Proteomic Indicators of Health Predict Alzheimer's Disease Biomarker Levels and Dementia Risk

Objective Few studies have comprehensively examined how health and disease risk influence Alzheimer's disease (AD) biomarkers. The present study examined the association of 14 protein‐based health indicators with plasma and neuroimaging biomarkers of AD and neurodegeneration. Methods In 706 cognitively normal adults, we examined whether 14 protein‐based health indices (ie, SomaSignal® tests) were associated with concurrently measured plasma‐based biomarkers of AD pathology (amyloid‐β [Aβ] 42/40 , tau phosphorylated at threonine‐181 [pTau‐181]), neuronal injury (neurofilament light chain [NfL]), and reactive astrogliosis (glial fibrillary acidic protein [GFAP]), brain volume, and cortical Aβ and tau. In a separate cohort (n = 11,285), we examined whether protein‐based health indicators associated with neurodegeneration also predict 25‐year dementia risk. Results Greater protein‐based risk for cardiovascular disease, heart failure mortality, and kidney disease was associated with lower Aβ 42/40 and higher pTau‐181, NfL, and GFAP levels, even in individuals without cardiovascular or kidney disease. Proteomic indicators of body fat percentage, lean body mass, and visceral fat were associated with pTau‐181, NfL, and GFAP, whereas resting energy rate was negatively associated with NfL and GFAP. Together, these health indicators predicted 12, 31, 50, and 33% of plasma Aβ 42/40 , pTau‐181, NfL, and GFAP levels, respectively. Only protein‐based measures of cardiovascular risk were associated with reduced regional brain volumes; these measures predicted 25‐year dementia risk, even among those without clinically defined cardiovascular disease. Interpretation Subclinical peripheral health may influence AD and neurodegenerative disease processes and relevant biomarker levels, particularly NfL. Cardiovascular health, even in the absence of clinically defined disease, plays a central role in brain aging and dementia. ANN NEUROL 2024;95:260–273