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. 2024 Feb;95(2):260-273.
doi: 10.1002/ana.26817. Epub 2023 Nov 2.

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

Heather E Dark  1 , Clare Paterson  2 , Gulzar N Daya  1 , Zhongsheng Peng  1 , Michael R Duggan  1 , Murat Bilgel  1 , Yang An  1 , Abhay Moghekar  3 , Christos Davatzikos  4 , Susan M Resnick  1 , Kelsey Loupy  2 , Missy Simpson  2 , Julián Candia  5 , Thomas Mosley  6 , Josef Coresh  7 , Priya Palta  8   9 , Luigi Ferrucci  5 , Allison Shapiro  10 , Stephen A Williams  2 , Keenan A Walker  1
Affiliations

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

Heather E Dark et al. Ann Neurol. 2024 Feb.

Abstract

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 Aβ42/40 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 Aβ42/40 , 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.

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Conflict of interest statement

Potential Conflicts of Interest

The SomaLogic co-authors (C.P., K.L., M.S., and S.A.W.) were/are all employees of SomaLogic, Inc., which has a commercial interest in the results. The remaining authors (H.E.D., G.N.D., Z.P., M.R.D., M.B., Y.A., A.M., C.D., S.M.R., J.C., T.M., J.C., P.P., A.S., L.F., and K.A.W.) have no competing interests.

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