Individual-Level Factors Associated With 10-Year Incidence of Alzheimer Disease and Related Dementias in the VA Million Veteran Program.

BACKGROUND AND OBJECTIVES: Approximately 450,000 Veterans are living with Alzheimer disease and related dementias (ADRD), and the high prevalence of ADRD represents a major public health challenge for the Veterans Health Administration. While advancing age and genetic predisposition are well-established ADRD risk factors, growing evidence suggests that additional modifiable factors may also play an important role. This study leveraged data from the VA Million Veteran Program (MVP) to (1) estimate 10-year incidence of ADRD and (2) evaluate associations between a broad range of individual-level risk and resilience factors and incident ADRD in a large, nationally representative sample of Veterans. METHODS: This retrospective cohort study included Veterans aged ≥65 years at MVP enrollment who completed the MVP Baseline Survey and had VA electronic health record (EHR) data available. Individual-level variables including sociodemographic factors, military-specific characteristics, military environmental exposures (MEEs), health conditions, and health behaviors were characterized using MVP Baseline Survey data and supplemented with EHR data as available. The primary outcome was ADRD, which was determined using a validated algorithm based on International Classification of Diseases diagnosis codes extracted from the EHR. Associations between each risk/resilience factor and incident ADRD were examined using separate Cox regression models adjusted for age, sex, and education. RESULTS: The sample included 245,949 Veterans (age: mean 73.16, SD 6.84 years; 2.59% female). Approximately 4.56% (n = 11,216) of the sample developed ADRD over 10 years. History of traumatic brain injury (TBI; hazard ratio [HR] 2.96, 95% CI 2.76-3.17), depression (HR 2.93, 95% CI 2.82-3.04), and alcohol use disorder (AUD; HR 2.35, 95% CI 2.19-2.53) were the health factors most strongly associated with ADRD. ADRD risk was also elevated among Veterans with a history of exposure to Agent Orange (HR 1.09, 95% CI 1.03-1.14), chemical/biological warfare agents (HR 1.31, 95% CI 1.23-1.39), and pyridostigmine bromide tablets (HR 1.67, 95% CI 1.44-1.93). DISCUSSION: Findings identified TBI, depression, AUD, and MEEs as key variables associated with ADRD in Veterans. These factors may represent important targets for prevention and intervention efforts aimed at improving the long-term health of aging Veterans. Additional work is needed to clarify the mechanisms through which these factors influence ADRD risk and to establish whether observed associations are causal.