# Early Cognitive Impairment as a Function of Alzheimer’s Disease Genes and Trauma

> **NIH VA I01** · VA BOSTON HEALTH CARE SYSTEM · 2020 · —

## Abstract

Late-onset Alzheimer’s disease (AD) is the most common form of age-related dementia. PTSD
and dementia co-occur more often than expected by chance. One potential reason for this
comorbidity is that AD genes may influence the risk for both AD and PTSD. APOE, the strongest
AD genetic risk factor, has also been implicated as a risk factor for combat-related PTSD. The
initial effects of these genes may be apparent in middle age, ahead of the usual age of AD onset.
Our recent MRI study found that an AD polygenic risk score (PRS; a genome-wide summary
measure of genetic risk) by mild traumatic brain injury (mTBI) interaction was associated with
cortical thickness and memory performance in a VA sample with mean age 35. In this project,
we will use Million Veterans Project data to examine association between AD risk genes and early
cognitive function deficits and PTSD symptomatology. Our AD genetic risk measures will include
a genome-wide measure of AD risk (PRS), APOE genotypes, and AD GWAS implicated variants
in genes such as ABCA7, CLU, and TNXRD1. We will evaluate the potential gene x environment
(GxE) effects between AD genes and TBI and combat trauma exposure. As early detection of AD
risk may be critical for treatment, we will be especially interested in identifying cognitive
phenotypes associated with AD risk ahead of the typical age of onset. Hence, we will perform
analyses within three age strata: early middle age (45-54), late middle age (55-64), and old age
(65+). Our measures of cognitive performance will include the presence/absence of a cognitive
impairment diagnosis in the medical record and factor scores computed from self-reported
cognitive impairment (MVP Lifestyle Survey Items) which we will validate using available cognitive
testing data from the medical record (e.g. MMSE and MOCA). Next, we will examine the potential
impact of AD genes on PTSD risk as well as potential GxE interactions involving trauma and TBI.
Finally, we will use a retrospective longitudinal design to determine if AD gene x TBI and trauma
interactions impact the progression to AD. With nearly half of all veterans over age 65, and many
at risk for cognitive impairment and subsequent AD, it is critical to advance methods for early
identification and treatment of cognitive symptoms and dementia. Understanding the interaction
between genetic risk and history of military trauma will be essential for tailoring early detection
methods to a veteran population. !

## Key facts

- **NIH application ID:** 9899737
- **Project number:** 5I01BX004192-02
- **Recipient organization:** VA BOSTON HEALTH CARE SYSTEM
- **Principal Investigator:** MARK W LOGUE
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899737

## Citation

> US National Institutes of Health, RePORTER application 9899737, Early Cognitive Impairment as a Function of Alzheimer’s Disease Genes and Trauma (5I01BX004192-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9899737. Licensed CC0.

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