitive, functional, neuropsychiatric, and health-related consequences in patients with

MCI and dementia after COVID-19 infection. However, the existing evidence discussed in this

review shows a clear trend: people with dementia have higher mortality risk and worse

cognitive outcomes. Also, some interesting questions remain open in the current research

landscape. For example, it would be helpful to know whether infected but previously

vaccinated patients with dementia still have an increased mortality risk. In addition, the role of

the different variants of SARS-CoV-2 and their differential effects on people with dementia is

crucial. Furthermore, we neither found studies fitting our eligibility criteria that investigated

the correlation between the severity of the COVID-19 infection and cognitive/functional

worsening, nor those that followed up patients beyond one year after infection.

5. CONCLUSION:

The existing literature indicates that dementia patients infected with SARS-CoV-2 face

increased mortality risks and more severe cognitive impairments compared to those uninfected.

15
Although these findings are based on limited evidence, our review underscores the existing

gaps in knowledge and underscores the need for further research in this area.

16
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7. ACKNOWLEDGEMENTS:

The authors acknowledge the contribution of all the members of WHO’s Neurology and

COVID-19 Global Forum working group on Follow-up and Long-term Impact.

8. CONLICT OF INTEREST:

None.

9. SOURCE OF FUNDING:

Nothing to report.

10. KEYWORDS:

Mild Cognitive Impairment, Dementia, mortality rate, SARS-CoV-2, COVID-19

20
Table 1. Characteristics of the included studies: methodological summary and main results

Table 2 . Study designs and quality scoring using Newcastle-Ottawa scale for non-randomised
studies in meta-analyses and classification according to AHRQ standards

Fig 1. PRISMA flow chart describing the screening and selection of articles

21
Appendix A

The search terms used were devised by an expert group of neurologists, geriatricians,
epidemiologists, and neuropsychologists and included the following keywords:
(“COVID-19” OR “Coronavirus” OR “COVID19” OR “SARS-CoV-2” OR
“Pandemic”) AND (“Major Cognitive disorder” OR “Dementia” OR “Mild Cognitive
Impairment” OR “Mild Neurocognitive Disorder” OR “MCI”) AND (“MMSE” OR
“MoCA” OR “Neuropsychology” OR “Executive function” OR “Attention” OR
“Language” OR “Visuospatial” OR “Dysexecutive syndrome” OR “Verbal fluency”
OR “Processing speed” OR “Functional Assessment” OR “Activities of Daily Living”
OR “ADL” OR “Quality of Life” OR “Death Rate” OR “Neuropsych*” OR
“Depression” OR “Anxiety” OR “Behavior” OR “Sleep” OR “insomnia” OR
“Somnolence” OR “Hypersomnolence” OR “Parasomnia” OR “Movement disorder”
OR “Irritability” OR “Hallucinat*” OR “Delusion*” OR “Apath*” OR “Indifference”
OR “Agitat*” OR “Euphori*” OR “Elation” OR “Elated” OR “Disinhibit*” OR
“Aggressi*” OR “Mood” OR “Affective” OR “Depress*” OR “Anxi*” OR “Obsessive
compulsive” OR “Mortality Rate” OR “Survival” OR “Death” OR “Deaths” OR
“Hospitalization” OR “Mortality” OR “Functional status” OR “Disability” OR
“Independent Living”)

Reference lists of publications were also screened to identify additional articles.

22
PRISMA flow chart describing the screening and selection of
articles

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and
Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097

For more information, visit www.prisma-statement.org.

Table 1. Characteristics of the included studies: methodological summary and main results

Table 1. Characteristics of the included studies: methodological summary and main results

Population COVID-19 Sex Dementia Time of Control Sex Dementia Reasons for
Authors Country setting cases Age (F%) Diagnosis Co-morbidity severity Assessment group Age (F%) severity Measures Results Exclusion

COHORT

Patients with dementia

had a three times higher
GDS 0-3:
risk of dying than patients
164 (55.2);
without dementia. The
GDS 4= 35
following factors were
(11.8), GDS
associated with higher in-
5= 38 (12.8), Lack of comparator
Lozano 45.1% patients had BI, GDS, hospital mortality in a
Acute Geriatric 134 86.3 GDS 6= 42 group and not
Montoya et., Spain Hospitalized
62.7* dementia of some CCI 24 hs NA NA NA NA CAM, CFS , multi-variant analysis:
Unit (6.6)* (14.1) , longitudinal follow
al 2021 degree CCI CURB-65 score=3–5 (HR
GDS 7 =18 up
7.99, 95% CI 3.55–19.96,
(6.1), GDS
p<0.001), incident
Dementia
delirium (HR 1.72, 1.10–
>4=134
2.70, p=0.017) and
(45.1)
dementia (HR 3.01, 95%
CI 1.37–6.705, p=0.017).
Cardiovascular
comorbidities,
diabetes,
COVID-19-associated
obesity, COPD,
crude case fatality rate of
Regional asthma,
31%, with a more than
Health pneumonia,
65-74 double risk of dying in
Assistance file Dementia neoplasm,
(12.7%) dementia patients
and the diagnosis identified electrolytes, SIR and SMR
Cascini et 2548 75-84 > 65 compared to the general Not longitudinal
Italy Integrated Hospitalized (44.7%)
69.9 by health chronic kidney, NA 14 months 35,181 Years
65.2 NA ratios were
al., 2022 population of the same follow up
Surveillance administrative gastric diseases, calculated.
>85 age and gender. The
System of databases. Parkinson’s,
(42.9%) SMRs 2.32 (95% CI
SARS-CoV-2 disease of the
2.05–2.65) for men, and
infections blood, chronic
2.82 (95% CI 2.55–3.11)
liver, fracture,
for women.
anxiety, alcohol
use disorder,
depression
 In a multivariate analysis,
mutually independent
predictors of worse
mortality after hospital
discharge were age >75
years, Eastern
Cooperative Oncology
Group status, white blood
Registry 357 cell count >7/L, red cell
Lack of comparator
project- Mild, 70, IQR distribution width >14%,
Lucijanic et group and not
Croatia Dubrava moderate, (60- 44.1* N/A CCI NA 4 months NA NA NA NA CCI urea on admission >10.5
al., 2022 longitudinal follow
University severe and 80)* mmol/L, mechanical
up
Hospital critical ventilation during
hospital stay, readmission
after discharge, absence
of obesity, presence of
chronic obstructive
pulmonary disease,
dementia, and metastatic
malignancy (P<0.05 for
all).
In patients aged 80 years
and older, death may not
necessarily be related to
BP, CAD, CHF, Physiological age. In contrast, the onset
COPD, GCS, parameters, of severe dementia
ICU, NEWS, Symptoms at significantly influences
8 pO2, HBP, admission, risk in this age group. Lack of comparator
Covino et al., Urban teaching Mild, 84 (82- cerebrovascular Radiographic Notably, severe dementia, group and not
Italy 46.4* Severe dementia NA 1 month NA NA NA NA
2020 hospital severe and 89)* disease, findings, oxygen levels (pO2) of 90 longitudinal follow
critical diabetes, Patient disease or below upon admission, up
dementia, presentation in and lactate
malignancy, ED, Clinical dehydrogenase levels
pneumonia history exceeding 464 U/L are
independent factors that
affect survival in these
patients.
HBP, asthma, Significant predictors for
Cases were
diabetes, HIV, mortality included
Ontatio 8.610 linked to health Lack of comparator
chronic kidney comorbidities such as
Ge et al., Laboratories Hospitalized 42.7 administrative group and not
Canada 52* N/A disease, cancer, NA 1 month NA NA NA NA solid organ transplant
2021 Information (21.9)* databases longitudinal follow
COPD, (p<0.001), dementia
System (OLIS) maintained in up
rheumatoid (p<0.001), chronic kidney
the ICES
arthritis, disease (p<0.001), severe
 inflammatory mental illness (p<0.001),
bowel disease, diabetes (p<0.001),
liver disease, chronic obstructive
severe mental pulmonary disease
illnessand solid (COPD) (p<0.001),
organ transplant cancer (p<0.001),HBP
(p<0.001).
CCI with the
Respiratory failure,
addition of
systemic inflammation,
obesity, Signs and
and renal impairment
respiratory rate, symptoms,
471 were associated with
oxygen laboratory Lack of comparator
Vlachogiannis Hospitalized 271 (14) early mortality, while
UK Hospital 74 (25) 47.3 N/A saturation on NA NA NA NA NA features, co- group and S and not
et al., 2022 days active cancer and
room air, morbidities, 4C longitudinal
dementia were associated
Glasgow Coma mortality and
with late mortality, after
Scale score, CFS
adjustment for age and
urea, and C-
sex.
reactive protein
We observed an elevated
risk of COVID-19
outcomes among
individuals with a
ICD-10 and ICD-9
neurodegenerative disease
(2014 primary
93,658 Demographical compared with the
neurodegenerative
(97.3%) factors, reference group. Among
2617 diseases, 345
Hu et al., 74.2 included in lifestyle, individuals with a Lack of comparator
UK UK Biobank Asyntomatic 53.6 vascular CCI NA 18 months 67.7 NA NA
2022 and mild
(5.84) the socioeconomic positive test result for group
neurodegenerative
unexposed status, BMI, SARS-CoV-2, individuals
diseases, 904 other
group Charlson Index with neurodegenerative
neurodegenerative
diseases had also a higher
diseases)
risk of COVID-19 related
death than others (fully
adjusted odds ratio 2.08;
95%CI 1.71–2.53).
Cognitive decline was
Hypertension, about three and a half
diabetes, times more frequent in
Memory Care AD: 7
31 dyslipidemia, patients who had COVID-
Facility of the Vascular dementia:
Merla et al., Moderate cerebrovascular 1.1 year 82 ± MMSE, BADL 19 (weighted hazard ratio
Italy Department of 83 ± 5 64 6 NA 80 70 NA Included
2023 and disease, [0.7–1.7] 5 and IADL 3.56, 95% confidence
Continuity of hospitalized Mixed: 13
cardiovascular interval 1.50–8.59, p =
Care in Trieste Other: 5
disease, chronic 0.004). MMSE score
kidney disease lowered on average by
1.7 points/year,
 independently of COVID-
19, but it lowered twice
faster in those who had
COVID-19 (3.3 vs. 1.7
points/year, respectively,
p < 0.050). Patients who
had COVID-19 had a
higher incidence of new
institutionalization than
those who did not have
the disease (45% versus
20%, p = 0.016,
respectively).
There was a significant
Burdwan
increase in fatigue (p =
Medical
ACE-III, FAB, 0.001) and depression (p
College and
AD: 4 Trail Making = 0.016) scores following
Hospital,
PD: 3 Test Part B, COVID-19. The mean
Dubey et al., Bangur Institute 14 65.6 ± Cardiovascular Lack of comparator
India 36 FTD: 2 NA 1 year NA NA NA NA CDR, Patient Frontal Assessment
2023 of Hospitalized 5.02 disease group
Vascular dementia: Health Battery (p < 0.001) and
Neurosciences,
5 Questionnaire Addenbrooke’s Cognitive
and private
and MRI Examination (p = 0.001)
cognitive
scores also significantly
specialty clinics
worsened.

CASE CONTROL

People with
dementia and GDS
≥ 6 were less
likely to be
infected by SARS-
CoV-2 virus with
BMI, AHT, an OR of 0.64 (95% Lack of comparator
Beobide
Residents that 116 85.68 COPD, 85.53 BMI, GDS, CI 0.43-0.97; p < group and not
Telleria et Spain 71.7 57: GDS ≥ 6 GDS ≥ 6 NA 181 72,6 GDS ≥ 6
al., 2022
lived in NHs Hospitalized (8.6) Dementia; (8.8) Frail VIG 0.05). Our results longitudinal follow
Diabetes show that up
advanced dementia
(GDS ≥ 6), COPD and
antipsychotic use
are variables
related to COVID-
19 mortality. a low
 Barthel Index or
advanced dementia
(GDS ≥ 6) were
factors associ-
ated with higher
COVID-19
mortality (p <
0.05). The
meanFrail-VIG
index of those who
died from COVID-
19 was 0.45(SD =
0.08), while for
those who
acquired the
infection and did
not die was 0.39
(SD = 0.11), the
difference being
sta-tistically
significant (p =
0.001). However,
the relation
between
COPDsufferers and
COVID-19
mortality was
statistically
significant(p =
0.026).
Risk factors for COVID-
19-associated mortality
Cambridge Socio-
included prescription of
University demographic
antipsychotics (aHR =
Hospitals variables, CCI,
165 239.4 3.06, 95%CI 1.40–6.69)
Chen et al., (CUH) National 85.6 85.2 medicine
UK Moderate 58,8 ICD-10 CCI NA and 363.8 1,325 59,8 NA and benzodiazepines Included
2023 Health Service (7.4) (7.1) utilization at
and severe days (aHR = 3.00, 95%CI
(NHS) baseline,
1.28–7.03).
Foundation laboratory
Abnormalities on
Trust blood results
investigation associated
with increased mortality
 included high white cell
count (aHR = 1.21,
95%CI 1.04–1.39), higher
absolute neutrophil count
(aHR = 1.28,
95%CI 1.12–1.46), higher
C-reactive protein (aHR =
1.01, 95%CI 1.00–1.02),
higher serum sodium
(aHR = 1.09,
95%CI1.01–1.19), and
higher ionized calcium
(aHR = 1.03, 95%CI
1.00–1.06).

CASE SERIES

In the 204 patients

included in the study,
death was associated with
older age (83.92 ± 6.76
versus 77.59 ± 9.48, t =
A semi-
2.77, p = 0.015) and with
structural
an advanced clinical
interview was
dementia stage (χ2 =
conducted to
8.58, p = 0.035). No
CDR, 16.7% the principal
statistically significant
classified as caregivers and
differences in the
very mild, included the
frequency of infection Lack of comparator
146 (72.1%) with 27.9% mild, following
Matias-Guiu Tertiary 204 78.02 between patients with AD group and not
Spain 58.3 AD and 57 (27.9%) HBP 28.4% NA NA NA NA NA items:
et al., 2020 hospital Hospitalized (9.42) (22, 15.1%) and FTD (8, longitudinal follow
with FTD moderate, diagnosis of
14.8%) (χ2 = 0.002, p = up
and 27.0% as COVID-19
0.964). Patients with AD
severe (RT-PCR) or
showed a higher risk of
dementia. serological test;
death in COVID-19 than
symptoms of
patients with FTD.
COVID-19; the
Differences in age and
need of hospital
rate of arterial
admission.
hypertension, two well-
known risk factors for
severity of COVID-19,
may be influencing
factors.

*Demographic data corresponding to the full sample of the research.

Reference of the table: Alzheimer's Disease (DA), Parkinson’s Disease (PD), Frontotemporal Dementia (FTD), Hazard Ratio (HR), The Charlson Comorbidity Index (CCI), Institute for Clinical Evaluative Sciences
(ICES), Body Mass Index (BMI); Hypertension (AHT), High Blood Pressure (HBP), Chronic Obstructive Pulmonary disease (COPD), Human Immunodeficiency Virus (HIV), Blood pressure (BP), Coronary Artery
Disease (CAD), Congestive heart failure (CHF), Glasgow Coma Scale (GCS), Intensive Care Unit (ICU), National Early Warning Score (NEWS), Peripheral Oxygen Saturation (pO2), Clinical Dementia Rating
(CDR), Global Deterioration Scale (GDS), Barthel Index (BI), Confusion Assessment Method (CAM), Age-standardized incidence (SIR) and mortality (SMR), Frailty Index based on the Comprehensive Geriatric
Assessment (Frail VIG), Coronavirus Clinical Characterisation Consortium (4C) mortality and Clinical Frailty Scale (CFS), Emergency Department (ED), International Classification of Diseases codes (ICD-10 and
ICD-9), Basal Activity of Daily Living (BADL), Mini-Mental State Examination (MMSE), Instrumental Activity of Daily Living ( IADL), Addenbrooke’s Cognitive Examination III (ACE-III), Frontal Assessment
Battery (FAB), Trail Making Test Part B (TMT B), Patient Health Questionnaire (PHQ), Brain magnetic resonance (MRI).
Table 2 . Study designs and quality scoring using Newcastle-
Ottawa scale for non-randomised studies in meta-analyses and

Table 2 . Study designs and quality scoring using Newcastle-Ottawa scale for non-randomised studies
in meta-analyses and classification according to AHRQ standards

Study Design Bias Rating Newcastle Ottawa AHRQ

Selection Comparability Outcome/
exposure
Merla., et al 2023 Cohort *** ** ** Good
Chen., et al 2023 Case control ** ** ** Good
Research in Context

Research in context

Systematic Review: Research from Medline, Web of Science, and Embase, following PRISMA

guidelines, reveals that although the full consequences of COVID-19 in people with dementia

are under-studied, recent studies indicate significant impacts on functional, cognitive, and

neuropsychiatric health outcomes.

Interpretation: Our systematic review suggests that dementia patients infected with SARS-

CoV-2 face increased mortality risks and more severe cognitive decline compared to

uninfected dementia patients.

Future Directions: Research must focus on the long-term cognitive impact of COVID-19 on

dementia, the role of SARS-CoV-2 variants on disease progression, and how prior vaccination

affects mortality risk in these patients

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