Sex differences in neuropsychiatric symptoms in Alzheimer’s disease dementia: a meta-analysis

Abstract

Background
Neuropsychiatric symptoms (NPS) are common in individuals with Alzheimer’s disease (AD) dementia, but substantial heterogeneity exists in the manifestation of NPS. Sex differences may explain this clinical variability. We aimed to investigate the sex differences in the prevalence and severity of NPS in AD dementia.

Methods
Literature searches were conducted in Embase, MEDLINE/PubMed, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, PsycINFO, and Google Scholar from inception to February 2021. Study selection, data extraction, and quality assessment were conducted in duplicate. Effect sizes were calculated as odds ratios (OR) for NPS prevalence and Hedges’ g for NPS severity. Data were pooled using random-effects models. Sources of heterogeneity were examined using meta-regression analyses.

Results
Sixty-two studies were eligible representing 21,554 patients (61.2% females). The majority of the included studies had an overall rating of fair quality (71.0%), with ten studies of good quality (16.1%) and eight studies of poor quality (12.9%). There was no sex difference in the presence of any NPS ( k = 4, OR = 1.35 [95% confidence interval 0.78, 2.35]) and overall NPS severity ( k = 13, g = 0.04 [− 0.04, 0.12]). Regarding specific symptoms, female sex was associated with more prevalent depressive symptoms ( k = 20, OR = 1.60 [1.28, 1.98]), psychotic symptoms (general psychosis k = 4, OR = 1.62 [1.12, 2.33]; delusions k = 12, OR = 1.56 [1.28, 1.89]), and aberrant motor behavior ( k = 6, OR = 1.47 [1.09, 1.98]). In addition, female sex was related to more severe depressive symptoms ( k = 16, g = 0.24 [0.14, 0.34]), delusions ( k = 10, g = 0.19 [0.04, 0.34]), and aberrant motor behavior ( k = 9, g = 0.17 [0.08, 0.26]), while apathy was more severe among males compared to females ( k = 11, g = − 0.10 [− 0.18, − 0.01]). There was no association between sex and the prevalence and severity of agitation, anxiety, disinhibition, eating behavior, euphoria, hallucinations, irritability, and sleep disturbances. Meta-regression analyses revealed no consistent association between the effect sizes across studies and method of NPS assessment and demographic and clinical characteristics.

Discussion
Female sex was associated with a higher prevalence and greater severity of several specific NPS, while male sex was associated with more severe apathy. While more research is needed into factors underlying these sex differences, our findings may guide tailored treatment approaches of NPS in AD dementia.

Full text

Eikelboometal.
Alzheimer’s Research & Therapy (2022) 14:48
https://doi.org/10.1186/s13195-022-00991-z
REVIEW
Sex dierences inneuropsychiatric
symptoms inAlzheimer’s disease dementia:
ameta-analysis
Willem S. Eikelboom1*†, Michel Pan1†, Rik Ossenkoppele2,3, Michiel Coesmans4, Jennifer R. Gatchel5,6,
Zahinoor Ismail7, Krista L. Lanctôt8,9, Corinne E. Fischer8,10, Moyra E. Mortby11,12, Esther van den Berg1 and
Janne M. Papma1
Abstract
Background: Neuropsychiatric symptoms (NPS) are common in individuals with Alzheimer’s disease (AD) dementia,
but substantial heterogeneity exists in the manifestation of NPS. Sex differences may explain this clinical variability. We
aimed to investigate the sex differences in the prevalence and severity of NPS in AD dementia.
Methods: Literature searches were conducted in Embase, MEDLINE/PubMed, Web of Science Core Collection,
Cochrane Central Register of Controlled Trials, PsycINFO, and Google Scholar from inception to February 2021. Study
selection, data extraction, and quality assessment were conducted in duplicate. Effect sizes were calculated as odds
ratios (OR) for NPS prevalence and Hedges’ g for NPS severity. Data were pooled using random-effects models.
Sources of heterogeneity were examined using meta-regression analyses.
Results: Sixty-two studies were eligible representing 21,554 patients (61.2% females). The majority of the included
studies had an overall rating of fair quality (71.0%), with ten studies of good quality (16.1%) and eight studies of poor
quality (12.9%). There was no sex difference in the presence of any NPS (k = 4, OR = 1.35 [95% confidence interval
0.78, 2.35]) and overall NPS severity (k = 13, g = 0.04 [− 0.04, 0.12]). Regarding specific symptoms, female sex was
associated with more prevalent depressive symptoms (k = 20, OR = 1.60 [1.28, 1.98]), psychotic symptoms (general
psychosis k = 4, OR = 1.62 [1.12, 2.33]; delusions k = 12, OR = 1.56 [1.28, 1.89]), and aberrant motor behavior (k =
6, OR = 1.47 [1.09, 1.98]). In addition, female sex was related to more severe depressive symptoms (k = 16, g = 0.24
[0.14, 0.34]), delusions (k = 10, g = 0.19 [0.04, 0.34]), and aberrant motor behavior (k = 9, g = 0.17 [0.08, 0.26]), while
apathy was more severe among males compared to females (k = 11, g = − 0.10 [− 0.18, − 0.01]). There was no asso-
ciation between sex and the prevalence and severity of agitation, anxiety, disinhibition, eating behavior, euphoria, hal-
lucinations, irritability, and sleep disturbances. Meta-regression analyses revealed no consistent association between
the effect sizes across studies and method of NPS assessment and demographic and clinical characteristics.
Discussion: Female sex was associated with a higher prevalence and greater severity of several specific NPS, while
male sex was associated with more severe apathy. While more research is needed into factors underlying these sex
differences, our findings may guide tailored treatment approaches of NPS in AD dementia.
© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
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Open Access
*Correspondence: w.eikelboom@erasmusmc.nl
†Willem S. Eikelboom and Michel Pan contributed equally to this work.
1 Department of Neurology and Alzheimer Center Erasmus MC, Erasmus
MC University Medical Center, PO Box 2040, 3000 CA Rotterdam, The
Netherlands
Full list of author information is available at the end of the article
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Eikelboometal. Alzheimer’s Research & Therapy (2022) 14:48
Background
Neuropsychiatric symptoms (NPS) are highly prevalent
in individuals with Alzheimer’s disease (AD) demen-
tia [1]. Although the majority of individuals with AD
dementia exhibit NPS during the course of their dis-
ease, there is substantial heterogeneity among individu-
als regarding the manifestation and evolution of NPS
[1, 2].
Emerging research has provided evidence for sex as
an important, yet understudied factor that may play an
important role in explaining clinical variability within
AD dementia [3]. Note that sex refers to the biologi-
cal and physiological difference between females and
males, while gender encompasses the social, environ-
mental, and cultural influences on the biological factors
in females and males [4]. Well-known sex differences in
AD dementia include the disproportionate higher prev-
alence and lifetime risk for developing AD dementia
in females compared to males [5], with previous stud-
ies showing that females are shown to be more vulner-
able to AD pathology and AD risk factors compared to
males [6–8]. Furthermore, prior research has suggested
more severe cognitive deficits and faster cognitive
decline among females with AD dementia [8–10].
Prior studies on sex differences in NPS in AD demen-
tia have reported mixed findings. While several stud-
ies have suggested that females show a greater and a
wider range of NPS [11, 12], others did not to find any
sex differences in the prevalence and severity of NPS in
AD dementia [13, 14]. When looking at specific NPS,
female sex has been related to the presence of affective
symptoms and psychotic symptoms [15, 16], whereas
apathy and agitation were more prevalent in males [16,
17]. Determining sex differences in NPS prevalence and
severity in individuals with AD has important clini-
cal implications [18]. is knowledge may not only aid
personalized assessment, but also guide interventions
for NPS in AD. Furthermore, sex differences may have
health policy and resource allocation implications for
NPS screening and management.
To date, sex differences in NPS in AD dementia have
not been systematically reviewed. erefore, we aimed
to review the existing literature on sex differences in
specific NPS in AD using a meta-analytic approach.
In addition, we examined the sources of heterogene-
ity across studies including study setting, methods
of NPS assessment, and demographic and clinical
characteristics.
Methods
is systematic review was preregistered with PROS-
PERO (CRD42020168064) and conducted conform to
the PRISMA guidelines [19].
Search strategy
In consultation with a research librarian, databases
Embase, MEDLINE/PubMed, Web of Science Core
Collection, Cochrane Central Register of Controlled
Trials, PsycINFO, and Google Scholar were searched
from inception to February 2021 (see full search queries
in Additional file1: eTable1). Studies included in the
most recent meta-analysis summarizing the prevalence
of NPS in AD dementia were also screened [20]. Refer-
ence lists of identified studies were manually checked
for potential studies of interest. Finally, experts on the
author team were consulted to ensure that no relevant
studies were missing.
Study selection
Articles were screened and selected based on the fol-
lowing criteria: (A) NPS prevalence (dichotomous data)
and/or NPS severity (continuous data) for females and
males separately. We included papers that referred to
both sex differences and gender differences. Further-
more, sex differences had to be reported for either
overall NPS burden or specific symptoms and not for
clusters of NPS due to its limited comparability. (B)
Clinical diagnosis of AD dementia based on either the
Diagnostic and Statistical Manual of Mental Disorders
(DSM) or International Classification of Diseases (ICD)
classification systems or conventional consensus cri-
teria [21, 22]. (C) NPS were assessed using a validated
instrument such as the Neuropsychiatric Inventory
(NPI) [23] or established using well-defined diagnos-
tic criteria, e.g., depression in AD [24]. (D) Studies had
to report sufficient information needed to perform a
meta-analysis (e.g., means, standard deviations, fre-
quency tables, and/or odds ratios [OR]). (E) Studies
had a cross-sectional observational design. In case of
longitudinal data, only baseline data were used. Arti-
cles containing small selectively sampled populations
were excluded, e.g., sex- and age-matched samples. In
cases in which the same cohort of patients was used in
different studies, only the study with the largest N was
selected.
Keywords: Alzheimer’s disease, Behavioral and psychological symptoms of dementia, Behavioral symptoms, Meta-
analysis, Neuropsychiatry, Sex
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Eikelboometal. Alzheimer’s Research & Therapy (2022) 14:48
Two independent reviewers (W.S.E., M.P.) screened
titles and abstracts, and subsequently inspected full
texts for eligibility. Discrepancies were discussed, and
consensus was reached (with E.v.d.B.).
Data extraction
Data of each paper was extracted in duplicate (W.S.E.,
M.P.). In cases where statistical information was miss-
ing, an attempt was made to contact the study’s principal
investigator. is was unsuccessful in two studies.
Quality assessment
Two independent reviewers (W.S.E, M.P.) evaluated the
quality of each study using an adjusted quality assess-
ment tool for observational studies from the National
Heart, Lung, and Blood Institute (Additional file1: eTa-
ble 2) [25, 26]. Originally, this tool includes 14 quality
criteria covering the methodology and study population
characteristics. Since we only included cross-sectional
studies, we did not evaluate item 7 “Was the time frame
sufficient so that one could reasonably expect to see an
association between exposure and outcome if it existed?”,
item 10 “Was the exposure(s) assessed more than once
over time?”, and item 13 “Was loss to follow-up after
baseline 20% or less?”. Furthermore, item 14 “Were key
potential confounding variables measured and adjusted
statistically for their impact on the relationship between
exposure(s) and outcome(s)?” was also omitted since
studies were not required to include covariates in their
analyses.
Data synthesis andstatistical analysis
For this meta-analysis, we studied sex differences in NPS
for studies reporting on NPS prevalence and NPS sever-
ity. We examined sex differences in studies that reported
the prevalence of any NPS, total scores of NPS measures
(e.g., NPI total score), andthe prevalence and/or sever-
ity for specific NPS analogous to the twelve NPI domains:
delusions, hallucinations, agitation/aggression, depres-
sive symptoms, anxiety, euphoria, apathy, disinhibition,
irritability, aberrant motor behavior, nighttime behaviors,
and eating behaviors [23]. In addition, psychotic symp-
toms were also studied separately since studies used cri-
teria for psychosis in AD [27], psychosis domain score
of the Behavioural Pathology in Alzheimer’s Disease
(BEHAVE-AD) Scale [28], or NPI domains of halluci-
nations and delusions combined [23]. Note that instru-
ments such as the NPI assess neuropsychiatric symptoms,
while diagnostic criteria such as psychosis in AD or DSM
diagnosis of a major depressive episode capture neu-
ropsychiatric syndromes. In our analyses, these assess-
ment methods will initially be combined and denoted as
symptoms. Next, meta-regression analyses will be used
to examine the differences in the outcomes between
studies that used questionnaires (symptoms) and studies
that used diagnostic criteria (syndromes).
For the studies that reported on NPS prevalence, ORs
were calculated based on the 2 × 2 frequency tables
based on the following formula:
OR
=
(NPS
females
/non−NPS
females
)
(
NPSmales
/
non
−
NPSmales
) . An OR = 1 represents
that there is no sex difference in NPS, whereas an OR > 1
suggests that female sex is associated with higher odds of
having NPS and an OR < 1 suggest that male sex is asso-
ciated with higher odds of having NPS. For the studies
that reported on NPS severity, means and standard devi-
ations were converted into Hedges’ g using the following
formula: g =
M
1
−M2
SD
pooled
, where SDpooled was calculated based
on the following formula:
SD
pooled =

SD2
1+SD2
2
2
. If stud-
ies did not report the means and standard deviations,
reported effect sizes were converted to Hedges’ g using
conventional formulas [29]. A positive effect size indi-
cates more severe NPS for women compared to men.
Heterogeneity was assessed with the I2 statistic and
tested using Cochran’s Q-test [30]. e I2 statistic is an
appraisal of the consistency of the effect sizes: > 25% sug-
gests low, > 50% suggests moderate, and > 75% suggests
high inconsistency across studies. In case of a significant
Q statistic and moderate or high inconsistency across
studies, we conducted outliers/influential study diagnos-
tics. Influential studies were identified if one of the fol-
lowing was true: DFFITS value > 3√(p/(k − p)) where
p is the number of model coefficients and k is the num-
ber of studies, lower tail of a chi-square distribution of p
degrees of freedom cutoff by the Cook’s distance > 50%,
hat value > 3(p/k), and/or the DFBETAS value > 1 [31]. In
case influential cases were identified, leave-1-out meta-
analyses were conducted to examine how individual stud-
ies affected the summary statics. Based on these analyses
and visual examination of the forest plots, we excluded
one study in the meta-analysis for studies reporting on
the prevalence of any NPS, one study in the meta-anal-
ysis on psychotic symptoms prevalence, one study in the
meta-analysis on irritability prevalence, one study in the
meta-analysis on agitation prevalence, and one study in
the meta-analysis on aberrant motor behavior prevalence
(see Additional file 1: eTable 8). For meta-analyses on
NPS severity, one study was identified as an outlier in the
meta-analyses on the total scores of NPS measures, agita-
tion, aberrant motor behavior, anxiety, apathy, delusions,
depressive symptoms, disinhibition, euphoria, and hallu-
cinations (see Additional file1: eTable8).
e following meta-regression and subgroup analyses
were selected a priori: study setting (community-based
vs. clinic sample), clinical relevance (neuropsychiat-
ric symptoms vs. a clinically relevant cutoff score or
clinical criteria for NPS syndrome), method of NPS
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Eikelboometal. Alzheimer’s Research & Therapy (2022) 14:48
assessment (proxy vs. self-reported), NPI vs. non-NPI
measures, mean age of patients, mean years of educa-
tion of patients, mean Mini-Mental State Examination
(MMSE) score, mean disease duration in years, per-
centage of APOE-ε4 carriers, and study quality (poor/
fair/good). In addition, we ran subgroup analyses for
studies reporting significant sex differences in age,
MMSE score, proportion APOE-ε4 carriers, and/or dis-
ease duration compared to studies that did not find sex
differences in these characteristics. We tested whether
the heterogeneity across studies was explained by these
moderators using omnibus Wald-type tests. We con-
ducted meta-regression analyses including studies that
were identified as outliers and only if a minimum of six
studies was available for continuous moderators and at
least four studies were available for each subgroup of
categorical moderators [32].
Funnel plot asymmetry was evaluated as an indication
for publication bias. Begg’s rank tests and Egger’s regres-
sion tests were used to test for funnel plot asymmetry.
If any of these tests was indicative of funnel plot asym-
metry, the trim-and-fill method was used to estimate the
number of missing studies and to recompute the sum-
mary statistics based on complete data [33].
In order to aggregate studies that reported multiple
independent outcomes, we used multilevel meta-analyses
including a random factor for study. Multilevel meta-
analyses were conducted for 18 outcomes across the 17
studies that reported the severity of depressive symp-
toms. Because substantial heterogeneity between studies
was expected, random-effects models were applied for all
analyses. All analyses were conducted using the metafor
package in R v4.0 [34].
Results
Characteristics ofincluded studies
A total of 1997 unique articles were obtained and
screened for eligibility (Fig.1). Next, the full texts of 191
records were reviewed, of which 62 met all the inclusion
criteria (Additional file1: eTable3).
e 62 studies included 21,554 individuals with AD
dementia, including 13,201 (61%) females and 8353
(39%) males. e majority of studies assessed NPS using
a proxy instrument (k = 49, 79%), of which 31 used the
NPI and four used its questionnaire form. Six studies
additionally used self-report scales (10%). In eight stud-
ies (13%), clinicians established NPS based on a DSM
diagnosis, an ICD-9 diagnosis, or criteria for depression
in AD [24], psychosis in AD [27], or apathy in AD [35].
Fig. 1 PRISMA flow diagram of the literature search. Note: created with BioRe nder. com
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Eikelboometal. Alzheimer’s Research & Therapy (2022) 14:48
Information on the characteristics of the informant
who rated NPS was reported in four studies [36–39], of
which two reported these characteristics for male and
female patients separately [37, 38]. e majority of the
informants were the spouse [36–39], which was primar-
ily the case for male patients (66–86% for male patients
and 21–38% in female patients) [37, 38]. e majority
of caregivers were female [36–39], although to a lesser
extent for female patients (90% for male patients and
61% for female patients) [37]. Clinical AD diagnoses
were supported by positive AD biomarkers in subsam-
ples of only two studies. Information on APOE-ε4 sta-
tus was reported in 13 studies, and percentage APOE-ε4
carriers ranged from 22% to 68% (Additional file 1:
eTable 3). Forty studies provided dichotomous NPS
measures, while 17 studies reported continuous NPS
measures and five studies reported both dichotomous
and continuous outcomes. is resulted in 43 studies
reporting on NPS prevalence and 22 studies reporting
on NPS severity.
Study quality
e majority of the included studies had an overall rating
of fair quality (44, 71%), with ten studies of good quality
(16%) and eight studies of poor quality (13%) (Additional
file1: eTable2).
Sex dierences inany NPS andtotal scores ofNPS
measures
ere was no sex difference in the prevalence of any NPS
(k = 4, OR = 1.35 [95% CI, 0.78, 2.35], P = 0.28), with
low heterogeneity across studies (I2 = 32.74%, Q = 4.01,
P = 0.25) (Table1 and Fig.2). We also found no relation-
ship between sex and total severity scores of NPS instru-
ments (k = 13, g = 0.04 [− 0.04, 0.12], P = 0.31), with low
heterogeneity across studies (I2 = 0.00%, Q = 7.54, P =
0.82) (Table2 and Fig.2).
Sex dierences intheprevalence ofspecic NPS
We observed a higher prevalence among females com-
pared to males for psychotic symptoms (k = 4, OR = 1.62
[1.12,2.33], P = 0.01), depressive symptoms (k = 20, OR
= 1.60 [1.28, 1.98], P < 0.001), delusions (k = 12, OR =
1.56 [1.28, 1.89], P < 0.001), and aberrant motor behavior
(k = 6, OR = 1.47 [1.09, 1.98], P = 0.01) (Fig.3). e het-
erogeneity across the studies included in these meta-anal-
yses was moderate for depressive symptoms (I2 = 58.19%,
Q = 51.99, P < 0.001), but low for the meta-analyses on
psychotic symptoms (I2 = 0.00%, Q = 1.98, P = 0.58),
delusions (I2 = 0.00%, Q = 8.51, P = 0.67), and aberrant
motor behavior (I2 = 0.00%, Q = 2.51, P = 0.78). ere
were no significant sex differences in the prevalence of the
remaining NPS (Table1 and Additional file1: eFigure1).
Sex dierences intheseverity ofspecic NPS
e results showed that female sex was associated with
more severe depressive symptoms (k = 16, g = 0.24
[0.14, 0.34], P < 0.001), delusions (k = 10, g = 0.19 [0.04,
0.43], P = 0.01), and aberrant motor behavior (k = 9,
g = 0.17 [0.08, 0.26], P < 0.001). Furthermore, apathy
was more severe among males compared to females (k
= 11, g = − 0.10 [− 0.18, − 0.01], P = 0.02) (Fig.4). We
Table 1 Sex differences in the prevalence of neuropsychiatric symptoms in Alzheimer’s disease dementia
Abbreviations: k number of studies, NPS neuropsychiatric symptoms
a OR odds ratio. OR = 1 no sex dierences; OR > 1 female sex associated with NPS; OR < 1 male sex associated with NPS
NPS kOR [95% CI]az statistic P Q statistic P Q statistic I2 statistic
Any NPS present (outlier excluded) 4 1.35 [0.78, 2.35] 1.07 0.28 4.01 0.25 32.74
Psychotic symptoms (outlier excluded) 4 1.62 [1.12, 2.33] 2.56 0.01 1.98 0.58 0.00
Depressive symptoms 20 1.60 [1.28, 1.98] 4.20 < 0.001 51.99 < 0.001 58.19
Delusions 12 1.56 [1.28, 1.89] 4.45 < 0.001 8.51 0.67 0.00
Aberrant motor behavior (outlier excluded) 6 1.47 [1.09, 1.98] 2.53 0.01 2.51 0.78 0.00
Anxiety 8 1.42 [0.74, 2.71] 1.05 0.29 23.37 0.00 78.49
Eating behavior 5 1.31 [0.97, 1.76] 1.78 0.08 5.40 0.25 22.00
Disinhibition 8 1.17 [0.80, 1.70] 0.81 0.42 13.54 0.06 42.07
Irritability (outlier excluded) 5 1.14 [0.83, 1.56] 0.80 0.43 6.11 0.19 0.00
Hallucinations 9 1.03 [0.79, 1.35] 0.24 0.81 9.89 0.27 14.23
Agitation (outlier excluded) 10 1.00 [0.75, 1.35] 0.01 0.99 16.63 0.06 46.06
Euphoria 6 0.98 [0.57, 1.68] − 0.08 0.93 6.56 0.26 14.77
Apathy 12 0.92 [0.73, 1.17] − 0.65 0.51 17.66 0.09 36.92
Sleep disturbances 8 0.86 [0.63, 1.16] − 0.99 0.32 14.49 0.04 62.49
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Eikelboometal. Alzheimer’s Research & Therapy (2022) 14:48
found moderate heterogeneity across studies includ-
ing in the meta-analyses on delusions (I2 = 58.78%,
Q = 19.99, P = 0.02) and depressive symptoms (I2 =
44.29%, Q = 30.15, P = 0.02), while heterogeneity was
low for aberrant motor behavior (I2 = 0.00%, Q = 3.25,
P = 0.92) and apathy (I2 = 0.00%, Q = 5.00, P = 0.89).
ere were no significant sex differences in the sever-
ity of the remaining NPS (Table2 and Additional file1:
eFigure2).
Meta‑regression analyses
We did not find any consistent association between effect
sizes across studies and clinical relevance (symptoms vs.
syndromes), NPI vs. non-NPI measures, years of educa-
tion, MMSE score, proportion APOE-ε4 carriers, and
study quality (poor/fair/good) (Additional file1: eTable4
and eTable5). Meta-regression analysis was not possible
for study setting (community vs. clinic-based samples)
because there was a paucity of studies with community
Fig. 2 Forest plots for the prevalence of any NPS and severity of NPS total scores. Abbreviations: AD, Alzheimer’s disease; NPS, neuropsychiatric
symptoms
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Eikelboometal. Alzheimer’s Research & Therapy (2022) 14:48
Table 2 Sex differences in the severity of neuropsychiatric symptoms in Alzheimer’s disease dementia
Abbreviations: k number of studies, NPS neuropsychiatric symptoms
a Hedges’ g = 0 no sex dierences; Hedges’ g > 0 female sex associated with NPS; Hedges’ g < 0 male sex associated with NPS
NPS kHedges’ g [95% CI]az statistic P Q statistic P Q statistic I2 statistic
Total score NPS measure (outlier excluded) 13 0.04 [− 0.04, 0.12] 1.03 0.31 7.54 0.82 0.00
Depressive symptoms (outlier excluded) 16 0.24 [0.14, 0.34] 4.59 < 0.001 30.15 0.02 44.29
Delusions (outlier excluded) 10 0.19 [0.04, 0.34] 2.53 0.01 19.99 0.02 58.78
Aberrant motor behavior (outlier excluded) 9 0.17 [0.08, 0.26] 3.56 < 0.001 3.25 0.92 0.00
Anxiety (outlier excluded) 10 0.11 [0.00, 0.22] 1.98 0.05 13.27 0.01 25.15
Sleep disturbances 6 0.11 [− 0.02, 0.24] 1.62 0.11 5.66 0.34 21.77
Disinhibition (outlier excluded) 10 0.08 [− 0.05, 0.21] 1.16 0.25 17.01 0.05 46.48
Eating behavior 6 0.07 [− 0.04, 0.18] 1.28 0.20 3.23 0.67 0.00
Hallucinations (outlier excluded) 10 0.07 [− 0.13, 0.26] 0.65 0.51 36.63 < 0.001 77.20
Agitation (outlier excluded) 11 0.01 [− 0.07, 0.10] 0.26 0.79 12.53 0.25 3.12
Irritability 11 0.00 [− 0.08, 0.07] − 0.10 0.92 14.91 0.14 0.00
Euphoria (outlier excluded) 10 0.00 [− 0.10, 0.10] − 0.04 0.97 8.10 0.52 14.55
Apathy (outlier excluded) 11 − 0.10 [− 0.18, − 0.01] − 2.25 0.02 5.00 0.89 0.00
Fig. 3 Forest plots for the prevalence of specific neuropsychiatric symptoms. Abbreviations: AD, Alzheimer’s disease
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

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Eikelboometal. Alzheimer’s Research & Therapy (2022) 14:48
samples available, and meta-regression for method of
NPS assessment (proxy vs. self-report) was only possible
for depressive symptoms but showed no difference.
Due to insufficient data, we were not able to compare
the effect sizes on NPS prevalence of studies reporting
significant sex differences in demographic or clinical
characteristics with studies that did not. For all studies
combined reporting on NPS severity, we found compa-
rable effect sizes when comparing studies that reported
significantly lower MMSE scores for females compared
to males (k = 5, g = 0.39 [− 0.19, 0.97]) with studies
that reported no sex differences in MMSE scores (k =
10, g = 0.38 [− 0.14, 0.89], QM = 0.00, P = 0.97). Of
the 20 studies that tested the sex differences in age, only
two reported older age among females and one study
reported younger age in females compared to males.
Nine studies tested the sex differences in APOE status,
and three found a higher percentage of APOE-ε4 carri-
ers among females. All five studies that compared dis-
ease duration between females and males found no sex
difference.
Publication bias
Begg’s rank test and Egger’s regression test indicated fun-
nel plot asymmetry for the meta-analysis on the preva-
lence of depressive symptoms and the prevalence of
agitation (Additional file1: eTable6) (Additional file 1:
eFigure3). However, publication bias was considered less
likely as similar estimates were obtained when adjusting
for potential publication bias using trim-and-fill method
(Additional file1: eTable7). We found no indication of
publication bias for the remaining meta-analyses (Figs.5
and 6, Additional file1: eFigure4).
Fig. 4 Forest plots for the severity of specific neuropsychiatric symptoms. Abbreviations: AD, Alzheimer’s disease
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

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Eikelboometal. Alzheimer’s Research & Therapy (2022) 14:48
Discussion
Our meta-analysis suggests that female sex is associated
with a higher prevalence and greater severity of depres-
sive symptoms, aberrant motor behavior, and psychotic
symptoms in AD dementia, while male sex is related to
increased severity of apathy in AD dementia. ese asso-
ciations were robust and generally not affected by char-
acteristics relating to the study sample or the method of
NPS measurement.
With this meta-analysis, we provide further evidence
for greater NPS burden in females with AD dementia
found in prior studies [11, 12, 15, 16] and increased sever-
ity of apathy among males with AD dementia [16]. How-
ever, we found no evidence for higher prevalence rates
of agitation/aggression in males that have been reported
previously [17]. Sex differences in affective symptoms in
AD dementia are in line with higher prevalence rates of
lifetime anxiety and mood disorders among females in
the general population [40]. Studies on sex differences in
psychotic symptoms in the general population have gen-
erally shown higher prevalence rates among males [41],
which is in contrast to the findings of our meta-analysis
in AD dementia. e sex differences observed in this
meta-analysis may be explained in part by a prior history
of psychiatric illness, although we were not able to verify
this as the included studies did not report lifetime history
of psychiatric illnesses. Yet, emergent psychiatric symp-
toms are common symptoms in AD [1, 20] and cannot be
fully explained by prior psychiatric disorders but are also
related to neurobiological and psychosocial factors asso-
ciated with AD.
Sex differences in genetics and neurodegenerative and
pathophysiologic processes related to AD may partly
explain the observed associations, as previous studies
Fig. 5 Funnel plots for the prevalence of neuropsychiatric symptoms. Abbreviations: AMB, aberrant motor behavior; NPS, neuropsychiatric
symptoms
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Page 10 of 13
Eikelboometal. Alzheimer’s Research & Therapy (2022) 14:48
have indicated greater amyloid-β burden, tau pathology,
and loss of brain volume in females compared to males
[6–8]. In addition, sex differences in APOE status may
also contribute to the differences found in NPS. However,
prior studies have reported inconsistent associations
between NPS and AD-related biomarkers and APOE ε4
carriership (e.g., [42, 43]), suggesting that neurobiological
factors alone cannot explain these sex differences. Several
other biological and medical factors including sex hor-
mones and cardiovascular disease have been related to
sex differences in the risk for AD dementia and its clini-
cal manifestation (e.g., [44, 45]). Whether and how these
factors may play a role in sex differences in NPS in AD
dementiawarrants further investigation.
Sex differences in NPS may also be explained by the
differences in other clinical and demographic character-
istics in AD dementia [10, 18]. For example, females may
exhibit more NPS as prior studies suggested that females
may be diagnosed later in the disease process potentially
leading to more symptoms at diagnosis [46]. Included
samples in our study did not reveal sex differences in
disease duration and we found comparable results when
accounting for the sex differences in MMSE. Although
a few studies have shown that associations between sex
and NPS were independent of characteristics such as age,
education level, cognitive functioning, and ethnicity (e.g.,
[11, 15]), more studies are needed to examine how sex
differences in the clinical and demographic characteris-
tics contribute to sex differences in NPS in AD dementia.
Moreover, as NPS were most often assessed using proxy
instruments, it would also be interesting to compare
informant characteristics for female and male patients.
However, only two of the 62 included studies reported
these characteristics for female and male patients sepa-
rately making it impossible to examine whether inform-
ant characteristics affected our findings.
Fig. 6 Funnel plots for the severity of neuropsychiatric symptoms. Abbreviations: AMB, aberrant motor behavior; NPS, neuropsychiatric symptoms
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 11 of 13
Eikelboometal. Alzheimer’s Research & Therapy (2022) 14:48
e findings of this study may have important impli-
cations. First, our findings suggest that sex is a differen-
tial factor explaining interindividual differences in the
prevalence and severity of specific NPS. ese findings
may guide the early detection of specific NPS in AD
dementia. Second, our results may provide a starting
point in informing underlying mechanisms of NPS in
AD dementia. More research is needed to study why
females with AD are more prone to exhibit significant
depressive symptoms, aberrant motor behavior, and
psychotic symptoms, and why males are more prone
to display severe apathy. Potentially, this research may
provide insight into the sex-related differences in neu-
robiological mechanisms, medical conditions, and
cultural factors including gender roles underlying the
interindividual differences in the manifestation of NPS
in AD dementia. In addition, both pharmacological
and psychosocial treatment approaches for NPS in AD
dementia are currently identical for females and males.
Determining if the sex differences we observed in NPS
are subserved by different underlying neurobiological
and/or psychosocial mechanisms is critical to personal-
ize treatment. If differences do exist, they could inform
sex-specific pharmacological and non-pharmacological
intervention that target NPS in AD dementia [47, 48].
is study has some limitations. First, we used meta-
regression analyses in order to investigate sources of
heterogeneity across studies. Although this approach
is commonly used, meta-regression analyses should be
interpreted with caution as these analyses may have low
power and are prone to ecological bias, i.e., a relation-
ship found at the sample level may not represent the
individual level [49]. Second, in case of substantial het-
erogeneity across studies, we decided to exclude outli-
ers or otherwise influential studies, i.e., based on low
number of participants or disproportionate males to
females ratio (Additional file1: eTable8 and eTable9)
[50]. Although most researchers emphasize the impor-
tance of examining the potential outliers and influential
studies when confronted with substantial heterogeneity
across studies, outlier diagnostics remain under debate
in the context of meta-analyses [30]. ird, the major-
ity of the included samples were derived from memory
clinics and day care centers, while nursing home pop-
ulations were not available. Fourth, only two studies
supported AD dementia diagnoses with AD biomark-
ers, whereas the remaining studies used solely a clini-
cal diagnosis of AD dementia and thereby increasing
the likelihood of including other etiologies than AD.
Finally, the majority of the included studies primarily
established NPS based on proxy-based instruments. To
further support our findings, future studies are needed
in which AD diagnoses are validated by AD biomarkers
and the presence of NPS are based on updated diagnos-
tic criteria [51–53]. Finally, it remains unclear whether
the associations between sex and NPS in AD dementia
change during the course of the disease as we investi-
gated these relationships using cross-sectional data.
Future longitudinal studies are needed to provide more
insight into the effects of sex on NPS over the course of
AD dementia.
Conclusion
In AD dementia, female sex is associated with greater
prevalence and severity of depressive symptoms, psy-
chotic symptoms, and aberrant motor behavior, while
males exhibit more severe apathy compared to females.
While more research is needed to identify factors
underlying the sex differences in NPS in AD dementia,
these findings may guide tailored treatment approaches
of NPS in AD dementia.
Abbreviations
AD: Alzheimer’s disease; BEHAVE-AD: Behavioural pathology in Alzheimer’s
disease; DSM: Diagnostic and Statistical Manual of Mental Disorders; ICD: Inter-
national Classification of Diseases; MMSE: Mini-Mental State Examination; NPI:
Neuropsychiatric Inventory; NPS: Neuropsychiatric symptoms; OR: Odds ratio.
Supplementary Information
The online version contains supplementary material available at https:// doi.
org/ 10. 1186/ s13195- 022- 00991-z.
Additional le1: eTable1. Search strategy literature search. eTable2.
Study quality assessment. eTable3. Characteristics of included studies.
eTable4. Meta-regression analyses prevalence specific NPS. eTable5.
Meta-regression analyses severity specific NPS. eTable6. Publication bias
measures for all meta-analyses. eTable7. Duval and Tweedie’s trim-and-
fill method to adjust for publication bias. eTable8. Sex differences in
the prevalence NPS for meta-analyses that excluded outliers. eTable9.
Sex differences in the severity of NPS for meta-analyses that excluded
outliers. eFigure1. Forest plots for meta-analyses prevalence specific NPS.
eFigure2. Forest plots for meta-analyses severity specific NPS. eFigure3.
Funnel plots for meta-analyses prevalence specific NPS. eFigure4. Funnel
plots for meta-analyses severity specific NPS.
Acknowledgements
The authors wish to thank Dr. Sabrina Meertens-Gunput and Dr. Wichor Bramer from
the Erasmus MC Medical Library for developing and updating the literature search.
Authors’ contributions
WSE, MP, RO, EvdB, and JMP designed the study in consultation with MC, JRG,
ZI, KLL, CEF, and MEM. WSE and MP conducted the literature search, study
selection, and data extraction. WSE analyzed the data and interpreted the
data assisted by MP, RO, EvdB, and JMP. WSE and MP drafted the first version of
the manuscript, while RO, MC, JRG, ZI, KLL, CEF, MEM, EvdB, and JMP critically
reviewed the manuscript. JMP and EvdB supervised the study. JMP and RO
acquired funding for this study. All authors read and approved the final version
of the manuscript.
Funding
This project was supported by an Alzheimer Nederland and Memorabel
ZonMw Grant 733050823 (Deltaplan Dementie) to JMP and RO. The funders
had no role in the study design, data collection and analysis, decision to
publish, or preparation of the manuscript.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 12 of 13
Eikelboometal. Alzheimer’s Research & Therapy (2022) 14:48
Availability of data and materials
The datasets supporting the conclusions of this article are available upon
reasonable request.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1 Department of Neurology and Alzheimer Center Erasmus MC, Erasmus MC
University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Nether-
lands. 2 Department of Neurology, Alzheimer Center Amsterdam, Amsterdam
University Medical Centers, PO Box 7057, 1007 MB Amsterdam, The Nether-
lands. 3 Clinical Memory Research Unit, Lund University, Simrisbanvägen 14,
212 24 Malmö, Sweden. 4 Department of Psychiatry, Erasmus MC University
Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands. 5 Division
of Geriatric Psychiatry, McLean Hospital, Harvard Medical School, 115 Mill St.,
Belmont, MA 02478, USA. 6 Department of Psychiatry, Massachusetts General
Hospital, Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA.
7 Departments of Psychiatry, Clinical Neurosciences, and Community Health
Sciences, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Dr. NW,
Calgary, AB T2N 4N1, Canada. 8 Department of Psychiatry, University of Toronto,
Toronto, ON M5S 1A1, Canada. 9 Hurvitz Brain Sciences Research, Sunnybrook
Health Sciences Centre, Toronto, ON M4N 3M5, Canada. 10 Keenan Research
Centre for Biomedical Science, St. Michael’s Hospital, 36 Queen St. E, Toronto,
ON M5B 1W8, Canada. 11 School of Psychology, University of New South Wales,
Sydney, NSW 2052, Australia. 12 Neuroscience Research Australia, Sydney, NSW
2031, Australia.
Received: 19 January 2022 Accepted: 17 March 2022
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