Background: The brain receives a disproportionately high share of systemic blood flow, such that subclinical reductions in cardiac output relate to reduced cerebral blood flow (CBF). We extend prior cross-sectional findings by examining associations between cardiac output and longitudinal CBF and cerebrovascular reactivity (CVR) among middle-aged and older adults over 11 years. We further examine the modifying effects of apolipoprotein E (APOE)-ε4, a genetic susceptibility risk factor for Alzheimer’s disease (AD), and plasma p-tau₂₃₁, an AD biomarker.
Methods: Vanderbilt Memory and Aging Project participants free of dementia, stroke, and heart failure (n=751, 67±9 years, 53% female, 35% APOE-ε4 positive, 4.5±3.0 years follow-up) underwent baseline echocardiography to quantify cardiac output (L/min). Resting CBF (mL/100 grams/min) and hypercapnia-induced CVR were quantified from pseudo-continuous arterial spin labeling. Linear regression (cross-sectional) and linear mixed effects (longitudinal) models with follow-up time interaction terms related baseline cardiac output to regional CBF and CVR, adjusting for baseline age, sex, education, race/ethnicity, body surface area, APOE-ε4 status, modified Framingham Stroke Risk Profile score, and cognitive status. Secondary models tested cardiac output x APOE-ε4 status and cardiac output x plasma p-tau₂₃₁interactions.
Results: Longitudinal models revealed lower baseline cardiac output related to faster decline in CBF over time in the temporal lobes (β=0.11, p=0.04), frontal lobes (β=0.14, p=0.05), and whole brain gray matter (β=0.13, p=0.05). APOE-ε4 status modified the association between lower baseline cardiac output and faster decline in CBF over time in the frontal lobes (β=-0.32, p=0.03) and whole brain (β=-0.22, p=0.09), with associations present in APOE-ε4 non-carriers only (p-values<0.01). However, post-hoc age stratification revealed this association was driven by younger participants (under the median age). Plasma p-tau₂₃₁ modified the association between cardiac output and CBF decline in the frontal lobes (β=-0.02, p=0.01) and whole brain (β=-0.01, p=0.04). All associations were null with CVR (p-values>0.05).
Conclusion: Among middle-aged and older adults, lower baseline cardiac output is associated with a faster decline in longitudinal CBF, particularly in middle-aged individuals with no genetic predisposition to AD. Results suggest that subtle changes in cardiac function interact with AD pathological burden to affect brain health over time, independently of severe vascular risk.