Sex differences in the association between cardiovascular diseases and dementia subtypes: a prospective analysis of 464,616 UK Biobank participants

Abstract

Background
Whether the association of cardiovascular diseases (CVDs) with dementia differs by sex remains unclear, and the role of socioeconomic, lifestyle, genetic, and medical factors in their association is unknown.

Methods
We used data from the UK Biobank, a population-based cohort study of 502,649 individuals. We used Cox proportional hazards models to estimate sex-specific hazard ratios (HRs) and 95% confidence intervals (CI), and women-to-men ratio of HRs (RHR) for the association between CVD (coronary heart diseases (CHD), stroke, and heart failure) and incident dementia (all-cause dementia, Alzheimer's Disease (AD), and vascular dementia (VD)). The moderator roles of socioeconomic (education, income), lifestyle (smoking, BMI, leisure activities, and physical activity), genetic factors ( APOE allele status), and medical history were also analyzed.

Results
Compared to people who did not experience a CVD event, the HRs (95%CI) between CVD and all-cause dementia were higher in women compared to men, with an RHR (Female/Male) of 1.20 (1.13, 1.28). Specifically, the HRs for AD were higher in women with CHD and heart failure compared to men, with an RHR (95%CI) of 1.63 (1.39, 1.91) and 1.32 (1.07, 1.62) respectively. The HRs for VD were higher in men with heart failure than women, with RHR (95%CI) of 0.73 (0.57, 0.93). An interaction effect was observed between socioeconomic, lifestyle, genetic factors, and medical history in the sex-specific association between CVD and dementia.

Conclusion
Women with CVD were 1.5 times more likely to experience AD than men, while had 15% lower risk of having VD than men.

Full text

Dongetal. Biology of Sex Dierences (2022) 13:21
https://doi.org/10.1186/s13293-022-00431-5
RESEARCH
Sex dierences intheassociation
betweencardiovascular diseases anddementia
subtypes: aprospective analysis of464,616 UK
Biobank participants
Caiyun Dong1,2, Chunmiao Zhou1,2, Chunying Fu1,2, Wenting Hao1,2, Akihiko Ozaki3,4, Nipun Shrestha5,
Salim S. Virani6, Shiva Raj Mishra7,8 and Dongshan Zhu1,2,9*
Abstract
Background: Whether the association of cardiovascular diseases (CVDs) with dementia differs by sex remains
unclear, and the role of socioeconomic, lifestyle, genetic, and medical factors in their association is unknown.
Methods: We used data from the UK Biobank, a population-based cohort study of 502,649 individuals. We used
Cox proportional hazards models to estimate sex-specific hazard ratios (HRs) and 95% confidence intervals (CI), and
women-to-men ratio of HRs (RHR) for the association between CVD (coronary heart diseases (CHD), stroke, and
heart failure) and incident dementia (all-cause dementia, Alzheimer’s Disease (AD), and vascular dementia (VD)). The
moderator roles of socioeconomic (education, income), lifestyle (smoking, BMI, leisure activities, and physical activity),
genetic factors (APOE allele status), and medical history were also analyzed.
Results: Compared to people who did not experience a CVD event, the HRs (95%CI) between CVD and all-cause
dementia were higher in women compared to men, with an RHR (Female/Male) of 1.20 (1.13, 1.28). Specifically, the
HRs for AD were higher in women with CHD and heart failure compared to men, with an RHR (95%CI) of 1.63 (1.39,
1.91) and 1.32 (1.07, 1.62) respectively. The HRs for VD were higher in men with heart failure than women, with RHR
(95%CI) of 0.73 (0.57, 0.93). An interaction effect was observed between socioeconomic, lifestyle, genetic factors, and
medical history in the sex-specific association between CVD and dementia.
Conclusion: Women with CVD were 1.5 times more likely to experience AD than men, while had 15% lower risk of
having VD than men.
Highlights
• Whether the incidence and timing of dementia is affected by an interaction of sex with cardiovascular diseases
(CVD) events is unclear.
© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
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Open Access
*Correspondence: dongshan.zhu@uq.net.au
1 Centre for Health Management and Policy Research, School of Public
Health, Cheeloo College of Medicine, Shandong University, Jinan 250012,
China
Full list of author information is available at the end of the article

Page 2 of 11
Dongetal. Biology of Sex Dierences (2022) 13:21
Introduction
ere is a significant sex difference in prevalence
of dementia, especially in Alzheimer’s disease (AD)
[1]. About two-thirds of AD patients are women [2].
Women show faster cognitive decline after diagnosis of
mild cognitive impairment (MCI) or dementia, suggest-
ing that sex is a crucial variable in disease severity and
consequent heterogeneity [3].
Among women aged 60years or older, studies showed
a higher prevalence of AD and MCI than men of the
same age [4]. ese differences are not fully explained
by societal and lifestyle risk factors [5]. Other factors
may contribute to sex differences, including differences
in longevity, biological factors (reproduction, sex hor-
mones), gender roles and opportunities (education and
income, leisure activities post-retirement), and medical
factors [6]. For example, early surgically induced men-
opause has been shown to be associated with higher
risk of cognitive decline and dementia [7], although the
findings with natural menopause were inconsistent [8,
9].
Increasingly, cardiovascular diseases (CVD), including
coronary heart disease (CHD), stroke, and heart failure,
have been shown to affect the risk of developing vascular
dementia (VD) [10] and AD [11]. Studies have examined
the sex differences in the association between major car-
diovascular risk factors (e.g., hypertension and diabetes)
in midlife and dementia [12, 13], while sex differences
between CVD events (i.e., CHD, stroke and heart failure)
and dementia remain unclear. Further, in the association
between CVD and dementia, there might be sex-specific
interactions with social (e.g., education, income, and
leisure activities), lifestyle (smoking, body mass index
(BMI), leisure activities, and physical activities), genetic
factors (apolipoprotein E (APOE) allele status), and med-
ical history (hypertension and diabetes status). Accord-
ingly, we designed this study to assess the sex-specific
difference in dementia risk associated with CVDs, includ-
ing its unique interaction with social, behavioral, genetic,
and medical factors.
Methods
Participants
e UK Biobank is a large population-based prospec-
tive cohort study that recruited over 502,000 participants
aged 40–70 years from 2006 to 2010. Individuals were
invited to attend one of the 22 centers for baseline assess-
ment. Written informed consent was obtained for collec-
tion of questionnaire and biological data. All participants
were linked to hospital data and national death regis-
tries from England, Scotland, and Wales [12] to deter-
mine the date of the first diagnosis of CVD and dementia
after the baseline assessment. UK Biobank received
ethical approval from the UK National Health Service’s
National Research Ethics Service (ref 11/NW/0382).
is research was conducted under UK Biobank applica-
tion number 68369. A prospective analysis was adopted
based on participants with no dementia at baseline, and
if a participant had dementia during follow-up and also
experienced CVD, his/her diagnosis of CVD had to be
in advance of dementia. is study is reported as per the
Strengthening the Reporting of Observational Studies in
Epidemiology (STROBE) guidelines (Additional file1).
Exposure andoutcome variables
e exposure variable was the occurrence of first non-
fatal CVD event (a composite of either incident CHD
or heart failure or stroke). Physician-diagnosed CVD
was ascertained from hospital medical records. When
ascertained from hospital records, CHD was defined by
the International Classification of Diseases 10th Edition
(ICD-10) codes I21–I25, or defined by ICD-9 codes 410–
413. Incident stroke was defined by the ICD-10 codes
I60–I61, and I63–I64, or ICD-9 codes 430–434. Heart
failure was defined by the ICD-10: I50.
e study endpoint was incident fatal or non-fatal all-
cause dementia, including dementia subtypes of AD and
VD. e ICD-10 codes F00, F01, F02, F03, G30, G31·0,
G31·8 and ICD-9 code 290·1 were used to identify par-
ticipants with all-cause dementia if one or more of these
codes were recorded as a primary or secondary diagnosis
• We evaluated the sex-specific difference in dementia risk associated with CVDs, including its unique interaction
with social, behavioral, genetic, and medical factors.
• Women with coronary heart disease and heart failure were 1.6 and 1.3 times more likely to develop Alzheimer’s
disease than men with the same condition.
• Men with heart failure had 1.4 times higher risk of having vascular dementia than women.
• Socioeconomic, lifestyle, genetic, and medical factors moderated the sex-specific association between CVD and
dementia.
Keywords: Sex difference, Coronary heart diseases, Stroke, Heart failure, Alzheimer’s disease, Vascular dementia,
Cohort study

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Dongetal. Biology of Sex Dierences (2022) 13:21
in the health records. Incident AD was defined by ICD-
10 codes F00, G30 and ICD-9 code 290·1. Incident VD
was defined by ICD-10 code F01. Outcome adjudication
for incident dementia was conducted by the UK Biobank
Outcome Adjudication team.
Covariates
We included the following factors in the analyses as
covariates according to evidence from previous stud-
ies [11, 12]: age at baseline, race/ethnicity, years of edu-
cation, income level, smoking status, physical activity
strength, number of leisure activities, BMI, hypertension
status, type 2 diabetes status, and APOE allele status.
Race/ethnicity was categorized as white and non-white.
Years of education was categorized as ≤ 10, 11–12,
and > 12years. Income level was divided into four cate-
gories of level 1 (Less than £18,000), level 2 (£18,000 to
£30,999), level 3 (£31,000 to £51,999), and level 4 (greater
than 52,000). Smoking status was categorized as current,
former, or never smokers. Physical activity level was cate-
gorized as light (< 600 metabolic equivalent (MET)-min/
week), moderate (600 to < 3000 MET-min/week), and
high (≥ 3000 MET-min/week) based on standard scor-
ing criteria. Number of leisure activities was categorized
as none, one, and two or more. BMI was categorized
according to the World Health Organization criteria
as < 25 kg/m2, 25 to 29.9kg/m2, and ≥ 30 kg/m2. Hyper-
tension or diabetes status was dichotomized as present or
absent based on self-report at baseline. APOE allele sta-
tus was based on two single nucleotide polymorphisms
(SNPs): rs7412 and rs429358. Participants with APOE
e4 allele (e3/e4, e4/e4, and occasionally e2/e4 genotypes)
were compared with those with the e2/e2, e2/e3, or e3/e3
genotype.
Statistical analyses
Baseline characteristics are presented as means and
standard deviation (SD) for continuous variables and as
percentages (%) for categorical variables. Cox propor-
tional hazards regression models were used to estimate
the sex-specific hazard ratios (HR) and 95% confidence
intervals (CI) between CVD (including any CVD, CHD,
stroke, and heart failure) and dementia (including all-
cause dementia, AD, and VD). e proportional hazards
(PH) assumption was tested graphically using a plot of
the log cumulative hazard, where the logarithm of time
is plotted against the estimated log cumulative hazard.
e curves for the two CVD status (experienced or not)
were approximately parallel; thus, the PH assumption
was deemed reasonable. e interaction term between
CVD types and sex was used to obtain the women-to-
men ratio of hazard ratios (RHR) for each dementia type
and the type of CVD event. Hospital inpatient data and
death data were censored on the 30 January 2021 or when
death, fatal, or non-fatal dementia was recorded. For par-
ticipants who experienced a dementia, follow-up time
was calculated as their age when dementia was diagnosed
minus baseline age; for participants without experiencing
dementia, follow-up time was defined as their age at last
follow-up (censored date) minus baseline age. We first
analyzed CVD types and incident all-cause dementia, fol-
lowed by separate analyses for incident AD and VD. HRs
(95% CI) were adjusted for age at baseline, race/ethnicity,
years of education, income level, smoking status, physical
activity level, number of leisure activities, BMI, hyper-
tension status, type 2 diabetes status, and APOE4 allele
status.
Subgroup analysis andsensitivity analysis
To examine whether timing of CVD occurrence mod-
erates the association between CVD and dementia, we
divided people with CVD into two categories of age of
first C VD < 65years and ≥ 65years. Also, to examine the
association between CVD and timing of dementia, peo-
ple were separated by age of diagnosis of dementia < 75
and ≥ 75 years. In addition, we also examined the role
of gender related social factors (i.e., education, income,
and leisure activities), lifestyle factors (smoking, BMI,
and physical activities), genetic factors (number of APOE
e4 allele), and medical history (hypertension and diabe-
tes status) on the sex-specific association between CVD
and all-cause dementia by combining these factors with
sex and CVD. ese factors with each type of CVD and
dementia subtypes were also analyzed. Finally, to avoid
reverse causation, we performed a sensitivity analysis,
including CVD events which occurred at least 3 and 5
years before dementia.
Results
Characteristics ofparticipants (Table1)
Overall, 464,616 participants were included in the analy-
sis, with a mean (SD) age at baseline of 56.6 (8.1) years,
and 54.0% of them were females. A majority of them
(94.9%) were White individuals. e mean (SD) follow-
up was 11.2 (1.5) years. e crude incidence rates of all-
cause dementia were 9.2 for women and 12.4 for men, per
10,000 person-years. In both males and females, the inci-
dence of dementia was lower in people with higher edu-
cational level, higher income level, and a greater number
of leisure activities, while the incidence was higher in
people with diabetes, hypertension, and two apoE4
alleles. Besides, in females, the prevalence of dementia
was higher in underweight women than in normal or
overweight/obese women. In males, the prevalence of
dementia was higher in ever smokers.

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Dongetal. Biology of Sex Dierences (2022) 13:21
Table 1 Characteristics of participants by sex, CVD and dementia experienced or not, n (%)
Characteristics N CVD experienced or not Dementia experienced or not
Female (n = 251,039) Male (n = 213,577) Female (n = 251 039) Male (n = 213,577)
No
(n = 239,138) Yes
(n = 11,901) No
(n = 189,827) Yes
(n = 23,750) No
(n = 248,461) Yes
(n = 2578) No
(n = 210,628) Yes
(n = 2949)
Race/ethnicity
White 440,922 227,070 (51.5) 11,267 (2.6) 179,911 (40.8) 22,674 (5.1) 235,855 (53.5) 2482 (0.6) 199,760 (45.3) 2825 (0.6)
Non-White 23,694 12,068 (50.9) 634 (2.7) 9916 (41.9) 1076 (4.5) 12,606 (53.2) 96 (0.4) 10,868 (45.9) 124 (0.5)
Education level (years)
< = 10 228,838 115,524 (50.5) 7674 (3.4) 91,069 (39.8) 14,571 (6.4) 121,590 (53.1) 1608 (0.7) 103,844 (45.4) 1796 (0.8)
11–12 55,721 30,873 (55.4) 1170 (2.1) 21,461 (38.5) 2217 (4) 31,763 (57.0) 280 (0.5) 23,394 (42) 284 (0.5)
> 12 180,057 92,741 (51.5) 3057 (1.7) 77,297 (42.9) 6962 (3.9) 95,108 (52.8) 690 (0.4) 83,390 (46.3) 869 (0.5)
Physical activity level (MET)
Light (< 600) 105,714 55,336 (52.4) 3395 (3.2) 40,892 (38.7) 6091 (5.8) 58,142 (55) 589 (0.6) 46,295 (43.8) 688 (0.7)
Moderate
(600–3000) 186,389 99,987 (53.6) 4710 (2.5) 72,402 (38.8) 9290 (5) 103,610 (55.6) 1087 (0.6) 80,512 (43.2) 1180 (0.6)
High (≥ 3000) 172,513 83,815 (48.6) 3796 (2.2) 76,533 (44.4) 8369 (4.9) 86,709 (50.3) 902 (0.5) 83,821 (48.6) 1081 (0.6)
Income level (£)
Less than
18,000 104,445 57,177 (54.7) 4994 (4.8) 34,189 (32.7) 8085 (7.7) 61,014 (58.4) 1157 (1.1) 41,134 (39.4) 1140 (1.1)
18,000 to
30,999 113,933 60,359 (53) 3156 (2.8) 43,862 (38.5) 6556 (5.8) 62,825 (55.1) 690 (0.6) 49,542 (43.5) 876 (0.8)
31,000 to
51,999 120,669 61,580 (51) 2044 (1.7) 52,124 (43.2) 4921 (4.1) 63,212 (52.4) 412 (0.3) 56,514 (46.8) 531 (0.4)
Greater than
52,000 125,569 60,022 (47.8) 1707 (1.4) 59,652 (47.5) 4188 (3.3) 61,410 (48.9) 319 (0.3) 63,438 (50.5) 402 (0.3)
No. of leisure activities
No 131,434 67,325 (51.2) 3877 (3) 52,972 (40.3) 7260 (5.5) 70,384 (53.6) 818 (0.6) 59,303 (45.1) 929 (0.7)
One 202,587 101,469 (50.1) 4987 (2.5) 85,320 (42.1) 10,811 (5.3) 105,303 (52) 1153 (0.6) 94,739 (46.8) 1392 (0.7)
Two or more 130,595 70,344 (53.9) 3037 (2.3) 51,535 (39.5) 5679 (4.4) 72,774 (55.7) 607 (0.5) 56,586 (43.3) 628 (0.5)
Body mass index (kg/m2)
Under-
weight < 18.5 2398 1847 (77.0) 68 (2.8) 445 (18.6) 38 (1.6) 1887 (78.7) 28 (1.2) 470 (19.6) 13 (0.5)
Normal
[18.5,25.0) 153,058 96,724 (63.2) 2739 (1.8) 49,653 (32.4) 3942 (2.6) 98,551 (64.4) 912 (0.6) 52,847 (34.5) 748 (0.5)
Overweight
[25.0,30.0) 198,230 87,839 (44.3) 4369 (2.2) 95,114 (48) 10,908 (5.5) 91,227 (46) 981 (0.5) 104,683 (52.8) 1339 (0.7)
Obese > = 30 110,930 52,728 (47.5) 4725 (4.3) 44,615 (40.2) 8862 (8) 56,796 (51.2) 657 (0.6) 52,628 (47.4) 849 (0.8)
Smoking status
Never 254,650 143,769 (56.5) 5821 (2.3) 96,819 (38) 8241 (3.2) 148,187 (58.2) 1403 (0.6) 103,917 (40.8) 1143 (0.5)
Past 162,083 74,956 (46.3) 4582 (2.8) 70,301 (43.4) 12,244 (7.6) 78,601 (48.5) 937 (0.6) 81,077 (50) 1468 (0.9)
Current 47,883 20,413 (42.6) 1498 (3.1) 22,707 (47.4) 3265 (6.8) 21,673 (45.3) 238 (0.5) 25,634 (53.5) 338 (0.7)
Diabetes status
No 440,477 231,924 (52.7) 10,368 (2.4) 178,735 (40.6) 19,450 (4.4) 239,963 (54.5) 2329 (0.5) 195,749 (44.4) 2436 (0.6)
Yes 24,139 7214 (29.9) 1533 (6.4) 11,092 (46) 4300 (17.8) 8498 (35.2) 249 (1) 14,879 (61.6) 513 (2.1)
Hypertension status
No 336,017 183,668 (54.7) 4749 (1.4) 136,517 (40.6) 11,083 (3.3) 186,945 (55.6) 1472 (0.4) 145,983 (43.5) 1617 (0.5)
Yes 128,599 55,470 (43.1) 7152 (5.6) 53,310 (41.5) 12,667 (9.9) 61,516 (47.8) 1106 (0.9) 64,645 (50.3) 1332 (1)
APOE
No apoE4 112,993 56,186 (49.7) 3135 (2.8) 47,608 (42.1) 6064 (5.4) 58,874 (52.1) 447 (0.4) 53,030 (46.9) 642 (0.6)
One apoE4 342,293 178,142 (52) 8535 (2.5) 138,430 (40.4) 17,186 (5) 184,815 (54) 1862 (0.5) 153,568 (44.9) 2048 (0.6)
Two apoE4 9330 4810 (51.6) 231 (2.5) 3789 (40.6) 500 (5.4) 4772 (51.2) 269 (2.9) 4030 (43.2) 259 (2.8)

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Dongetal. Biology of Sex Dierences (2022) 13:21
CVD events anddementia (Table2)
Compared to people who did not experience any CVD
event, people who experienced CVD had higher risk of
all-cause dementia, AD, and VD, with HRs (95% CI) of
2.20 (2.06, 2.35), 1.71 (1.53, 1.90), and 3.37 (2.98, 3.82)
respectively. e association of CVD with AD was higher
in women (HR 2.07, 95% CI: 1.75–2.45) than in men
(1.46, 1.26–1.68), with an RHR (Female/Male) of 1.50
(1.34, 1.67). After the relationships between specific types
of CVD events and AD were analyzed, the sex difference
was only observed for the association between CHD and
AD, or heart failure and AD, with RHR (Female/Male)
95% CI of 1.63 (1.39, 1.91) and 1.32 (1.07, 1.62), respec-
tively. In contrast to the sex difference between CVD and
AD, the association of overall CVD with VD was higher
in men (3.35, 2.87–3.91) than in women (2.77, 2.21–3.47),
with an RHR (female/male) of 0.86 (0.75, 0.98). After
types of CVD and VD were analyzed, the sex difference
was only observed between heart failure and VD, with an
RHR (95% CI) (female/male) of 0.73 (0.57, 0.93). Sensi-
tivity analysis, including CVD events which occurred at
least three years or five before occurrence of dementia,
showed consistent results (Additional file 1: Tables S1
and S2).
Subgroup analyses byage whenexperienced CVD,
socioeconomic, lifestyle, genetic, andmedical factors
Analyses stratified by age when experienced CVD (before
or after 65years) showed that in women, the associations
of CVD with AD and VD were not different by age at
the onset of CVD, while men with CVD after age 65 had
higher risk of AD and VD than those with CVD before age
65 (Fig.1). e risk of dementia was much higher in peo-
ple with two apoE4 alleles in both men and women. Peo-
ple who experienced CVD and had two apoE4 alleles had
around 10 times higher risk of having dementia (Fig.2).
In people without CVD, higher income level was related
to lower risk of dementia, while in people with CVD, a
J-shape relationship was observed between income level
and dementia (Fig. 3). Both lower and higher income
levels were related to higher risk of dementia, but the
increased risk was greater in those with lower incomes.
e roles of education, leisure activity, BMI, smoking,
physical activity, hypertension and diabetes status in
CVDs, and dementia subtypes are shown in Additional
file1: Figs. S1–S7. In people with CVD, a J-shape rela-
tionship was observed between BMI level and VD. Both
lower and higher BMI levels were related to higher risk of
VD, but the increased risk was greater in those with lower
BMI. When BMI was assessed in 10years before dementia
diagnosis (i.e., late-life BMI), greater BMI was related to
lower risk of dementia (Additional file1: TableS3). Higher
number of leisure activities was consistently linked to
lower risk of dementia, and no protective effect of educa-
tion on VD was observed in CVD patients.
Discussion
CHD anddementia
A few systematic reviews and meta-analysis have
examined the association between CHD and all-cause
Table 2 Sex-specific hazard ratios (HRs) and 95%CIs between cardiovascular disease (CVD) events and dementia subtypes: a
prospective analysis
All HRs were adjusted for age at baseline, race/ethnicity, educational years, income level, physical activity level, leisure activities, body mass index (BMI), smoking
status, diabetes status, hypertension status, and APOE
Dementia Sex Did not
experience any
CVD event
Experienced any
CVD Only experienced
CHD Only experienced
stroke Only
experienced
heart failure
All-cause dementia All participants Reference 2.20 (2.06, 2.35) 1.69 (1.53, 1.86) 2.37 (2.05, 2.75) 2.19 (1.95, 2.46)
Female Reference 2.31 (2.07, 2.57) 1.84 (1.55, 2.18) 2.40 (1.91, 3.02) 2.10 (1.73, 2.54)
Male Reference 2.01 (1.85, 2.18) 1.52 (1.35, 1.71) 2.24 (1.86, 2.71) 2.14 (1.85, 2.47)
Ratio of HR (female/
male) 1.20 (1.13, 1.28) 1.28 (1.15, 1.42) 1.12 (0.97, 1.31) 1.00 (0.89, 1.13)
Alzheimer’s disease All participants Reference 1.71 (1.53, 1.90) 1.50 (1.28, 1.75) 1.48 (1.12, 1.95) 1.57 (1.28, 1.92)
Female Reference 2.07 (1.75, 2.45) 1.92 (1.50, 2.46) 1.44 (0.93, 2.23) 1.76 (1.30, 2.40)
Male Reference 1.46 (1.26, 1.68) 1.25 (1.03, 1.53) 1.44 (1.00, 2.06) 1.39 (1.05, 1.82)
Ratio of HR (female/
male) 1.50 (1.34, 1.67) 1.63 (1.39, 1.91) 1.06 (0.80, 1.41) 1.32 (1.07, 1.62)
Vascular dementia All participants Reference 3.37 (2.98, 3.82) 2.01 (1.66, 2.45) 5.01 (4.00, 6.27) 2.99 (2.41, 3.72)
Female Reference 2.77 (2.21, 3.47) 1.94 (1.34, 2.79) 4.13 (2.78, 6.14) 2.27 (1.52, 3.41)
Male Reference 3.35 (2.87, 3.91) 1.89 (1.50, 2.38) 5.24 (3.98, 6.91) 3.22 (2.49, 4.16)
Ratio of HR (Female/
Male) 0.86 (0.75, 0.98) 1.05 (0.84, 1.30) 0.82 (0.64, 1.04) 0.73 (0.57, 0.93)

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Dongetal. Biology of Sex Dierences (2022) 13:21
dementia and dementia subtypes [14, 15]. A recent review
found that CHD was associated with 27% higher risk of
all-cause dementia, and analyses with dementia subtypes
showed that the significant association was only observed
between CHD and VD (RR 1.34, 95% CI 1.28–1.39), but
not with AD (0.99, 0.92–1.07) [14]. Similarly, Wolters
FJ etal. reported that the association of CHD with all-
cause dementia and AD were (1.27, 1.08–1.50) and (1.07,
0.90–1.28), respectively [15]. However, these reviews did
not separate the association by sex and examine the sex
difference. Consistent with prior studies, we found that
CHD was linked to 65% higher risk of all-cause dementia,
and significant associations were observed with dementia
subtypes of both AD and VD. In addition, there was also
sex differences in the relationship between CHD and all-
cause dementia and AD. Women who experienced CHD
was 1.60 times more likely to develop AD than men.
Heart failure anddementia
A recent review found that the RR (95% CI) between
heart failure and all-cause dementia, AD, was (1.59, 1.19–
2.13) and (1.44, 0.95–2.16), respectively [15]. Similarly,
Cannon et al. also reported that the risk for all-cause
dementia and cognitive impairment in the heart failure
population was 2.64 (95% 1.83–3.80) [16]. In line with
the findings of previous studies, we observed a higher
risk (HR 2.63, 95% CI 2.35–2.95) of all-cause dementia in
people with heart failure. In contrast to previous reviews
which reported no association between heart failure and
AD (possibly due to the high heterogeneity among stud-
ies) [15, 17], we also found significant associations with
AD (1.92, 1.56–2.35) and VD (3.67, 2.96–4.55). In addi-
tion, a clear sex difference was observed in the associa-
tion between heart failure and VD. Compared to women
with heart failure, men with heart failure were about 1.5
times (i.e., inverse of 0.68) more likely to develop VD.
Stroke anddementia
A review by Kuzma etal. found that patients with preva-
lent stroke were 2.18 (1.90–2.50) times more likely to
experience all-cause dementia [18]. Likewise, Zhu et al.
reported a 2.40 times higher risk of all-cause dementia in
people with stroke [19]. Consistent to previous findings,
we observed that people who experienced stroke had 2.39
times higher risk of developing all-cause dementia. Fur-
ther analyses showed that the elevated risk was mainly
reflected in the association with VD (HR: 5.05 with VD vs
1.51 with AD). Evidence has shown that stroke survivors
are at increased risk of developing post-stroke VD [20].
No substantial gender difference for the risk of AD and
Fig. 1 Sex differences in the association between cardiovascular diseases (CVD) and dementia by age when experienced CVD

Page 7 of 11
Dongetal. Biology of Sex Dierences (2022) 13:21
Fig. 2 Sex differences in the association between cardiovascular diseases (CVD) and dementia by apoE4 status

Page 8 of 11
Dongetal. Biology of Sex Dierences (2022) 13:21
Fig. 3 Sex differences in the association between cardiovascular diseases (CVD) and dementia by income levels

Page 9 of 11
Dongetal. Biology of Sex Dierences (2022) 13:21
VD after stroke was found, in line with previous report
[21].
Mechanisms
Several mechanisms might contribute to the sex differ-
ence in the association between CVD and dementia.
First, the development, manifestation, and complica-
tions of CVD may differ by sex [22], affecting the “heart-
to-brain” connection. Heart diseases (e.g., heart failure)
affect the cardiac output, leading to cerebral hypoperfu-
sion [23]. e latter contributes to the formation of tau-
containing neurofibrillary tangles and amyloid β (Aβ)
plaques which characterize AD [24]. Research has shown
heart failure with reduced ejection fraction (EF) more
frequently affects men, and heart failure with preserved
EF more frequently affects women [25]. Reduced EF have
exaggerated reductions in cerebral blood flow [26]. is
may explain why men with heart failure had greater risk
of VD than women in our finding. In addition, myocar-
dial infarctions (MI) are more severe in women than in
men. In the first year after MI, women are 1.5 times more
likely to die compared to their male counterparts [27].
Further, women were more likely than men to be older
and have a more complicated medical history at the time
of their MI [22], which may also affect the heart-to-brain
connection in women. Second, there might be an inter-
action between sex, cardiovascular, and genetic risk fac-
tors, which are all related to risk of CVD and dementia.
Hypertension in midlife increased the risk of dementia
among women only, although hypertension was more
prevalent among men in midlife [13]. Also, depression
and sleep disorders, both risk factors for AD, are also
known to be more prevalent in women [28]. Sex also
modulates the susceptibility to AD conferred by APOE
genotype. APOE e4 was associated with a higher risk
of AD in females than in males [29]. Also, there was a
strong association between APOE 4 (ε3ε4 and ε4ε4) and
CHD [30], indicating APOE 4 might be a confounder in
the relationship between CHD and AD. us, the sex
difference association between CVD and AD might be
cofounder by APOE4. Nevertheless, the APOE4 allele
status was adjusted in our analyses. e sex difference
between the two cannot be fully explained by the sex dif-
ferences in the association between APOE4 allele and
AD. Last, some sex-specific risk factors might play a role
in the observed sex differences. Pre-eclampsia has been
associated with higher risks of cardiovascular disease,
cognitive impairment later in life, and protein misfolding
with defective amyloid processing [3]. Early menopause
(either natural or surgical menopause) has been associ-
ated with higher risks of cognitive decline, and dementia
and 1.5–2 times elevated risk of CHD and stroke [31, 32].
ese female-specific factors confer excess risk to both
cardiovascular diseases and AD in women.
Socioeconomic, lifestyle, andmedical risk factors
Higher education and income, more leisure activities,
and greater physical activity are viewed as protective fac-
tors for both CVD and dementia, and women in older
cohorts often had less educational attainment and physi-
cal activity opportunity [3]. We found in people with no
CVD, higher education was protective against dementia,
while no clear protective effect was observed in people
with CVD (especially for VD). In people without expe-
riencing CVD, we found higher income was associated
with lower risk of dementia, while in people who expe-
rienced CVD, there was a J-shape relationship between
income level and dementia. It is possible that people with
higher income and heart disease may have more oppor-
tunity to be diagnosed earlier if they had dementia [33].
Either with or without CVD, we observed a consist-
ent trend that more leisure activities had lower risk of
dementia. Besides, the protective effect of leisure activity
is more evident in male CVD patients than females in the
association with VD. Although some studies found physi-
cal activity at midlife is associated with a decreased risk
of AD [6], we did not observe a clear association between
them. e evidence between the BMI and dementia is
still mixed. Two million-size population studies found
that risk of dementia decreased with the growing BMI
category, and per 5-kg/m2 increase in BMI was linked
to 29% lower risk of dementia [34, 35]. We also found
greater BMI was associated with less risk of AD in both
men and women, not interacted by CVD experienced
or not. Current smokers had elevated risk of dementia,
especially for VD in men who experienced CVD. Con-
sistent with Gong J etal. study [12], no clear interplay of
diabetes on the relationship between CVD and all-cause
dementia was observed, though risk of VD was higher in
men than women with CVD and diabetes.
Strengths andlimitations
One strength of our study was the large sample size
which enable us to explore the relationship between CVD
subtypes and dementia subtypes, considering joint effect
with socio-behavioral and biological factors. Also, both
CVD events and dementia outcomes were ascertained
through linkage to medical or insurance records, avoid-
ing self-reported bias. To the best of our knowledge, this
is the first study to systematically evaluate the sex dif-
ference in association between CVD and dementia sub-
types, and examine the roles of socioeconomic, lifestyle,
genetic, and medical factors in their associations. Our
study also has several limitations. When compared the
sex-specific association of CVD and dementia, we did

Page 10 of 11
Dongetal. Biology of Sex Dierences (2022) 13:21
not consider the severity of a certain CVD event in men
and women. MI is generally more severe in women than
in men over 65years of age [36]. e association of CHD
with dementia in females might be underestimated. Also,
there might be some other confounding factors that co-
drive the relationship between CVD and dementia, e.g.,
diet. In addition, the observed relationship is limited
to people of Caucasian ancestry, which may limit the
extrapolation of the results.
Perspectives andsignicance
Women with CVD had higher risk of developing all-
cause dementia than men. e risk for AD was greater in
women with CHD and heart failure than in men, while
the risk for VD was greater in men with heart failure than
in women. ere is no current cure for dementia, iden-
tifying sex-specific at-risk populations after experiencing
CVDs is essential for adopting sex-sensitive strategies
for secondary prevention of dementia. Further research
to explore the sex differences in CVD, including the dif-
ferences in clinical symptoms and treatment, may help
understand the sex-specific association between CVD
and dementia.
Supplementary Information
The online version contains supplementary material available at https:// doi.
org/ 10. 1186/ s13293- 022- 00431-5.
Additional le1. Additional information about the results of CVD events
which occurred at least three years or five before occurrence of dementia
and the roles of education, leisure activity, BMI, smoking, physical activ-
ity, hypertension, and diabetes status in CVDs and dementia subtypes.
TableS1. Sex-specific hazard ratios (HRs) between cardiovascular disease
and dementia subtypes (CVD events occurred at least three years before
dementia): sensitivity analysis. TableS2. Sex-specific hazard ratios (HRs)
between cardiovascular disease and dementia subtypes (CVD events
occurred at least five years before dementia): sensitivity analysis. Figure
S1. Sex differences in the association between cardiovascular diseases
(CVD) and dementia by educational years. Figure S2. Sex differences in
the association between cardiovascular diseases (CVD) and dementia by
number of leisure activities. Figure S3. Sex differences in the association
between cardiovascular diseases (CVD) and dementia by body mass index
(BMI). Figure S4. Sex differences in the association between cardiovas-
cular diseases (CVD) and dementia by smoking status. Figure S5. Sex
differences in the association between cardiovascular diseases (CVD) and
dementia by physical activities. Figure S6. Sex differences in the associa-
tion between cardiovascular diseases (CVD) and dementia by diabetes
status. Figure S7. Sex differences in the association between cardiovascu-
lar diseases (CVD) and dementia by hypertension status.
Acknowledgements
This research has been conducted using the UK Biobank resource. The authors
are grateful to UK Biobank participants.
Author contributions
DZ conceived the study and contributed to interpretation of the results. CD
did statistical analyses and draft the first manuscript. CZ, CF, and WH searched
databases and prepared data. AO, NS, SSV, SRM, and DZ contributed to critical
revision of the manuscript. All authors read and approved the final manuscript.
Funding
This study was supported by the Start-up Foundation for Scientific Research in
Shandong University (202099000066) and Science Fund Program for Excellent
Young Scholars (Overseas) in Shandong Province.
Availability of data and materials
UK Biobank data are available via www. ukbio bank. ac. uk. Syntax for the
generation of derived variables and for the analysis used for this study will be
submitted to UK Biobank for record.
Declarations
Ethics approval and consent to participate
All procedures performed in studies involving human participants were in
accordance with the ethical standards of the institutional and/or national
research committee and with the 1964 Helsinki declaration and its later
amendments or comparable ethical standards. As part of the UK Biobank
recruitment process, informed consent was obtained from all individual
participants included in this study.
Consent for publication
Not applicable.
Competing interests
Dr. Virani reports grants from Department of Veterans Affairs, NIH, World Heart
Federation, Tahir and Jooma Family, other from being an associate editor for
Innovations of American College of Cardiology (acc.org), outside the submit-
ted work. All the other authors report no conflicts.
Author details
1 Centre for Health Management and Policy Research, School of Public Health,
Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
2 NHC Key Lab of Health Economics and Policy Research, Shandong Univer-
sity, Jinan 250012, China. 3 Department of Breast Surgery, Jyoban Hospital
of Tokiwa Foundation, Iwaki, Fukushima, Japan. 4 Department of Gastrointesti-
nal Tract Surgery, Fukushima Medical University, Fukushima, Japan. 5 Depart-
ment of Primary Care and Mental Health, University of Liverpool, Liverpool,
UK. 6 Michael E. DeBakey VA Medical Center and Baylor College of Medicine,
Houston, TX, USA. 7 Academy for Data Sciences and Global Health, Kathmandu,
Nepal. 8 Melbourne School of Population and Global Health, The University
of Melbourne, Melbourne, VIC, Australia. 9 Department of Epidemiology,
School of Public Health, Cheeloo College of Medicine, Shandong University, 44
Wenhuaxi Road, Jinan 250012, Shandong, China.
Received: 26 February 2022 Accepted: 23 April 2022
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