Genetic Risk for Alzheimer Disease, Midlife Hypertension, and Dementia: The ARIC Neurocognitive Study

Topic: Amyloid, tau and blood-test diagnosis

Background and objectives Genetics represent a nonmodifiable risk factor for Alzheimer disease (AD), with 60%-80% heritability. Midlife hypertension is a modifiable risk factor for both dementia and death. Our primary objective was to determine how genetic risk for AD modifies the association between hypertension and dementia. Methods The Atherosclerosis Risk in Communities Study is an ongoing community-based prospective cohort study of 4 US centers. We analyzed White and Black participants free of dementia at age 55 years with genotypes and blood pressure measured at visit 1 (1987-1989). Three genetic risk groups (low, medium, high) were defined based on tertiles of a race-specific AD polygenic risk score. Dementia was ascertained through cognitive testing, informant interviews, hospitalization, codes and death records. Death was ascertained through the National Death Index. We examined the association of midlife hypertension with incident dementia within 3 genetic risk groups using Cox proportional-hazards and cumulative incidence function estimations. We used age 55 years as the time origin, with left truncation to allow entry at ages older than 55 years; age on December 31, 2022, was the administrative censoring date. Results Among 8,931 White and 2,666 Black participants, the median follow up time was 26.6 and 23.8 years, the mean age was 54.0/53.5 years, and 53.0%/62.5% were female, respectively. After adjusting for demographics, midlife hypertension was significantly associated with dementia incidence across all genetic risk groups among White participants (low risk hazard ratio [HR] 1.29; 95% CI 1.07-1.55, medium risk HR 1.34; 95% CI 1.13-1.58, high risk HR 1.19; 95% CI 1.03-1.38) and among Black participants at high genetic risk (HR 1.31; 95% CI 1.04-1.66). Associations for low and medium genetic risk Black participants were consistent but not statistically significant. There were no significant differences in association of hypertension with dementia by AD genetic risk group. Individuals with hypertension had a 0%-2% higher probability of developing dementia by age 80 and a 6%-13% lower probability of dementia-free survival to age 80 years vs those without hypertension, across race and genetic risk groups. Discussion Genetic risk for AD does not modify the association between hypertension and dementia. These data support the fact that all individuals with hypertension are likely to benefit from antihypertensive treatment.

Key findings

• Results Among 8,931 White and 2,666 Black participants, the median follow up time was 26.6 and 23.8 years, the mean age was 54.0/53.5 years, and 53.0%/62.5% were female, respectively.
• After adjusting for demographics, midlife hypertension was significantly associated with dementia incidence across all genetic risk groups among White participants (low risk hazard ratio [HR] 1.29; 95% CI 1.07-1.55, medium risk HR 1.34; 95% CI 1.13-1.58, high risk HR 1.19; 95% CI 1.03-1.38) and among Black participants at high genetic risk (HR 1.31; 95% CI 1.04-1.66).
• Associations for low and medium genetic risk Black participants were consistent but not statistically significant.
• There were no significant differences in association of hypertension with dementia by AD genetic risk group.

Why it matters

In this cohort, midlife hypertension was significantly associated with dementia incidence across all genetic risk groups among White participants and among Black participants. The study examined how genetic risk for Alzheimer's disease modifies the link between midlife hypertension and dementia.

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Study details

• Study designcohort
• Participants11,597
• Effect sizeMidlife hypertension HR for dementia 1.19-1.34 across genetic risk tertiles (white participants); 1.31 (95% CI 1.04-1.66) in high-risk Black participants
• Evidence strengthModerate

Limitations

Observational; polygenic risk scores are race-specific and less validated in Black participants; blood pressure measured at one midlife visit; treatment effects not directly tested.

Read the original

• DOI: 10.1212/WNL.0000000000218280
• PubMed: 42385118
• Original source →

May need a subscription Unpaywall, Europe PMC and OpenAlex found no free copy of the full text (checked 10 Oct 2026), so the publisher may charge for it. The PubMed abstract is free.

@article{morrill2026-42385118,
  author  = {Morrill, V. N. and Pike, JR. and Hu, J. and Fornage, M. and Surapaneni, A. and Walker, K. A. and Knopman, D. S. and Mosley, T. H. and Coresh, J. and Schneider, A. L. C. and others},
  title   = {{Genetic Risk for Alzheimer Disease, Midlife Hypertension, and Dementia: The ARIC Neurocognitive Study}},
  journal = {Neurology},
  year    = {2026},
  doi     = {10.1212/WNL.0000000000218280},
  pmid    = {42385118},
  url     = {https://doi.org/10.1212/WNL.0000000000218280}
}

Studies this one cites

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• Association of Lifestyle and Genetic Risk With Incidence of Dementia JAMA · 2019-08-01 · usefulness score 78/100 · Prevention and risk
• New insights into the genetic etiology of Alzheimer's disease and related dementias Nature Genetics · 2022-04 · usefulness score 77/100 · Genetics
• African ancestry GWAS of dementia in a large military cohort identifies significant risk loci Molecular psychiatry · 2022-12-22 · usefulness score 75/100 · Disparities
• Associations Between Midlife Vascular Risk Factors and 25-Year Incident Dementia in the Atherosclerosis Risk in Communities (ARIC) Cohort JAMA neurology · 2017-10-01 · usefulness score 74/100 · Prevention and risk
• Association of Midlife to Late-Life Blood Pressure Patterns With Incident Dementia JAMA · 2019-08-01 · usefulness score 71/100 · Disparities
• Estimating the Prevalence of Dementia and Mild Cognitive Impairment in the US: The 2016 Health and Retirement Study Harmonized Cognitive Assessment Protocol Project JAMA neurology · 2022-12-01 · usefulness score 71/100 · Getting a diagnosis
• Validation of a polygenic risk score for dementia in black and white individuals Brain and behavior · 2014-07-18 · usefulness score 70/100 · Disparities
• Contribution of Modifiable Midlife and Late-Life Vascular Risk Factors to Incident Dementia JAMA Neurology · 2025-07-01 · usefulness score 69/100 · How common it is
• Validation of newly derived polygenic risk scores for dementia in a prospective study of older individuals Alzheimer's & Dementia · 2023-05-12 · usefulness score 66/100 · Genetics
• Association of apolipoprotein E allele ϵ4 with late‐onset familial and sporadic Alzheimer's disease Neurology · 1993-08-01 · usefulness score 65/100 · Genetics
• Role of genes and environments for explaining Alzheimer disease Archives of general psychiatry · 2006-02-01 · usefulness score 64/100 · How common it is
• Midlife hypertension and 20-year cognitive change: the atherosclerosis risk in communities neurocognitive study JAMA neurology · 2014-10-01 · usefulness score 58/100 · How common it is

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