Neuroscience and Biobehavioral Reviews 130 (2021) 301–313

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Review article

Relationship between Central Obesity and the incidence of Cognitive

Impairment and Dementia from Cohort Studies Involving
5,060,687 Participants
Xingyao Tang a, Wei Zhao b, Ming Lu c, Xin Zhang c, Ping Zhang c, Zhong Xin c, Ran Sun c,
Wei Tian a, Marly Augusto Cardoso d, Jinkui Yang c, Rafael Simó e, f, Jian-Bo Zhou c, *, Coen D.
A. Stehouwer g
a
Beijing Tongren Hospital, Capital Medical University, Beijing, China
b
Department of Geriatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, China
c
Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
d
Department of Nutrition, School of Public Health, University of Sao Paulo, Sao Paulo, Brazil
e
Endocrinology and Nutrition Department, Hospital Universitari Vall d’Hebron. Diabetes and Metabolism Research Unit, Vall d’Hebron Institut de Recerca (VHIR),
Universitat Autònoma de Barcelona, Passeig de la Vall d’Hebron, 119, 08035, Barcelona, Spain
f
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
g
Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, the Netherlands

A R T I C L E I N F O A B S T R A C T

Keywords: Central obesity, measured by the waist circumference (WC) or waist-to-hip ratio, has been linked with metabolic
Central obesity dysfunction and structural abnormalities in the brain, two risk factors for cognitive impairment and dementia.
Cognitive impairment The current analysis was performed to understand the influence of central obesity on the incidence of cognitive
Dementia
impairment and dementia. It included 21 studies involving 5,060,687 participants and showed that a high WC
was associated with a greater risk of cognitive impairment and dementia (HR = 1.10, 95 % CI: 1.05–1.15),
compared with a low WC. Sub-group analysis showed that a high WC increased the likelihood of developing
cognitive impairment and dementia in individuals older than 65 years of age (HR = 1.13, 95 % CI: 1.08–1.19),
whereas no association was observed in individuals younger than 65 years of age (HR = 1.04, 95 % CI:
0.93–1.16). Furthermore, dose-response meta-analysis confirmed that a high WC was a risk factor for cognitive
impairment and dementia. In conclusion, central obesity, as measured by WC, was associated with a risk of
cognitive impairment and dementia.

1. Introduction circumference (WC), or waist-to-hip ratio (WHR), has been shown to

Cognitive impairment and dementia have become a social burden,
particularly in today’s aging population (Brookmeyer et al., 2011),
therefore, identifying risk factors and developing effective preventive
interventions is vital. Globally, approximately 46.8 million people have
been diagnosed with dementia, and the number is predicted to reach
74.7 million by 2030 and 131.5 million by 2050 (Prince et al., 2015).
There is evidence that risk factor modification can prevent 30–35 % of
the incidence of dementia (Norton et al., 2014).
Obesity, measured using the body mass index (BMI), waist
impact dementia (Cho et al., 2019; Singh-Manoux et al., 2018). BMI
represents a standard of the obesity status of the whole body, whereas
WC and WHR represent visceral obesity (Ambikairajah et al., 2020). A
previous meta-analysis, comprising 29 longitudinal cohort studies
involving 20,083 individuals, found that high BMI at mid-life increased
the risk of dementia, whereas high BMI later in life was associated with
decreased risk of dementia (Qu et al., 2020). However, individuals with
normal BMI could also have central obesity. Specific fat components are
associated with distinct metabolic profiles (Carr et al., 2004), and may
have different impacts on cognitive impairment and dementia. The

* Corresponding author at: Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, No1. Dongjiaomingxiang, Dongcheng District,
Beijing, 100730, China.
E-mail address: jbzhou@ccmu.edu.cn (J.-B. Zhou).

https://doi.org/10.1016/j.neubiorev.2021.08.028
Received 2 December 2020; Received in revised form 24 August 2021; Accepted 26 August 2021
Available online 28 August 2021
0149-7634/© 2021 Elsevier Ltd. All rights reserved.
X. Tang et al.
influence of central obesity on cognitive impairment and dementia is
controversial (West and Haan, 2009; Power et al., 2011), and more
convincing evidence is needed.
We previously found that central obesity had a more significant
impact on structural abnormalities in the brain than general obesity.
Given that structural abnormalities in the brain are closely linked with
cognitive impairment and dementia (O’brien et al., 2020), it is necessary
to clarify the relationship between central obesity and the incidence of
cognitive impairment and dementia. The current analysis aimed to
investigate the impact of central obesity, as measured by WC or WHR, on
the risk of cognitive impairment and dementia in prospective cohort
studies.
2. Methods:
2.1. Study inclusion
We searched PubMed, Embase, Web of Science, and Cochrane da­
tabases for relevant studies published up to 3rd June 2021. To study the
association between central obesity and dementia, we used both waist
circumference and waist-to-hip ratio as measures of central obesity, and
several types of cognitive impairment and dementia, including Alz­
heimer’s disease, and vascular dementia. Reference lists of eligible ar­
ticles were further searched for pertinent articles. Screening was
conducted independently by two reviewers (JBZ, XYT), and any dis­
crepancies were resolved through discussion. This analysis was con­
ducted according to the Preferred Reporting Items for Systematic
Reviews and Meta-Analysis Moher et al. (2010), and was not
pre-registered.
2.2. Inclusion and exclusion criteria
Studies were included if they met the following criteria: (1) original
article published in English, (2) longitudinal study design with more
than 1 year follow-up, measuring the association between baseline WC
and WHR and the incidence of cognitive impairment and dementia over
time, (3) WC measured at the umbilicus level at mid-respiration with the
participant standing erect, and WHR measured at the widest point
around the left and right greater trochanters, (4) clear dementia diag­
nosis, based on the Diagnostic and Statistical Manual of Mental Disor­
ders, Third and Fourth Edition, criteria (DSM-III and DSM-IV), National
Institute of Neurological and Communicative Disorders and Stroke­
–Alzheimer’s Disease and Related Disorders Association criteria
(NINCDS-ADRDA), the International Statistical Classification of Diseases
and Related Health Problems, 10th revision (ICD-10) criteria, and the
Mini Mental State Examination (MMSE) score, (5) included participants
who were over 18 years old, and (6) used hazard ratio (HR) of cox
proportional hazards model to measure the relationship, with the lowest
WC/WHR group set as the reference. Studies were excluded if they (1)
were reviews, case reports, studies on animals, or letters to the editors,
(2) did not clearly define clinical outcomes, (3) did not provide valid
data meeting the inclusion criteria, and (4) were duplicate studies.
For the meta-analysis, studies that measured the risk of cognitive
impairment and incidence of dementia in different WC or WHR groups
using HR and that set the lowest WC or WHR group as the reference were
included. In the dose-response analysis, studies with at least three cat­
egories of WC and WHR, and the number of cognitive impairment and
dementia cases presented based on the different categories of WC and
WHR were included. WC cut-off values greater than 102 cm in men and
88 cm in women were taken as the high cut-off value group, and WC cut-
off values less than 102 cm in men and 88 cm in women were taken as
the low cut-off values group.
2.3. Data extraction and quality assessment
Two investigators (JBZ, XYT) independently extracted relevant data
302
Neuroscience and Biobehavioral Reviews 130 (2021) 301–313
from 21 studies using similar standards, of study quality, population
characteristics, follow-up years, cognitive impairment, and dementia, as
well as measures of WC and WHR. Two different investigators (XYT,
CDA) independently used the Newcastle–Ottawa Quality Assessment
Scale criteria (NOS) (Stang, 2010) to assess the risk of bias in the studies
included. We rated the quality of the studies by awarding stars in each
domain following the guidelines of the Newcastle–Ottawa Scale. If there
was a disagreement, the investigators discussed the study with the other
authors to arrive at a consensus.
2.4. Statistical analysis
We used STATA version 12.0 (Stata Corporation, College Station, TX,
USA) to conduct the analysis. Heterogeneity between studies was eval­
uated by I2 metric and the variance between studies was evaluated using
Tau2. The random-effects model was used to measure the true effect,
which could vary from study to study. In the current analysis, random-
effects models were uesed to analyze association between WC and WHR
and the risk of cognitive impairment and dementia. Random effects
models give greater weight to smaller studies and typically have wider
confidence intervals (CIs) because the total effect is the average value of
the real effect of each study, which not only focuses on studies with large
sample sizes, but also accounts for all included studies to balance the
effect of each study. HRs were pooled across all studies and used as a
measure of association between the factors. HRs and their 95 % CI were
used to assess time-to-event outcomes in the cohort studies. Where
studies included both unadjusted and covariate-adjusted hazard ratios,
we chose the latter. Covariate adjustments included age, sex, education,
ethnicity, BMI, study center, apolipoprotein E-ε4 status, alcohol con­
sumption, smoking, exercise status, systolic blood pressure, fasting
blood glucose (FBG), and levels of triglycerides, cholesterol, high-
density lipoprotein cholesterol (HDL-C), low-density lipoprotein
cholesterol (LDL-C), aspartate aminotransferase (AST), and alanine
aminotransferase (ALT) in the serum, as well as economic status, inci­
dence of stroke, history of diabetes, hypertension, and cardiovascular
disease (CVD), Geriatric Depression Scale score, medication use, and
Charlson Comorbidity Index (CCI). Subgroup and sensitivity analyses
were conducted to identify potential sources of heterogeneity.
In the dose-response meta-analysis, we used the midpoint data for
each category (Crippa and Orsini, 2016), the incidence of cognitive
impairment and dementia, and the total number of participants. For the
open-ended upper interval, the value arbitrarily assigned was 1.5 times
that of the value at the low end of the interval. The aggregate general­
ized least squares; the trend (GLST) method from Greenland and Long­
necker (1992) was used to assess the dose-response relationship between
WC and WHR and the risk of cognitive impairment and dementia. We
used restricted cubic splines with three knots to explore a potential
non-linear association between WC or WHR levels and the risk of
cognitive impairment and dementia.
Potential publication bias was evaluated using Egger’s asymmetry
test (Egger et al., 1997) and visual inspection of a funnel plot.
Two-tailedtests were computed andp < 0.05 was considered statistically
significant.
3. Results
3.1. Literature search outcomes and validity assessment
We identified 1175 potentially relevant records, including 418 du­
plicates which were excluded from the study. The titles and abstracts of
the remaining 757 studies were screened. Subsequently, 599 publica­
tions were excluded, as they were reviews, letters, conference abstracts,
or unrelated studies, leaving 158 articles which were eligible for full-text
review. 129 of these studies were excluded because they were either
animal studies, did not provide data, or their data did not meet the in­
clusion criteria. A further eight studies were excluded because of a lack
X. Tang et al.
of appropriate data leaving 21 longitudinal studies (Cho et al., 2019;
Singh-Manoux et al., 2018; West and Haan, 2009; Power et al., 2011;
Gustafson et al., 2009; Beydoun et al., 2008; Luchsinger et al., 2012;
Zhang et al., 2017; Albala et al., 2016; Luchsinger et al., 2007; Muller
et al., 2007; Raffaitin et al., 2009; Ng et al., 2016; Solfrizzi et al., 2010;
Reitz et al., 2010; Liao et al., 2018; Bancks et al., 2021; Forti et al., 2010;
Lee et al., 2020a; Ma et al., 2020; Wu and Chen, 2021) involving 5,060,
687 participants which were included in the analysis (Fig. 1). Table 1
gives an overview of the 21 eligible studies.
3.2. Quality assessment
The included studies were of generally high quality (STable 1), with
quality assessment scores of 6–9 on the NOS evaluation tool. Of these,
one study(Albala et al., 2016) had a score of 6, five studies (Singh-Ma­
noux et al., 2018; Zhang et al., 2017; Raffaitin et al., 2009; Reitz et al.,
2010; Forti et al., 2010) had a score of 7, seven studies (West and Haan,
2009; Luchsinger et al., 2007; Muller et al., 2007; Ng et al., 2016; Sol­
frizzi et al., 2010; Bancks et al., 2021; Lee et al., 2020a) had a score of 8
and eight studies (Cho et al., 2019; Power et al., 2011; Gustafson et al.,
2009; Beydoun et al., 2008; Luchsinger et al., 2012; Liao et al., 2018; Ma
Fig. 1. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) study.
303
Neuroscience and Biobehavioral Reviews 130 (2021) 301–313
et al., 2020; Wu and Chen, 2021) had a score of 9.
3.3. Meta-analysis of the association between WC and the risk of
cognitive impairment and dementia
Nineteen studies (Cho et al., 2019; Singh-Manoux et al., 2018; West
and Haan, 2009; Power et al., 2011; Gustafson et al., 2009; Beydoun
et al., 2008; Luchsinger et al., 2012; Zhang et al., 2017; Albala et al.,
2016; Luchsinger et al., 2007; Muller et al., 2007; Raffaitin et al., 2009;
Ng et al., 2016; Solfrizzi et al., 2010; Bancks et al., 2021; Forti et al.,
2010; Lee et al., 2020a; Ma et al., 2020; Wu and Chen, 2021) involving
5,052,805 participants provided data on the association between WC
and the risk of cognitive impairment and dementia. Data are included in
STable 2. A total of 46 sets of data from the 19 studies measured WC as a
categorical variable using a random effects model. The pooled HR of the
association between high WC and the risk of cognitive impairment and
dementia was 1.10 (95 % CI: 1.05–1.15) compared with low WC,
although different studies had different cut-off values.
We conducted several subgroup analyses to better understand the
influence of central obesity on cognitive impairment and dementia.
Among people who were over 65 years of age, those with high WC had
 X. Tang et al.
Table 1
Characteristics of studies included.
study year country study cohort sample/n age/ women follow- cognitive impairment or waist circumstance (WC)/waist-to-hip ratio NOS covariate
mean ± (%) up dementia (WHR)
SD or time
range

Luchsinger 2007 United a longitudinal 907 77 (5.7) 69.90 % 5.1 The dementia diagnosis was The WC was used as continuous variables 8 age, sex, years of education, ethnic
States study by random years based on Diagnostic and and categorized by quartiles. group, and apolipoprotein E-ε4
sampling of Statistical Manual ofMental status
Medicare recipients Disorders, Fourth Edition,
65 years or older criteria, and required evidence
of cognitive deficit and
evidence of impairment in
social or occupational function
(Clinical Dementia Rating
Scale score of ≥1).
Muller 2007 United a multiethnic 2476 76.8 67.11 % 4.4 Dementia diagnosis was based Waist circumference of more than 94 cm for 8 age (timescale), sex, education,
States elderly cohort in (6.5) years on DSM-IV criteria and men or more than 80 cm for women. ethnic group, APOE allele,
the United States required evidence of cognitive smoking, cohort
deficit on neuropsychological
testing and evidence of social
or occupational function
impairment.
Beydoun 2008 United the Baltimore 3005 52.1 39.90 % 7.98 Diagnoses of dementia and Predicted values for waist circumference 7 education (years), ethnicity (non-
States Longitudinal Study (17.7) years dementia type were formulated were categorized into quintiles. Hispanic black vs. other), and
of Aging during multidisciplinary smoking status (former or current
evaluations based on smoker vs. nonsmoker)
prospectively collected
304

evidence using National

Institute of Neurological and
Communicative Disorders and
Stroke–Alzheimer’s Disease
and Related Disorders
Association criteria.
Gustafson 2009 Sweden the Prospective 1462 38− 60 100% 32 Dementia was diagnosed Central adiposity was defined as a waist 9 age, serum triglycerides, serum
Population Study of years according to DSM-III-R criteria. circumference ≥88 cm or a WHR > 0.80. cholesterol, systolic blood pressure,
Women age at menopause, education, and
diabetes
Raffaittin 2009 France the French Three- 7087 73.4 61.00 % 4 years All suspected dementia cases Large waist circumference (>88 cm in 8 age, sex, educational level, and city
City (3C) cohort. (4.9) were analyzed by a common women and >102 cm in men) center

Neuroscience and Biobehavioral Reviews 130 (2021) 301–313

independent committee of
neurologists according to the
criteria of the DSM-IV.
West 2009 United the Sacramento 1351 69.9 not 5.6 Dementia was diagnosed using Waist circumference tertiles for women 9 age, sex, education, body mass
States Area Latino Study (6.6) known years Diagnostic and Statistical were 43.3–88.9, 91.44–101.6, and index category, and height
on Aging (SALSA) Manual of Mental Disorders 104.14–142.24 cm, and for men, 40–88.9,
3rd edition and National 91.4–101.6, and 102–147.32 cm.
Institute of Neurologic
Disorders and Stroke-AD and
Related Disorders Association
criteria.
Forti 2010 Italy the Conselice Study 749 73.3 53.36 % 3.9 Dementia was diagnosed using Waist circumference (>88 cm in men, >102 7 age, sex, education, apolipoprotein
of Brain Ageing (6.1) (0.8) Diagnostic and Statistical cm in women) E e4 carrier status, sedentary
(CSBA) years Manual of Mental Disorders 4th lifestyle, cardiovascular disease,
edition. AD was diagnosed history of stroke,
using National Institute of hyperhomocysteinemia,
Neurologic Disorders and
(continued on next page)
 X. Tang et al.
Table 1 (continued )
study year country study cohort sample/n age/ women follow- cognitive impairment or waist circumstance (WC)/waist-to-hip ratio NOS covariate
mean ± (%) up dementia (WHR)
SD or time
range

Stroke-AD and Related inflammation status, and all of the

Disorders Association criteria. other criteria
VD was diagnosed using
National Institute of
Neurologic Disorders and
Stroke and Association
Internationale pur la
Recherche et I’Enseignement
en Neurosciences.
Reitz 2010 United a community- 1051 75.66 66.20 % 4.0 Dementia was diagnosed by Waist to hip ratio (WHR) was calculated as 6 age, sex, education, and ethnicity
States based, longitudinal (6.32) (1.36) consensus of neurologists, a continuous variable.
cohort study of years psychiatrists, and
Medicare recipients neuropsychologists based on
aged 65 years or Diagnostic and Statistical
older Manual of Mental Disorders
(Fourth Edition) criteria.
Solfrizzi 2010 Italy the Italian 2097 72.94 47.26 % 3.5 The diagnosis was based on the Abdominal obesity (waist circumference 6 age, sex (coded 0 for women and 1
Longitudinal Study (5.56) years Diagnostic and Statistical >102 cm for men and >88 cm for women) for men), education, Geriatric
on Ageing Manual of Mental Disorders, Depression Scale score, drink per
third edition revised (DSM-III- day, smoking status in pack-years
R) criteria for dementia (coded 0 for never smokers and 1
syndrome, the National for former and/or current
Institute of Neurological and smokers), fibrinogen, non-HDL
305

Communicative Disorders and cholesterol, ratio of apolipoprotein

StrokedAlzheimer’s Disease B to apolipoprotein A–I, coronary
and Related Disorders artery disease (coded 0 non-
Association (NINCDS-ADRDA) affected and coded 1 for affected by
criteria for possible and the disease) and stroke (coded
probable AD, and the 0 non affected and coded 1 for
International Statistical affected by the disease)
Classification of Diseases and
Related Health Problems, 10th
revision (ICD-10) criteria for
VaD and other dementing
diseases.

Neuroscience and Biobehavioral Reviews 130 (2021) 301–313

Power 2011 Australia The Health In Men 12,047 72.1 0% 7.1 The diagnosis of dementia was Classified men with 94 cm ≤ WC<102 cm 9 age, marital status, education,
Study (HIMS) (4.4) (3.0) defined according to the as having mild central obesity, and those alcohol consumption, fat intake
years following ICD-9 and ICD-10 with WC ≥ 102 cm as having marked from milk, physical activity, and
codes. central obesity. A WHR ≥ 0.9 indicated the prevalent diabetes, dyslipidaemia
presence of obesity. and coronary heart disease
Luchsinger 2012 United the Washington 1459 75.9 67.30 % 9 years The diagnosis of dementia was The WC and WHR were used as continuous 9 sex, age, ethnicity, education,
States Heights-Inwood (6.5) based on standard research variables and categorized by quartiles. APOE e4 allele, type 2 diabetes,
Columbia Aging criteria and required evidence hypertension, heart disease, non-
Project of cognitive decline. HDL cholesterol, HDL cholesterol,
and stroke
Albala 2016 Chile the Santiago de 667 60 (3.3) 70 % 15 Dementia was defined with a Waist circumference (>88 cm in men, >102 8 sex, age and education
Chile SABE study years screening test validated for cm in women)
and the Chile consisting of a score <22
ALEXANDROS on the Mini Mental State
study Examination (MMSE) and a
score >5 in the Pfeffer
Activities Questionnaire.
(continued on next page)
 X. Tang et al.
Table 1 (continued )
study year country study cohort sample/n age/ women follow- cognitive impairment or waist circumstance (WC)/waist-to-hip ratio NOS covariate
mean ± (%) up dementia (WHR)
SD or time
range

Ng 2016 Singapore The Singapore 1519 64.9 64.80 % 3 years The Chinese modified version Central obesity (waist circumference ≥90 8 sex, age, education, APOE-ε4
Longitudinal (6.8) of the MiniMental State cm for men and ≥80 cm for women) genotype, smoking, and physical,
Ageing Study Examination (MMSE) with social, and productive activities
(SLAS) education-stratified norms was score
used to screen for dementia and
MCI.
Zhang 2017 China the CSPPT (China 16,791 60.1 59.75 % 4.5 Cognitive impairment was Abdominal adiposity was assessed using 7 study center, age, education,
Stroke Primary (7.4) years determined according to the WC and defined as high if WC ≥ 90 cm for smoking, alcohol drinking, marital
Prevention Trial) education-specific cutoff points men and ≥80 cm for women. status, living conditions, physical
of MMSE in China: ≤17 for activity, PHQ scores, systolic blood
illiterate people, ≤20 for pressure at baseline, mean systolic
people with 1–6 years of blood pressure during the follow-
education (primary school), up, estimated glomerular filtration
and ≤24 for people with >6 rate, new stroke (for all cognitive
years of education (middle impairment only), diabetes mellitus
school or higher). at baseline, new diabetes mellitus
during the follow-up, and
treatment allocation
Singh- 2018 Europe the Whitehall II 10,308 45.0 33.15 % 30 Directly using comprehensive Waist circumference categories were small 7 age, sex, education, diabetes, CVD
Manoux Study (6.0) years tracing of electronic health (≤94/80 cm in men/ women), intermediate and CVD medication
records for dementia (94 to ≤102/80 to ≤88 cm in men/
ascertainment in three women), and large (≥102/88 cm in men/
databases. women). Waist-to-hip ratio, we used values
306

≥1.0 in men and 0.85 in women to denote

obesity.
Liao 2018 China a cohorh from 6831 55 49.20 % 10 The ICD-9-CM codes 290–294 The WC was used as continuous variable. 9 age, gender, marital status,
Chang Gung (45− 75) years and 331, at least 3 consecutive education, occupational category,
Memorial Hospital outpatient visits, and the cigarette smoking, alcohol
prescription of related drinking, and betel nut chewing
medications were used to
define dementia.
Cho 2019 Korea the large-scale 872,082 70.4 54.42 % 6.46 Dementia was identified by WC categories were classified into 5-cm 9 age, BMI, alcohol consumption,
National Health (4.7) years principal or secondary increments: < 65, 65 to < 70, 70 to < 75, 75 smoking and exercise status,
Screening diagnosis based on to < 80, 80 to < 85 (reference for women), systolic BP, FBS, HDL-C, LDL-C,
Examination International Classification of 85 to < 90 (reference for men), 90 to < 95, AST, ALT, economic status, history

Neuroscience and Biobehavioral Reviews 130 (2021) 301–313

(NHSE) database Diseases, Tenth Revision codes 95 to < 100, 100 to < 105, 105 to < 110, of diabetes, hypertension, and CVD,
(F00, F01, F03, G30, and G318) and ≥ 110 cm. and CCI
Lee 2020 Korea a biennial National 4,106,590 55.8 45.50 % 4.9 Dementia was defined as Abdominal obesity was defined as waist 8 age, sex, smoking, alcohol, regular
Health Screening (10.1) years antidementia drugs prescribed circumference ≥ 90 cm for men and ≥ 85 exercise, stroke, depression, and
Program (NHSP) at least twice with codes for AD cm for women chronic kidney disease
(ICD-10 F00 or G30), VD (ICD-
10 F01), or other dementia
(ICD-10 F02, F03, G23.1 or
G31).
Ma 2020 England the English 5538 63.4 54.57 % 15 Dementia was diagnosed Abdominal obesity was defined as WC > 88 9 age, sex, APOE E4, education,
Longitudinal Study (9.3) years according to the adapted short- cm for women and >102 cm for men. marital status, smoking status,
of Ageing (ELSA) form Informant Questionnaire physical activity, hypertension and
on Cognitive Decline in the diabetes at baseline.
Elderly (IQCODE)
questionnaire.
Bancks 2021 United The Multi-Ethnic 977 63.5 52.30 % 10 Incident dementia (death or Waist circumference was measured at the 8 age at exam, sex, race/ethnicity,
States Study of (9.6) years hospitalization) was site of maximumcircumferencemidway diabetes medication use, field
(continued on next page)
 X. Tang et al. Neuroscience and Biobehavioral Reviews 130 (2021) 301–313

an increased risk of cognitive impairment and dementia (HR = 1.13, 95

density lipoprotein cholesterol, and

% CI: 1.08–1.19), whereas no significant association was observed in

smoking, coronary artery disease,

hypertension and type 2 diabetes
center, educational attainment,
people younger than 65 years (HR = 1.04, 95 % CI: 0.93–1.16).

family income, smoking status,

pressure medication use, low-

systolic blood pressure, blood
alcohol use, physical activity,

age, gender, education level,

Geographical analysis showed that individuals of Asian descent

cholesterol medication use.

demonstrated a significant association between high WC and the risk of
cognitive impairment and dementia (HR = 1.14, 95 % CI: 1.08–1.20),

Abbreviation: SD, standard deviation; NOS, Newcastle–Ottawa Quality Assessment Scale criteria; WC, waist circumference; WHR, waist-to-hip ratio; AD, Alzheimer’s disease; VD, vascular dementia.
whereas individuals of American, European, and Oceanic descent
showed no effect of high WC on these parameters (HR = 1.00, 95 % CI:
covariate

0.81–1.24, HR = 0.97, 95 % CI: 0.75–1.25 and HR = 0.95, 95 % CI:

0.82–1.10, respectively). Sub-group analysis showed a significant asso­
ciation between high WC with dementia (HR = 1.12, 95 % CI:
1.07–1.17), but not with cognitive impairment (HR = 0.92, 95 % CI:
NOS

0.74–1.14). For studies that did not further divide the state of dementia
9

and cognitive impairment, the pooled HR wasHR was 2.16 (95 % CI:
waist circumstance (WC)/waist-to-hip ratio

105 cm for women and ≥ 110 cm for men.

Abdominal obesity: waist circumference >

1.33–3.52). We conducted further analysis based on the cut-off values of

between the lower ribs and the umbilicus.
Abdominal obesity was defined as WC ≥

WC. Seven studies (Gustafson et al., 2009; Albala et al., 2016; Raffaitin
90 for men and > 80 cm for women

et al., 2009; Solfrizzi et al., 2010; Bancks et al., 2021; Forti et al., 2010;
Ma et al., 2020) with WC cut-off values greater than 102 cm in men and
88 cm in women were taken as the high cut-off value group. Twelve
studies (Cho et al., 2019; Singh-Manoux et al., 2018; West and Haan,
2009; Power et al., 2011; Beydoun et al., 2008; Luchsinger et al., 2012;
Zhang et al., 2017; Luchsinger et al., 2007; Muller et al., 2007; Ng et al.,
2016; Lee et al., 2020a; Wu and Chen, 2021) with WC cut-off values less
than 102 cm in men and 88 cm in women were taken as the low cut-off
(WHR)

value group. Significant association between central obesity and de­

mentia only existed in the low cut-off value group (HR = 1.11, 95 %CI:
1.06–1.16), but not in the high cut-off value group (HR = 0.87, 95 %CI:
(MCI) was defined as a score of
F03, F04, G30, G31 (excluding
determined according to ICD9:
290, 294, 331.0, 331.1, 331.2,

< 27 out of 30. Dementia was

331.82, 331.83, 331.9, 438.0,
and 780.93; ICD10: F00, F01,

defined as a score of < 17 for

0.67–1.13) (Fig. 2).

than 6 years), and < 24 for
illiterate subjects, < 20 for
Mild cognitive impairment

elementary education (less

Some studies provided data stratified by sex. For men, 5 studies (Cho
G31.2), I69.91, and R41.

subjects receiving higher

cognitive impairment or

subjects receiving only

et al., 2019; Power et al., 2011; Beydoun et al., 2008; Zhang et al., 2017;
Ma et al., 2020) provided 13 sets of data with a pooled HR of 1.06 (95 %
CI: 0.97–1.16), which indicated a non-significant impact of high WC on
cognitive impairment and dementia. Among women, results from 13 sets
education.
dementia

of data from 5 studies (Cho et al., 2019; Gustafson et al., 2009; Beydoun
et al., 2008; Zhang et al., 2017; Ma et al., 2020) indicated that high WC
was associated with an increased risk of cognitive impairment and de­
mentia (HR = 1.18, 95 % CI: 1.09–1.27) compared with those with low
follow-

years
time

WC (Fig. 3). Additionally, some studies analyzed association between

up

10

WC and different dementia subtypes, including Alzheimer’s disease and

vascular dementia. Eight studies (Beydoun et al., 2008; Luchsinger et al.,
60.06 %
women

2012, 2007; Muller et al., 2007; Raffaitin et al., 2009; Solfrizzi et al.,
(%)

2010; Forti et al., 2010; Lee et al., 2020a) with 20 sets of data were
associated with Alzheimer’s disease and the pooled results showed that a
mean ±

high WC was negatively associated with Alzheimer’s disease (HR =

range
SD or

(2.7)
age/

63.6

0.83, 95 % CI: 0.69− 0.99). Severe central obesity cases were not asso­
ciated with Alzheimer’s disease (HR = 1.05, 95 % CI: 0.58–1.87).
Further analysis limited to those older than 65 years of age showed that
sample/n

high WC was inversely associated with Alzheimer’s disease (HR = 0.68,

5693

95 % CI: 0.56− 0.82), after setting low WC as the reference group.

However, the pooled results of studies with participants younger than 65
years of age showed that high WC was not associated with Alzheimer’s
population-based
Atherosclerosis

disease (HR = 1.07, 95 % CI: 0.81–1.42). Because of limited data on the

study cohort

time to AD onset, we could not conduct further analysis. Four studies

the Taiwan
biobank, a

research
(MESA)

(Raffaitin et al. (2009); Solfrizzi et al., 2010; Forti et al., 2010; Lee et al.,
2020a) mentioned vascular dementia, and the pooled association be­
tween high WC and vascular dementia was non-significant (HR = 0.92,
95 % CI: 0.62–1.34) (SFig. 1).
country

Further sensitivity analysis was conducted to assess potential het­

China

erogeneity. For studies that provided more than three categories of WC

values, we chose the highest value as a measure of severe central obesity.
2021
Table 1 (continued )

Because of the different cut-off values in each study, we did not set a
year

strict cut-off definition of severe obesity. Outcomes from 9 sets of data

from 7 studies (Cho et al., 2019; Singh-Manoux et al., 2018; West and
Haan, 2009; Power et al., 2011; Beydoun et al., 2008; Luchsinger et al.,
study

2012, 2007) suggested significant association between severe central

Wu

obesity and the risk of cognitive impairment and dementia in the high

307
X. Tang et al. Neuroscience and Biobehavioral Reviews 130 (2021) 301–313

Fig. 2. Association of categories of waist circumference with cognitive impairment and dementia.
A. Subgroup analysis of the association of category waist circumference with cognitive impairment and dementia according to age.
B. Subgroup analysis of the association between category waist circumference with cognitive impairment and dementia according to geographical location.
C. Subgroup analysis of the association between category waist circumference with cognitive impairment and dementia according to cognitive impairment and
dementia type.
D. Subgroup analysis of the association between category waist circumference with cognitive impairment and dementia according to different WC cut-off values.
Abbreviation: HR, hazard ratio; CI, confidence interval.
Where I2 is the variation in effect estimates attributable to heterogeneity, overall is the pooled random effect estimate of all studies. subtotal is the pooled random-
effects estimate of sub-group analysis studies. Weights are from the random-effects analysis. %Weight is the weight assigned to each study, based on the inverse of the
within- and between-study variance. The size of the grey boxes around the point estimates reflects the weight assigned to each study.

308
X. Tang et al. Neuroscience and Biobehavioral Reviews 130 (2021) 301–313

Fig. 3. Association of categories of waist circumference with cognitive impairment and dementia by sex.

WC group (HR = 1.32, 95 % CI: 1.00–1.74) compared with the lowest

Table 2
WC group. Studies with more than 5 years of follow up (12 studies (Cho
Results of the association between category waist circumference with cognitive
et al., 2019; Singh-Manoux et al., 2018; West and Haan, 2009; Power
impairment and dementia after removing Zhang et al.
et al., 2011; Gustafson et al., 2009; Beydoun et al., 2008; Luchsinger
HR (95 %CI) before HR (95 %CI) after
et al., 2012; Albala et al., 2016; Luchsinger et al., 2007; Bancks et al.,
removing Zhang et al. removing Zhang et al.
2021; Ma et al., 2020; Wu and Chen, 2021) with 37 sets of data) showed
that high WC was associated with increased risk of cognitive impairment high WC and risk of cognitive 1.10 (1.05, 1.15) 1.13 (1.08, 1.18)
impairment and dementia
and dementia (HR = 1.16, 95 %: 1.10–1.21) compared with low WC. sub-group analysis according to
Fifteen studies (Cho et al., 2019; West and Haan, 2009; Power et al., age
2011; Gustafson et al., 2009; Beydoun et al., 2008; Luchsinger et al., among those older than 65 1.13 (1.08, 1.19) 1.13 (1.08, 1.19)
2012, 2007; Muller et al., 2007; Ng et al., 2016; Solfrizzi et al., 2010; years old
among those younger than 65 1.04 (0.93, 1.16) 1.12 (0.98, 1.29)
Liao et al., 2018; Bancks et al., 2021; Lee et al., 2020a; Ma et al., 2020;
years old
Wu and Chen, 2021) had NOS scores higher than 8 and provided 38 sets
of data. The pooled effect of these high-quality studies was significant, sub-group analysis according to
with an HR of 1.14 (95 % CI: 1.09–1.19). Additionally, we used data geographical distribution
with more than four covariables (sex, age, education, and ethnicity). A among those in Asia 1.14 (1.08, 1.20) 1.18 (1.13, 1.24)
total of 16 studies (Cho et al., 2019; Power et al., 2011; Gustafson et al., among those in America 1.00 (0.81, 1.24) 1.00 (0.81, 1.24)
among those in Europe 0.97 (0.75, 1.25) 0.97 (0.75, 1.25)
2009; Beydoun et al., 2008; Luchsinger et al., 2012; Zhang et al., 2017; among those in Oceania 0.95 (0.82, 1.10) 0.95 (0.82, 1.10)
Luchsinger et al., 2007; Muller et al., 2007; Ng et al., 2016; Solfrizzi
et al., 2010; Liao et al., 2018; Ma et al., 2020; Wu and Chen, 2021) sub-group analysis according to
provided 40 sets of data and the results showed that high WC increased cognitive impairment or
the risk of cognitive impairment and dementia (HR = 1.09, 95 %: dementia
high WC and risk of cognitive 0.92 (0.74, 1.14) 1.41 (1.01, 1.97)
1.04–1.14) compared with low WC.
impairment
Only one study (Zhang et al., 2017) identified a common basic dis­ high WC and risk of dementia 1.12 (1.07, 1.17) 1.12 (1.07, 1.17)
ease, hypertension. We repeated all analyses after removing this study. high WC and risk of cognitive 2.16 (1.33, 3.52) 2.16 (1.33, 3.52)
The relationship between high WC and cognitive impairment in all impairment and dementia
participants changed from non-significant to significant (HR = 1.41, 95
sub-groups analysis according to
% CI: 1.01–1.97) compared with the lowest WC group. When analyzing
different WC cut-off values
the different sexes, high WC increased the risk of dementia in men (HR = high WC cut-off values 0.84 (0.63, 1.11) 0.84 (0.63, 1.11)
1.11, 95 % CI: 1.02–1.21), with the association changing from (men>100 cm and women>85
non-significant to significant. The results of the other analyses remained cm)
similar (Table 2). low WC cut-off values 1.11 (1.06, 1.16) 1.15 (1.10, 1.20)
(men≤100 cm and women≤85
Four studies (Gustafson et al., 2009; Luchsinger et al., 2012; Zhang cm)
et al., 2017; Liao et al., 2018) involving 26,543 participants provided
continuous data on the relationship between WC and risk of cognitive sensitivity analysis
impairment and dementia. Results indicated that increased WC was not analysis among women 1.18 (1.09, 1.27) 1.22 (1.14, 1.31)
associated with increased risk of cognitive impairment or dementia (HR analysis among men 1.06 (0.97, 1.16) 1.11 (1.02, 1.21)

= 1.00, 95 % CI: 0.98–1.01) (SFig. 2). Additionally, the results remained
non-significant after removing the study by Zhang et.al. (Zhang et al.,
2017), (HR = 1.01, 95 % CI: 0.98–1.04).
Additionally, we conducted a dose-response meta-analysis of the
association between WC values and the risk of dementia. Three studies
(Cho et al., 2019; Power et al., 2011; Luchsinger et al., 2007) with 885,
036 individuals provided more than three categories of WC (STable 3).
Because all three studies did not provide the median or mean data of
Abbreviation: HR, hazard risk; CI, confidence interval; WC, waist
circumference.
each category, we chose the midpoint of each category. In this analysis,
individuals with higher WC had a higher risk of cognitive impairment
and dementia (Fig. 4).

309
X. Tang et al.
Fig. 4. Dose-response association of waist circumference level with dementia.
A. Analysis of the association between category waist circumference with
cognitive impairment and dementia among men.
B. Analysis of the association between category waist circumference with
cognitive impairment and dementia among women.
Abbreviation: HR, hazard risk; CI, confidence interval.
Where I2 is the variation in effect estimates attributable to heterogeneity,
overall is the pooled random effect estimate of all studies. subtotal is the pooled
random-effects estimate of sub-group analysis studies. Weights are from the
random-effects analysis. %Weight is the weight assigned to each study, based
on the inverse of the within- and between-study variance. The size of the grey
boxes around the point estimates reflects the weight assigned to each study.
3.4. Meta-analysis of the association between WHR and risk of cognitive
impairment and dementia
Four studies (Singh-Manoux et al., 2018; Power et al., 2011; Gus­
tafson et al., 2009; Luchsinger et al., 2012) with 26,200 participants
provided 6 sets of data on the relationship between high WHR and risk of
cognitive impairment and dementia. Data are provided in STable 2. The
pooled association between high WHR and the risk of cognitive
impairment and dementia was non-significant (HR = 1.12, 95 % CI:
0.80–1.58) compared with low WHR. Sub-group analysis based on age
indicated that high WHR had no impact on cognitive impairment and
dementia among participants who were both older than 65 years (HR =
1.08, 95 % CI: 0.68–1.72) and younger than 65 years (HR = 1.29, 95 %
CI: 0.88–1.91). Because of limited data, we could not conduct sub-group
analysis based on sex. Sensitivity analysis showed no change in the re­
sults after removing studies one-at-a-time (SFig. 3).
Three studies (Gustafson et al., 2009; Luchsinger et al., 2012; Reitz
et al., 2010) containing 3972 subjects focused on the impact of contin­
uous WHR on cognitive impairment and dementia. The pooled result
was non-significant, showing that continuous WHR was not associated
with cognitive impairment and dementia (HR = 1.11, 95 % CI:
0.99–1.24) (SFig. 3).
3.5. Publication bias
According to the Cochrane Handbook (Higgins et al., 2019), as a rule
of thumb, tests for funnel plot asymmetry should be used only when
enough studies are included in the meta-analysis, because including too
few studies reduces the power of distinguishing real asymmetry from
coincidence. In this study, analysis of the relationship between WC and
WHR and cognitive impairment and dementia using the Egger test
resulted in a p value of 0.349, indicating no significant bias. The funnel
figure of these studies showed a symmetrical inverted distribution,
consistent with the results of the Egger test (SFig. 4).
4. Discussion
A total of 21 cohort studies focusing on both WC and WHR as
310
Neuroscience and Biobehavioral Reviews 130 (2021) 301–313
measures of central obesity were included in the current analysis. We
found that high WC, but not WHR, was associated with a greater risk of
cognitive impairment and dementia. The harmful impact of high WC on
cognitive impairment and dementia remained in individuals older than
65 years of age, but this relationship was non-significant in those below
the age of 65 years. Sex-stratified analyses showed significant associa­
tion between high WC and cognitive impairment and dementia among
women, but not among men. When the analyses included only in­
dividuals with Alzheimer’s disease as the outcome, significant negative
associations were observed between higher WC and cognitive impair­
ment and dementia.
4.1. Findings from our analysis and comparisons with other studies
The current analysis focused on the associations between WC and
WHR and cognitive impairment and dementia only in cohort studies,
and the results indicated that high WC increased the risk of cognitive
impairment and dementia, whereas WHR did not. In line with our
findings, a longitudinal study involving 1049 participants used sagittal
abdominal diameter (SAD) at mid-life as the standard of central obesity
and showed that compared with individuals in the lowest quintile of
SAD, individuals in the highest quintile had a nearly three-fold greater
risk of dementia (HR = 2.72; 95 % CI: 2.33–3.33) (Tezapsidis et al.,
2009). Another meta-analysis indicated that high WC was protective
(Lee et al., 2020b), but the age range was greater than that in our
analysis. Evidence showed that obesity may have different impacts on
cognitive health in different age groups (Fitzpatrick et al., 2009), thus
analyses involving participants with a wider age range may yield con­
flicting results. A study involving 924 elderly persons in a Swedish
community-dwelling found no association between WHR and dementia.
We excluded this study because of the inappropriate statistical method
used (Arnoldussen et al., 2018); the results were analyzed using odds
ratio (OR) with multivariable logistic regression, which dose not factor
in time. Additionally, a case-control study used WHR as the measure­
ment of abdominal obesity and found a significant influence of high
WHR (women>0.8, men>0.9) on Alzheimer’s disease after adjusting for
age, sex, and location (Razay et al., 2006). In the current analysis, we
undertook more comprehensive potential covariate adjustments,
including age, sex, education, ethnicity, BMI, alcohol consumption,
smoking and exercise status, systolic blood pressure, FBG, HDL-C,
LDL-C, AST, ALT, economic status, history of diabetes, hypertension,
CVD, and CCI. However, the study involved a small sample size with no
follow-up design. Current analysis emphasized the significant associa­
tion between high WC and the risk of cognitive impairment and de­
mentia in individuals older than 65 years of age. Similarly, a protective
role of high WC was shown in individuals older than 65 years when
Alzheimer’s disease was taken as the outcome. Further, Zuin et al.
(2021) focused on the relationship between metabolic syndrome and the
risk of late onset Alzheimer’s disease and found a lower risk of AD in
individuals with increased abdominal circumference (HR = 0.84; 95 %
CI: 0.74− 0.95), which was consistent with our results. However, when
we limited analyses to those studies with severe central obesity, the
results became non-significant. This means that a non-linear relation­
ship may exist between central obesity and AD. However, the underlying
mechanism is not clear and further studies are needed.
A previous meta-analysis was performed to study the relationship
between body mass index (BMI) and risk of cognitive impairment and
dementia (Qu et al., 2020). This study found that high mid-life BMI was
a risk factor for cognitive impairment and dementia, whereas high
late-life BMI appeared to confer protective effects. Higher BMI may also
result from increased accumulation of fat in regions other than the
abdominal area, and other studies have shown no association between
general obesity and dementia but found a positive association between
central obesity and dementia (Gustafson et al., 2009; Luchsinger et al.,
2012). The Women’s Health Initiative Memory Study had similar find­
ings (Kerwin et al., 2011). Women with optimal weight but high WHR
X. Tang et al.
(≥0.8) were at more than two-fold greater risk of cognitive impairment
than those with high BMI. Another cohort study involving 872,082
participants over the age of 65 years demonstrated that men and women
with optimal weight but with abdominal obesity had a considerably
higher risk of dementia compared with those without abdominal obesity
(Cho et al., 2019). Additionally, West et al. demonstrated a 61 %
decrease in the rate of dementia in obese subjects after adjusting for WC
(HR = 0.39, 95 % CI: 0.20− 0.78) (West and Haan, 2009). Thus, WC may
be a more accurate index for identifying the risk of cognitive impairment
and dementia compared with BMI, and these results emphasize the
importance of measuring WC and BMI simultaneously for accurate
prediction of cognitive impairment and dementia risk.
In the sub-group analysis, a significant association between high WC
and the risk of cognitive impairment and dementia was found only in
individuals of Asian descent. Analysis of individuals of American, Eu­
ropean, and Oceanic descent showed that high WC had no effect on the
risk of cognitive impairment and dementia. An accumulating body of
evidence suggests that the relationship between obesity, measured by
BMI or WC, and cardiovascular and metabolic diseases differs between
ethnic groups (Deurenberg et al., 2002, 1998; Barcelo et al., 2017;
Agyemang et al., 2012; Ong et al., 2009). Our analysis revealed, for the
first time, the varied impacts of high WC on the risk of cognitive
impairment and dementia in different ethnic groups. However, the
outcomes need more rigorous evidence for confirmation.
4.2. Potential mechanisms of the effect of obesity
Although other complications of obesity (comorbidities such as hy­
pertension and diabetes) can be indirectly detrimental to cognitive
performance, the mechanism underlying the association between cen­
tral obesity and cognitive impairment and dementia is still not fully
understood. Central obesity and dementia may be linked through several
pathways. One of the potential mechanisms underlying the association
between adiposity and cognitive performance involves the fat-brain axis
(Elmquist and Neuroscience, 2004) and the
hypothalamic-pituitary-adipose tissue axis (Schäffler et al., 2005).
Another potential mechanism may be associated with hormones
secreted by adipose tissue, such as leptin and adiponectin, which have
been shown to regulate energy expenditure and hyperphagic responses
through their interactions with the hypothalamus (Funahashi et al.,
2003; Speakman, 2004; Narita et al., 2009), and thus influence cognitive
performance. Different effects of central obesity on different types of
dementia may be explained by differences in pathogenesis and disease
progression. For example, obesity not only presented with
neuro-inflammation leading to subsequent AD-related cognitive decline
(Khan and Hegde, 2020), it also damaged the blood vessel walls,
affecting the progression of vascular dementia (Iadecola, 2013). The
relationship between adiposity and cognitive performance might form a
vicious cycle; obesity leads to poor cognitive performance, which in turn
leads to increased obesity (Suemoto et al., 2015). However, another
vicious cycle may exist in individuals developing Alzheimer’s disease
who often show unexplained weight loss and consequently a reduction
in waist circumference before the onset of the disease (Cova et al., 2016;
Guérin et al., 2005). Finally, researchers found that adipose tissue is an
active endocrine organ, and compared with subcutaneous adipose tis­
sue, visceral adipose tissue produce more pro-inflammatory mediators
(Lessard et al., 2011; Gaens et al., 2015), which have effects on declining
cognitive performance (Darweesh et al., 2018; Pou et al., 2007).
4.3. Public health impact
Dementia is a growing clinical and socio-economical problem in
today’s aging population (Fleszar et al., 2019). Estimates show that ten
million people develop dementia every year (Lagunin et al., 2020), and
the World Health Organization has designated dementia as a public
health priority (World Health O., 2012). Central obesity has adverse
311
Neuroscience and Biobehavioral Reviews 130 (2021) 301–313
impacts on many aspects of health, including diabetes, hypertension,
insulin resistance (Meshram et al., 2016), metabolic dysfunction
(Shuster et al., 2012), stroke (Preiss et al., 2013), and impairment of the
central nervous system (Hryhorczuk et al., 2013). The current analysis
showed central obesity, as measured by large WC, to be associated with
an increased risk of cognitive impairment and dementia. With the
increasing prevalence of central obesity, individuals need to focus on
maintaining normal WC.
4.4. Strengths and limitations of the study
Although our analysis revealed valuable information regarding as­
sociations between central obesity, as measured by WC and WHR, and
the risk of cognitive impairment and dementia, a few important
strengths and limitations of the study merit mentioning. One of the
strengths of our study is that the data were adjusted for multiple cova­
riates, explicit inclusion criteria were enforced, and the search strategy
was thorough and comprehensive.
However, the study also has some limitations. Studies included in the
current analysis had different cut-off values for the WC. When we con­
ducted sub-group analysis and dose-response meta-analysis to explore
the influence of different cut-off values, we found significant associa­
tions in studies with low cut-off values. Thus, more studies are needed to
confirm the optimal cut off value. For example, more studies involving
smaller WC span groups and dose-response analysis are needed to
confirm the specific definition of severe central obesity. Studies focused
on central obesity, as measured by WHR, and its association with the risk
of cognitive impairment and dementia are few, and more evidence is
needed to verify the association. Additionally, lack of data on the rela­
tionship between central obesity and specific sub-types of dementia
limited the analyses. Because of different physiological and pathological
mechanisms, the impact of central obesity on Alzheimer’s disease and
vascular dementia requires validation studies. There was also a lack of
information on the decrease in WC levels. Some reports concluded that
weight change had an impact on dementia (Lee et al., 2020b; Stewart
et al., 2005; Lo et al., 2012). The influence of changes in central obesity
on cognitive impairment and dementia needs to be investigated.
Furthermore, measurements of WC and WHR could not distinguish the
varied levels of fat distribution in the abdominal area. The distribution
of abdominal adipose tissues such as visceral adiposity and abdominal
subcutaneous adiposity may have different effects on cognitive impair­
ment (Kamogawa et al., 2010). However, our analysis was limited
because of limited studies associated with it. Finally, the heterogeneity
in the results may be because of differences in dementia subtypes as well
as sex. However, as some articles did not provide relevant information,
we were unable to analyze additional sources of heterogeneity.
4.5. Future prospects
Although WC and WHR are commonly used as estimates of central
obesity, other indices also exist. SAD is an effective parameter and
longitudinal evidence showed that central obesity measured by SAD was
associated with an increased risk of dementia (Whitmer et al., 2008). A
per 6.5 mm increase in subscapular skinfold thickness increased the risk
of dementia, with an RR = 1.21 (95 % CI: 1.06, 1.40) (Kalmijn et al.,
2000). Another cohort study used the same variable and found that
subscapular and triceps skinfold thickness were associated with a higher
risk of dementia (HR = 1.72, 95 % CI: 1.36–2.18 and HR = 1.59, 95 %
CI: 1.24–2.04, respectively) (Whitmer et al., 2005). Further studies
should focus on the most sensitive parameter for measuring the rela­
tionship between central obesity and dementia.
Combined with a previous study on the association between BMI and
cognitive impairment and dementia (Qu et al., 2020), our study extends
the knowledge on the association between high WC and the risk of
cognitive impairment and dementia. Whether peripheral obesity has a
similar impact on cognitive impairment and dementia is unclear and
X. Tang et al.
requires further studies. Some studies used thigh circumference as the
measure of peripheral obesity, but the results were inconsistent. One
longitudinal study involving 6583 individuals showed that a high thigh
circumference had no effect on dementia (HR = 1.01, 95 % CI:
0.81–1.31) (Whitmer et al., 2008), while another study found that a high
right thigh circumference was associated with decreased risk of de­
mentia (HR = 0.93, 95 % CI: 0.90− 0.96) (Liao et al., 2018).
5. Conclusions
The current study indicated that central obesity, as measured by WC,
was associated with an increased risk of cognitive impairment and de­
mentia, particularly in individuals over 65 years of age. Associations
between reduced central obesity and peripheral adiposity and the risk of
cognitive impairment and dementia need to be analyzed further.
Data availability statement
All data used in the current analysis were obtained directly from the
published studies.
Disclosure statement
Authors are solely responsible for the design and conduct of this
study, all study analyses, the drafting and editing of the manuscript, and
its final contents.
Funding statement
This work was supported by the National Natural Science Foundation
of China (No.82070851, 81870556, 81930019), Beijing Municipal
Administration of Hospital’s Youth Program (QML20170204), Excellent
Talents in Dongcheng District of Beijing.
Declaration of Competing Interest
None.
Acknowledgments
Authors are solely responsible for the design and conduct of this
study, all study analyses, the drafting and editing of the manuscript, and
its final contents.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.neubiorev.2021.08.0
28.
References
Agyemang, C., De-Graft Aikins, A., Bhopal, R., 2012. Ethnicity and cardiovascular health
research: pushing the boundaries by including comparison populations in the
countries of origin. Ethn. Health 17 (6), 579–596.
Albala, C., Angel, B., Lera, L., et al., 2016. Low leptin availability as a risk factor for
dementia in chilean older people. Dement. Geriatr. Cogn. Dis. Extra 6 (2), 295–302.
Ambikairajah, A., Tabatabaei-Jafari, H., Walsh, E., et al., 2020. Longitudinal changes in
fat mass and the Hippocampus. Obesity (Silver Spring, Md.) 28 (7), 1263–1269.
Arnoldussen, I., Sundh, V., Bäckman, K., et al., 2018. A 10-Year follow-up of adiposity
and dementia in swedish adults aged 70 years and older. J. Alzheimers Dis. 63 (4),
1325–1335.
Bancks, M.P., Carnethon, M., Chen, H., et al., 2021. Diabetes subgroups and risk for
complications: the Multi-Ethnic Study of Atherosclerosis (MESA). J. Diabetes
Complicat. 35 (6).
Barcelo, A., Arredondo, A., Gordillo-Tobar, A., et al., 2017. The cost of diabetes in Latin
America and the Caribbean in 2015: evidence for decision and policy makers.
J. Glob. Health 7 (2), 020410.
312
Neuroscience and Biobehavioral Reviews 130 (2021) 301–313
Beydoun, M.A., Lhotsky, A., Wang, Y., et al., 2008. Association of adiposity status and
changes in early to mid-adulthood with incidence of Alzheimer’s disease. Am. J.
Epidemiol. 168 (10), 1179–1189.
Brookmeyer, R., Evans, D., Hebert, L., et al., 2011. National estimates of the prevalence
of Alzheimer’s disease in the United States. Alzheimer’s Dementia: J. Alzheimer’s
Assoc. 7 (1), 61–73.
Carr, D., Utzschneider, K., Hull, R., et al., 2004. Intra-abdominal fat is a major
determinant of the National Cholesterol Education Program Adult Treatment Panel
III criteria for the metabolic syndrome. Diabetes 53 (8), 2087–2094.
Cho, G.J., Hwang, S.Y., Lee, K.M., et al., 2019. Association between waist circumference
and dementia in older persons: a nationwide population-based study. Obesity Silver
Spring (Silver Spring) 27 (11), 1883–1891.
Cova, I., Clerici, F., Rossi, A., et al., 2016. Weight loss predicts progression of mild
cognitive impairment to alzheimer’s disease. PLoS One 11 (3), e0151710.
Crippa, A., Orsini, N., 2016. Dose-response meta-analysis of differences in means. BMC
Med. Res. Methodol. 16, 91.
Darweesh, S., Wolters, F., Ikram, M., et al., 2018. Inflammatory markers and the risk of
dementia and Alzheimer’s disease: a meta-analysis. Alzheimers Dement. 14 (11),
1450–1459.
Deurenberg, P., Yap, M., Van Staveren, W.A., 1998. Body mass index and percent body
fat: a meta analysis among different ethnic groups. Int. J. Obes. Relat. Metab. Disord.
22 (12), 1164–1171.
Deurenberg, P., Deurenberg-Yap, M., Guricci, S., 2002. Asians are different from
Caucasians and from each other in their body mass index/body fat per cent
relationship. Obes. Rev. 3 (3), 141–146.
Egger, M., Davey Smith, G., Schneider, M., et al., 1997. Bias in meta-analysis detected by
a simple, graphical test. BMJ (Clinical research ed.) 315 (7109), 629–634.
Elmquist, J., Neuroscience, Flier J., 2004. The fat-brain axis enters a new dimension.
Science (New York, N.Y.) 304 (5667), 63–64.
Fitzpatrick, A.L., Kuller, L.H., Lopez, O.L., et al., 2009. Midlife and late-life obesity and
the risk of dementia: cardiovascular health study. Arch. Neurol. 66 (3), 336–342.
Fleszar, M., Wiśniewski, J., Zboch, M., et al., 2019. Targeted metabolomic analysis of
nitric oxide/L-arginine pathway metabolites in dementia: association with
pathology, severity, and structural brain changes. Sci. Rep. 9 (1), 13764.
Forti, P., Pisacane, N., Rietti, E., et al., 2010. Metabolic syndrome and risk of dementia in
older adults. J. Am. Geriatr. Soc. 58 (3), 487–492.
Funahashi, H., Yada, T., Suzuki, R., et al., 2003. Distribution, function, and properties of
leptin receptors in the brain. Int. Rev. Cytol. 224, 1–27.
Gaens, K., Ferreira, I., Van De Waarenburg, M., et al., 2015. Protein-bound plasma Nε-
(Carboxymethyl)lysine is inversely associated with central obesity and inflammation
and significantly explain a part of the central obesity-related increase in
inflammation: the Hoorn and CODAM studies. Arterioscler. Thromb. Vasc. Biol. 35
(12), 2707–2713.
Greenland, S., Longnecker, M., 1992. Methods for trend estimation from summarized
dose-response data, with applications to meta-analysis. Am. J. Epidemiol. 135 (11),
1301–1309.
Guérin, O., Andrieu, S., Schneider, S., et al., 2005. Different modes of weight loss in
Alzheimer disease: a prospective study of 395 patients. Am. J. Clin. Nutr. 82 (2),
435–441.
Gustafson, D.R., Bäckman, K., Waern, M., et al., 2009. Adiposity indicators and dementia
over 32 years in Sweden. Neurology 73 (19), 1559–1566.
Higgins, J.P.T., Thomas, J., Chandler, J., et al., 2019. Cochrane Handbook for Systematic
Reviews of Interventions.
Hryhorczuk, C., Sharma, S., Fulton, S., 2013. Metabolic disturbances connecting obesity
and depression. Front. Neurosci. 7, 177.
Iadecola, C., 2013. The pathobiology of vascular dementia. Neuron 80 (4), 844–866.
Kalmijn, S., Foley, D., White, L., et al., 2000. Metabolic cardiovascular syndrome and risk
of dementia in Japanese-American elderly men: the Honolulu-Asia aging study.
Arterioscler. Thromb. Vasc. Biol. 20 (10), 2255–2260.
Kamogawa, K., Kohara, K., Tabara, Y., et al., 2010. Abdominal fat, adipose-derived
hormones and mild cognitive impairment: the J-SHIPP study. Dement. Geriatr. Cogn.
Disord. 30 (5), 432–439.
Kerwin, D., Gaussoin, S., Chlebowski, R., et al., 2011. Interaction between body mass
index and central adiposity and risk of incident cognitive impairment and dementia:
results from the Women’s Health Initiative Memory Study. J. Am. Geriatr. Soc. 59
(1), 107–112.
Khan, M.S.H., Hegde, V., 2020. Obesity and diabetes mediated chronic inflammation: a
potential biomarker in alzheimer’s disease. J. Pers. Med. 10 (2).
Lagunin, A., Ivanov, S., Gloriozova, T., et al., 2020. Combined network pharmacology
and virtual reverse pharmacology approaches for identification of potential targets
to treat vascular dementia. Sci. Rep. 10 (1), 257.
Lee, J., Shin, D., Han, K., et al., 2020a. Changes in metabolic syndrome status and risk of
dementia. J. Clin. Med. 9 (1).
Lee, C., Woodward, M., Batty, G., et al., 2020b. Association of anthropometry and weight
change with risk of dementia and its major subtypes: a meta-analysis consisting 2.8
million adults with 57 294 cases of dementia. Obes. Rev. 21 (4), e12989.
Lessard, A., Alméras, N., Turcotte, H., et al., 2011. Adiposity and pulmonary function:
relationship with body fat distribution and systemic inflammation. Clin. Invest. Med.
34 (2), E64–70.
Liao, P., Lin, T., Ting, M., et al., 2018. Chest width, waist circumference, and thigh
circumference are predictors of dementia. Int. J. Geriatr. Psychiatry 33 (8),
1019–1027.
Lo, A., Pachana, N., Byrne, G., et al., 2012. Relationship between changes in body weight
and cognitive function in middle-aged and older women. Int. J. Geriatr. Psychiatry
27 (8), 863–872.
X. Tang et al.
Luchsinger, J.A., Patel, B., Tang, M.X., et al., 2007. Measures of adiposity and dementia
risk in elderly persons. Arch. Neurol. 64 (3), 392–398.
Luchsinger, J.A., Cheng, D., Tang, M.X., et al., 2012. Central obesity in the elderly is
related to late-onset Alzheimer disease. Alzheimer Dis. Assoc. Disord. 26 (2),
101–105.
Ma, Y., Ajnakina, O., Steptoe, A., et al., 2020. Higher risk of dementia in English older
individuals who are overweight or obese. Int. J. Epidemiol. 49 (4), 1353–1365.
Meshram, I., Vishnu Vardhana Rao, M., Sudershan Rao, V., et al., 2016. Regional
variation in the prevalence of overweight/obesity, hypertension and diabetes and
their correlates among the adult rural population in India. Br. J. Nutr. 115 (7),
1265–1272.
Moher, D., Liberati, A., Tetzlaff, J., et al., 2010. Preferred reporting items for systematic
reviews and meta-analyses: the PRISMA statement. Int. J. Surg. 8 (5), 336–341.
Muller, M., Tang, M.X., Schupf, N., et al., 2007. Metabolic syndrome and dementia risk in
a multiethnic elderly cohort. Dement. Geriatr. Cogn. Disord. 24 (3), 185–192.
Narita, K., Kosaka, H., Okazawa, H., et al., 2009. Relationship between plasma leptin
level and brain structure in elderly: a voxel-based morphometric study. Biol.
Psychiatry 65 (11), 992–994.
Ng, T.P., Feng, L., Nyunt, M.S., et al., 2016. Metabolic syndrome and the risk of mild
cognitive impairment and progression to dementia: follow-up of the Singapore
longitudinal ageing study cohort. JAMA Neurol. 73 (4), 456–463.
Norton, S., Matthews, F., Barnes, D., et al., 2014. Potential for primary prevention of
Alzheimer’s disease: an analysis of population-based data. Lancet Neurol. 13 (8),
788–794.
O’brien, J., Firbank, M., Ritchie, K., et al., 2020. Association between midlife dementia
risk factors and longitudinal brain atrophy: the PREVENT-Dementia study. J. Neurol.
Neurosurg. Psychiatr. 91 (2), 158–161.
Ong, S.K., Fong, C.W., Ma, S., et al., 2009. Longitudinal study of the socio-demographic
determinants of changes in body weight and waist circumference in a multi-ethnic
Asian population. Int. J. Obes. (Lond) 33 (11), 1299–1308.
Pou, K., Massaro, J., Hoffmann, U., et al., 2007. Visceral and subcutaneous adipose tissue
volumes are cross-sectionally related to markers of inflammation and oxidative
stress: the Framingham Heart Study. Circulation 116 (11), 1234–1241.
Power, B.D., Alfonso, H., Flicker, L., et al., 2011. Body adiposity in later life and the
incidence of dementia: the health in men study. PLoS One 6 (3), e17902.
Preiss, D., Giles, T., Thomas, L., et al., 2013. Predictors of stroke in patients with
impaired glucose tolerance: results from the Nateglinide and Valsartan in Impaired
Glucose Tolerance Outcomes Research trial. Stroke 44 (9), 2590–2593.
Prince, M., Wimo, A., Guerchet, M., et al., 2015. World alzheimer report 2015. The
global impact of dementia. An Analysis of Prevalence, Incidence, Cost and Trends.
Qu, Y., Hu, H., Ou, Y., et al., 2020. Association of body mass index with risk of cognitive
impairment and dementia: a systematic review and meta-analysis of prospective
studies. Neurosci. Biobehav. Rev. 115, 189–198.
Raffaitin, C., Gin, H., Empana, J.P., et al., 2009. Metabolic syndrome and risk for incident
Alzheimer’s disease or vascular dementia: the Three-City Study. Diabetes Care 32
(1), 169–174.
Razay, G., Vreugdenhil, A., Wilcock, G., 2006. Obesity, abdominal obesity and Alzheimer
disease. Dement. Geriatr. Cogn. Disord. 22 (2), 173–176.
313
Neuroscience and Biobehavioral Reviews 130 (2021) 301–313
Reitz, C., Tang, M.X., Schupf, N., et al., 2010. A summary risk score for the prediction of
Alzheimer disease in elderly persons. Arch. Neurol. 67 (7), 835–841.
Schäffler, A., Binart, N., Schölmerich, J., et al., 2005. Hypothesis paper Brain talks with
fat–evidence for a hypothalamic-pituitary-adipose axis? Neuropeptides 39 (4),
363–367.
Shuster, A., Patlas, M., Pinthus, J., et al., 2012. The clinical importance of visceral
adiposity: a critical review of methods for visceral adipose tissue analysis. Br. J.
Radiol. 85 (1009), 1–10.
Singh-Manoux, A., Dugravot, A., Shipley, M., et al., 2018. Obesity trajectories and risk of
dementia: 28 years of follow-up in the Whitehall II Study. Alzheimers Dement. 14
(2), 178–186.
Solfrizzi, V., Scafato, E., Capurso, C., et al., 2010. Metabolic syndrome and the risk of
vascular dementia: the Italian Longitudinal Study on Ageing. J. Neurol. Neurosurg.
Psychiatry 81 (4), 433–440.
Speakman, J., 2004. Obesity: the integrated roles of environment and genetics. J. Nutr.
134, 2090S–2105S.
Stang, A., 2010. Critical evaluation of the Newcastle-Ottawa scale for the assessment of
the quality of nonrandomized studies in meta-analyses. Eur. J. Epidemiol. 25 (9),
603–605.
Stewart, R., Masaki, K., Xue, Q., et al., 2005. A 32-year prospective study of change in
body weight and incident dementia: the Honolulu-Asia Aging Study. Arch. Neurol.
62 (1), 55–60.
Suemoto, C., Gilsanz, P., Mayeda, E., et al., 2015. Body mass index and cognitive
function: the potential for reverse causation. Int. J. Obes. (Lond) 39 (9), 1383–1389.
Tezapsidis, N., Smith, M., Ashford, J., 2009. Central obesity and increased risk of
dementia more than three decades later. Neurology 72 (11), 1030–1031 author reply
1031.
West, N.A., Haan, M.N., 2009. Body adiposity in late life and risk of dementia or
cognitive impairment in a longitudinal community-based study. J. Gerontol. A Biol.
Sci. Med. Sci. 64 (1), 103–109.
Whitmer, R., Gunderson, E., Barrett-Connor, E., et al., 2005. Obesity in middle age and
future risk of dementia: a 27 year longitudinal population based study. BMJ (Clinical
research E.d.) 330 (7504), 1360.
Whitmer, R.A., Gustafson, D.R., Barrett-Connor, E., et al., 2008. Central obesity and
increased risk of dementia more than three decades later. Neurology 71 (14),
1057–1064.
World Health O, 2012. Dementia: a Public Health Priority. World Health Organization,
Geneva.
Wu, S.E., Chen, W.L., 2021. Longitudinal trajectories of metabolic syndrome on different
neurocognitive domains: a cohort study from the Taiwan biobank. Aging 13 (11),
15400–15412.
Zhang, J., Tang, G., Xie, H., et al., 2017. Higher adiposity is associated with slower
cognitive decline in hypertensive patients: secondary analysis of the china stroke
primary prevention trial. J. Am. Heart Assoc. 6 (10).
Zuin, M., Roncon, L., Passaro, A., et al., 2021. Metabolic syndrome and the risk of late
onset Alzheimer’s disease: an updated review and meta-analysis. Nutr. Metab.
Cardiovasc. Dis.