Cognitively Healthy Centenarian Brains resist Tau Accumulation and exhibit lower APOE, early proteasome response and maintained β-oxidation

Abstract Brains from cognitively intact centenarians offer a unique window into mechanisms of neuroprotection. We quantified 3,448 proteins by LC–MS/MS in middle temporal gyrus (MTG) from 88 Alzheimer’s disease (AD) patients, 53 controls (50–99 years) and 49 centenarians (100+). After adjustment for cell type composition, Aβ abundance associated with only five proteins, revealing upregulation of HTRA1, LRP1 and NRXN1 as early AD-associated changes. Conversely, tau abundance associated with ∼20% of the quantified proteome, revealing GPRIN1 as the top tau-associated protein. One-third of centenarians had high Aβ abundance, often with Braak neurofibrillary tangle stages IV/V, yet all maintained low local tau abundance. Centenarians showed maintained proteostasis (low ubiquitin peptides, high proteasome components), high PCSK1 (prohormone maturation), high PFKFB2 (glycolysis regulation), mitochondria-coupled lipid β-oxidation and lower APOE levels. Together, these findings suggest a model of neuroprotection in which Aβ facilitates tau seeding, and where proteostatic and metabolic adaptations buffer against additional tau accumulation in centenarians.