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Basic Science and Pathogenesis.

Paulina Tolosa Tort1, Meri Okorie2, Ana I Boeriu2

  • 1Department of Psychiatry and Behavioral Sciences, University of California - San Francisco, San Francisco, CA, USA.

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|December 25, 2025
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Summary
This summary is machine-generated.

Modifiable lifestyle factors can alter Alzheimer's disease (AD) genetic risk, influencing outcomes for APOE and polygenic risk scores (PRS). Integrating these factors is key for personalized AD risk assessment.

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Area of Science:

  • Neuroscience
  • Genetics
  • Epidemiology

Background:

  • Alzheimer's disease (AD) is influenced by genetic and environmental factors.
  • APOE*ε4 allele is a major genetic risk factor; polygenic risk scores (PRS) capture additional liability.
  • Dementia clinical risk scores (CRS) integrate clinical/lifestyle factors, but population-specific effects require investigation.

Purpose of the Study:

  • Investigate if modifiable risk profiles moderate the effects of APOE and AD-PRS on AD and mild cognitive impairment (MCI).
  • Assess these interactions across diverse populations.

Main Methods:

  • Utilized data from 20,755 participants (NACC and ADNI).
  • Constructed a modified Cardiovascular Risk Factors, Aging, and Incidence of Dementia (mCAIDE) score.
  • Generated a cross-ancestry AD-PRS and assessed additive interactions using logistic regression, stratified by race/ethnicity and genetic ancestry.

Main Results:

  • A favorable mCAIDE profile reduced APOE*ε4-associated risk and risk from high AD-PRS.
  • An unfavorable mCAIDE profile weakened APOE*ε2's protective effect and the protection of low AD-PRS.
  • These trends were most pronounced in European and African ancestry groups.

Conclusions:

  • Modifiable risk factors significantly moderate genetic risk for AD.
  • Integrating genetic and environmental factors is crucial for personalized AD risk assessment.