Heart Function May Affect Brain Aging in Alzheimer’s Risk Carriers

In a longitudinal study conducted at Vanderbilt Health, including investigators from the Vanderbilt Memory and Alzheimer’s Center (VMAC), researchers found that lower cardiac output is associated with accelerated cerebral atrophy among older adults who carry the APOE-e4 allele, a genetic risk factor for Alzheimer’s disease.

The study, published in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, followed 756 participants over an 11-year period and examined whether reduced cardiac function could lead to adverse brain health outcomes even in the absence of cardiovascular disease. The research used data from the Vanderbilt Memory and Aging Project (VMAP), a unique longitudinal cohort designed to investigate vascular contributions to brain aging.

The study found that subclinical cardiac dysfunction at baseline was associated with greater cross-sectional and longitudinal rates of atrophy in individuals who are APOE-e4 carriers. Among APOE-e4 carriers, lower cardiac output at study entry was associated with smaller volumes across the entire brain as well as in the temporal and occipital lobes specifically. When following participants over time, lower cardiac output at study entry predicted greater temporal lobe atrophy, an area implicated in Alzheimer’s disease, among APOE-e4 carriers.

“This study is among the first and largest to examine the impact of subclinical cardiac dysfunction on neurodegeneration over time, and among the first to evaluate how APOE-e4 status modifies these associations,” said Elizabeth Moore, MD, PhD, first author of the study.

“Our findings suggest that even subtle reductions in cardiac function may have important implications for brain health, particularly among individuals at increased genetic risk for Alzheimer’s disease,” said Moore. “This study highlights that a precision medicine approach that accounts for genetic information is an important direction for specifically tailoring prevention and screening efforts for Alzheimer’s disease.”

VMAP, launched in 2012, is designed to identify modifiable risk factors for cognitive decline and Alzheimer’s disease through longitudinal investigation of vascular health. Participants in this study completed a comprehensive evaluation during enrollment, which included fasting blood draw, physical examinations, clinical interview with medication review, echocardiogram and brain MRI. Assessments were repeated at 18-month, three-year, five-year, seven-year, nine-year and 11-year follow-up visits.

The original legacy participants were ages 60 and older and enrolled between 2012 and 2014. The legacy participants were either cognitively unimpaired or met diagnostic criteria for mild cognitive decline (MCI). In 2021, the study expanded and enrolled participants ages 50 and older who were cognitively unimpaired. The combined cohort included 756 adults ages 50-92 (67±9, 47% males, 81% non-Hispanic white), with 600 participants who were cognitively unimpaired.

In summary, this longitudinal study expanded knowledge on how even subtle changes in cardiovascular health can impact brain aging. Among older adults who are APOE-e4 carriers, lower baseline cardiac output was associated with smaller brain volumes cross-sectionally and larger inferior lateral ventricle volumes over time. Results suggest periodic cardiac screening may be an important future prevention effort in this population, and Alzheimer’s genetic risk information should be considered with tailored precision medicine efforts for prevention and treatment.

Reference: Moore EE, Zhang P, Khan OA, et al. Lower cardiac output is a risk factor for faster cerebral atrophy over a 11‐year follow‐up period in APOE‐ ε4 carriers. Alzheimer’s Dementia. 2026;22(8):e71598. doi: 10.1002/alz.71598

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