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Sex differences in the association of vascular risk and APOE Genotype with cognitive decline and dementia: evidence from a U.S. longitudinal study
Journal article   Open access   Peer reviewed

Sex differences in the association of vascular risk and APOE Genotype with cognitive decline and dementia: evidence from a U.S. longitudinal study

Longjian Liu, Jintong Hou, Saishi Cui, Xiaopeng Zhao, Zuolu Liu, J. Craig Longenecker, Nathalie S. May, Jin Jun Luo, Rose Ann DiMaria-Ghalili and Howard J. Eisen
Lancet Regional Health - Americas (Online), v 54, 101346
Feb 2026
DOI: https://doi.org/10.1016/j.lana.2025.101346
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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https://doi.org/10.1016/j.lana.2025.101346View
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Abstract

Cognitive decline Genetic risk Longitudinal study Sex differences Vascular risk Dementia
Sex differences in the association between vascular factors and cognitive outcomes remain unclear. We aimed to investigate the associations of blood pressure metrics (hypertension, systolic blood pressure [SBP), pulse pressure, ankle and brachial pressures, and ankle to brachial pressure index [ABI]) with the risk of cognitive decline and dementia. We conducted a population-based longitudinal analysis using data from the Atherosclerosis Risk in Communities (ARIC) study (begun in 1987–1989) in the United States. We analyzed a total of 12,268 participants aged 45–64 years who had validated exposure measurements, cognitive function tests (first administrated 1990–1992), and followed up for incidence of dementia through December 2019. Cognitive function was assessed using the Digit Symbol Substitution Test, the Delayed Word Recall Test, and the Word Fluency Test. Dementia cases were identified through a standardized clinical evaluation process, mostly adjudicated by expert reviewers. We performed sex-stratified analyses to examine the associations of blood pressure metrics and APOE ε4 allele with the risk of cognitive decline and dementia. Over a median follow-up of 26.4 years, 2698 participants developed dementia. Women aged 55–64 had a significantly higher incidence of dementia than men aged 55–64 (14.8 vs. 11.8 per 1000 person-years; p <0.0001). After adjusting for key covariates, SBP, pulse pressure, ankle and brachial pressures were significantly associated with cognitive decline in women (p < 0.05). In men, pulse pressure and ankle pressure showed a significant association. In longitudinal analyses, baseline hypertension and elevated brachial pressure were significantly associated with increased dementia risk in women, whereas in men, elevated brachial pressure and decreased ABI were significantly associated with dementia risk. Individuals with APOE ε4 allele had significantly higher risk of dementia in both sexes. A joint effect of APOE ε4 allele and elevated blood pressure metrics conferred a greater relative excess risk of dementia in women vs. men. These findings highlight notable sex differences in the association between vascular factors and cognitive decline and dementia risk. Women appear more vulnerable to both genetic and vascular risk factors, emphasizing the need for sex-specific approaches in research, prevention, and intervention strategies for cognitive impairment. NIH.

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Collaboration types
Domestic collaboration
Web of Science research areas
Health Care Sciences & Services
Public, Environmental & Occupational Health
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