Brain proteinopathies associated physiological changes leading to cognitive resilience in Alzheimer's disease

Alzheimer's disease (AD) pathology has been well characterized, however the molecular mechanisms underlying resilience to the disease remain understudied. With the growing evidence of individuals who are resilient to AD and generation of cross-cohort multiomics data, it has become feasible to understand these mechanisms. In this study, we integrated longitudinal cognitive assessments, regional neuropathology, and matched prefrontal proteomic and metabolomic profiles across donors from two independent cohorts. We identified that asymptomatic AD (AsymAD) brains exhibited amyloid burdens comparable to AD but had fewer compact plaques, lower regional tau burden, and more restricted TDP-43 pathology. Across matched stages of amyloid, tau, and TDP-43 pathology, AsymAD was consistently distinguished from AD by preservation of mitochondrial translation and bioenergetics, synaptic programs, glutamatergic metabolites, and polyunsaturated membrane lipids. Longitudinal cognitive assessments further separated resilient from vulnerable AsymAD individuals despite comparable amyloid and TDP-43 burden, with vulnerability associated with greater neurofibrillary tangle accumulation. Both AsymAD groups retained a prefrontal proteome close to that of cognitively normal individuals, apart from amyloid-associated proteins, whereas mitochondrial, synaptic, and immune changes were largely confined to AD.