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Cited by 12Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsCognitive Abilities and Testing

Interactions between the apolipoprotein E4 gene and modifiable risk factors for cognitive impairment: a nationally representative panel study

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Kolli, Ajay, Zhou, Yunshu, Chung, Grace, Ware, Erin B., Langa, Kenneth M., Ehrlich, Joshua R.·2022·BMC Geriatrics
DOI 10.1186/s12877-022-03652-wPMC PMC9724385
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Abstract

Background: Few studies using rigorous clinical diagnosis have considered whether associations with cognitive decline are potentiated by interactions between genetic and modifiable risk factors. Given the increasing burden of cognitive impairment (CI) and dementia, we assessed whether Apolipoprotein E ε4 (APOE4) genotype status modifies the association between incident CI and key modifiable risk factors . Methods: Older adults (70+) in the US were included. APOE4 status was genotyped. Risk factors for CI were self-reported. Cognitive status (normal, CI, or dementia) was assigned by clinical consensus panel. In eight separate Cox proportional hazard models, we assessed for interactions between APOE4 status and other CI risk factors. Result: The analytical sample included 181 participants (mean age 77.7 years; 45.9% male). APOE4 was independently associated with a greater hazard of CI in each model (Hazard Ratios [HR] between 1.81–2.66, p < 0.05) except the model evaluating educational attainment (HR 1.65, p = 0.40). The joint effects of APOE4 and high school education or less (HR 2.25, 95% CI: 1.40–3.60, p < 0.001), hypertension (HR 2.46, 95% CI: 1.28–4.73, p = 0.007), elevated depressive symptoms (HR 5.09, 95% CI: 2.59–10.02, p < 0.001), hearing loss (HR 3.44, 95% CI: 1.87–6.33, p < 0.0001), vision impairment (HR 5.14, 95% CI: 2.31–11.43, p < 0.001), smoking (HR 2.35, 95% CI: 1.24–4.47, p = 0.009), or obesity (HR 3.80, 95% CI: 2.11–6.85, p < 0.001) were associated with the hazard of incident CIND (compared to no genetic or modifiable risk factor) in separate models. The joint effect of Apolipoprotein ε4 and type 2 diabetes was not associated with CIND (HR 1.58, 95% CI: 0.67–2.48, p = 0.44). Discussion: The combination of APOE4 and selected modifiable risk factors conveys a stronger association with incident CI than either type of risk factor alone.

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  • Some studies have suggested an interaction between APOE genotype and modifiable risk factors, whereby carrying the APOEε4 allele would multiply the increased Alzheimer disease risk associated with the risk factor alone or counteract the reduced Alzheimer disease risk conferred by a protective factor, such as education attainment or physical exercise.

    “Indeed, some studies have suggested an interaction between APOE genotype and several of these modifiable risk factors, whereby carrying the APOEε4 allele would multiply the increased AD risk associated with the risk factor alone (for example, cardiovascular risk factors30) or counteract the reduced AD risk conferred by a protective factor, such as education attainment31 or physical exercise32.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [30]

    The Results report interactions between APOE4 and cardiovascular risk factors, including hypertension, in predicting incident cognitive impairment without dementia (CIND). This supports the point attached to citation 30, but the study measured CIND rather than Alzheimer disease risk. Education and exercise are attached to other citations in the citing sentence. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Kolli, A., Zhou, Y., Chung, G., Ware, E. B., Langa, K. M., & Ehrlich, J. R.
Affiliations
  • University of California, San Francisco (US)
  • University of Michigan (US)
Corresponding author
Ehrlich, Joshua R.
ORCID
Venue
BMC Geriatrics
Publisher
Springer Science and Business Media LLC
Published
2022-12-06
Volume
22
Issue
1
Pages
938-938
ISSN
1471-2318 (ISSN-L)
DOI
10.1186/s12877-022-03652-w
PMC
PMC9724385
OpenAlex
W4311664746
Cited by
12
References
4
Citations by year
2026: 4 · 2025: 3 · 2024: 4 · 2023: 1
FWCI
1.30
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Geriatrics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute on Aging (P30AG012846, R01AG055406, R01AG067592, R01AG055654, U01AG009741)
  • National Institutes of Health (K23EY027848)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Cognitive Abilities and Testing
Keywords
APOE ε4, cognitive impairment, dementia, modifiable risk factors, gene-environment interaction, cognitive decline, hypertension, depressive symptoms, hearing loss, visual impairment, smoking, obesity, educational attainment, older adults, incident cognitive impairment
MeSH terms
Aged, Dementia, Female, Humans, Male, Risk Factors, Apolipoprotein E4, Cognitive Dysfunction

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