Multimorbidity and Associations with Cognition and Alzheimer's Disease Biomarkers.

OBJECTIVE

Multimorbidity, the coexistence of 2 or more chronic conditions, has been linked to cognitive aging and Alzheimer's disease (AD) and AD-related dementias, yet the mechanisms remain unclear. We aimed to examine the associations of multimorbidity with cognition and biomarkers across multiple mechanistic pathways.

METHODS

We cross-sectionally analyzed 3,808 dementia-free participants (mean age 64.9 ± 8.5 years, 62% female) from the Health and Aging Brain Study: Health Disparities. Multimorbidity burden was assessed using a latent construct derived from chronic conditions identified through objective measures, medical history, and self-report. A latent factor score for cognition was estimated using confirmatory factor analysis and neuropsychological tests. Using linear and logistic regression, we examined the associations of multimorbidity burden with biomarkers of AD (positron emission tomography [PET] amyloid, plasma β-amyloid 42/40, and phosphorylated tau [p-tau] measures), neurodegeneration (cortical thickness, hippocampal volume, and plasma neurofilament light and total tau), and cerebral small vessel disease (SVD) (magnetic resonance imaging white matter hyperintensities, cerebral microbleeds, and lacunes).

RESULTS

Greater multimorbidity burden was associated with worse cognition and biomarkers of AD (PET amyloid standardized uptake value ratios and positivity, p-tau181, and p-tau217), neurodegeneration (neurofilament light, total tau, cortical thickness, and hippocampal volume), and SVD (white matter hyperintensity volume and presence of lacune and cerebral microbleeds).

INTERPRETATION: Among dementia-free individuals, higher multimorbidity burden was associated with biomarkers for greater AD pathology, neurodegeneration, and SVD. These findings support a more holistic approach to managing chronic disease burden, which has the potential to reduce overall pathophysiological burden and delay cognitive decline. ANN NEUROL 2026;100:370-379.