# Implications of midlife alcohol use for risk of dementia in male and female twins: Unique contributions and interactions with APOE4

> **NIH NIH R21** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $468,534

## Abstract

Abstract
The purpose of this study is to examine alcohol consumption as a modifiable risk factor for Alzheimer's disease
and related dementias (ADRD). Approximately 40% of risk for dementia has been attributed to modifiable risk
factors, with heavy alcohol use in midlife (12+ standard US drinks weekly) added to the list of risk factors by
the Lancet Commission in 2020. It is well established that more women have ADRD and men have higher
rates of heavy drinking, yet alcohol-related problems occur at lower levels of consumption for women than for
men. Moreover, the APOE gene, one of the strongest genetic risk factors for ADRD, begins to increase risk for
women who have only one e4 allele but for men increased risk is only seen in those who have two e4 alleles.
Prior research has also been mixed as to whether APOE interacts with alcohol consumption to increase risk for
ADRD. This exploratory/developmental project will examine the relationships of midlife alcohol use and APOE
in over 32,000 male and female twins from the Swedish Twin Registry who have lifetime alcohol consumption
data and clinical or registry-based diagnoses of ADRD, plus APOE genotypes in over 8,000 twins, thus making
it possible to detect phenotypic relationships as well as additive (i.e. G+E) and interactive (i.e. GxE) genetic
and environmental relationships. Specifically, in Aim 1 we will delineate the relationship of mid-life alcohol
consumption with late-life ADRD diagnosis and age of onset, paying particular attention to whether these
relationships are similar in men and women. We will also explore whether incorporating alcohol consumption
levels from earlier and later adulthood adds to our understanding of alcohol consumption as a lifecourse risk
factor for ADRD. In Aim 2, we will test the alcohol consumption-APOE risk relationship with ADRD diagnosis
and age of onset, again focusing on sex differences in elucidating these relationships. Finally, in Aim 3 we will
leverage the genetically informative design of the Swedish Twin Registry to characterize differences in alcohol
involvement within ADRD discordant and concordant monozygotic and dizygotic twin pairs of both sexes,
thereby better understanding genetic contributions to alcohol-ADRD associations. This exploratory/
developmental research study will have the power to model alcohol risk for ADRD in nuanced ways and
broaden our understanding of how and why alcohol may affect ADRD risk. If successful, it will set the stage for
us to incorporate alcohol consumption as a risk factor for ADRD in more sophisticated models in future work.

## Key facts

- **NIH application ID:** 10885504
- **Project number:** 1R21AG087486-01
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Susan E. Luczak
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $468,534
- **Award type:** 1
- **Project period:** 2024-09-23 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885504

## Citation

> US National Institutes of Health, RePORTER application 10885504, Implications of midlife alcohol use for risk of dementia in male and female twins: Unique contributions and interactions with APOE4 (1R21AG087486-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10885504. Licensed CC0.

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