Life Course Modifiable Risk Factors for Dementia Stratified by ApoE-4 Status - Abstract

Sep 29, 2026

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Study applying the 2024 Lancet dementia risk factor model tests gene-by-environment effects by stratifying modifiable exposures according to ApoE-4 carrier status. Replication in a single cohort identifies only a restricted subset of risk factors linked to late-life dementia. Among ApoE-4 carriers, mid-life diabetes increases dementia odds while mid-life hypertension reduces risk; among non-carriers, mid-life hearing loss and diabetes relate to higher odds. Findings emphasize incorporating gene-by-environment interactions when formulating dementia risk models.

LanguageEnglish

CategoryHealthcare

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Abstract

Replication and stratification approach

ApoE-4 carriers findings

ApoE-4 non-carriers findings

Implications for dementia risk models

636 Innovation in Aging, 2025, Vol. 9, No. S2 (also controlling for age and sex), stratified by ApoE-4 carrier status. Replication of the 2024 Lancet model in a single cohort revealed only a restricted subset of modifiable risk factors that associated with late-life dementia status. Among APoE-4 carriers only, we found that mid-life diabetes increased dementia odds, whereas mid-life hypertension reduced risk for dementia. Among ApoE-4 non-carriers, only mid-life hearing loss and diabetes associated with increased dementia odds. Overall, we observed slightly divergent dementia risk profiles based on ApoE-4 status, such that mid-life diabetes emerged as the primary risk factor for dementia among ApoE-4 carriers, whereas mid-life hearing loss was found to be most strongly associated with dementia risk among ApoE-4 non-carriers. Resultant findings highlight the importance of considering gene-by-environment interactions when formulating dementia risk models. Abstract citation ID: igaf122.2174 LIFE COURSE MODIFIABLE RISK FACTORS FOR DEMENTIA STRATIFIED BY APOE-4 STATUS Victoria Williams1, Ralph Trane1, Kamil Sicinski2, Carol Roan2, Pamela Herd3, Michal Engelman4, and Sanjay Asthana1, 1. University of Wisconsin–Madison School of Medicine and Public Health, Madison, Wisconsin, United States, 2. University of Wisconsin–Madison, Madison, Wisconsin, United States, 3. University of Michigan, Ann Arbor, Michigan, United States, 4. University of Wisconsin-Madison, Madison, Wisconsin, United States The 2024 Lancet Commission identified 14 modifiable risk factors reliably associated with increased risk for dementia. However, dementia is a complex condition influenced by both genetic predisposition and environmental factors, with gene by environment interactions often overlooked in risk models. Theapolipoprotein (ApoE-4) allele confers the strongest genetic risk for Alzheimer’s disease, while also shown to modify the effects of environmental exposures on the dementia phenotype. We applied the Lancet risk factor model to a single cohort of 5,526 participants in the Wisconsin Longitudinal Study (WLS) . Risk factors were defined by Lancet cut-points and life-course timing criteria, drawing from 70 years of prospectively collected WLSdata. We used logistic regression with multiple imputation to model dementia outcomes by the Lancet model risk factors

FAQs

What is the purpose of stratifying dementia risk factors by ApoE-4 status?

To evaluate gene-by-environment interactions by checking how the associations of modifiable risk factors with late-life dementia differ between ApoE-4 carriers and non-carriers.

Which modifiable risk factor increased dementia odds among ApoE-4 carriers?

Mid-life diabetes increased dementia odds among ApoE-4 carriers.

What factors were most strongly associated with dementia risk among ApoE-4 non-carriers?

Mid-life hearing loss and diabetes were associated with increased dementia odds among ApoE-4 non-carriers.

Sep 29, 2026

Upload by Oliver