Deposition of Hyperphosphorylated Tau in Cerebellum of PS1 E280A Alzheimer's Disease

Early‐onset familial Alzheimer's disease (AD) caused by presenilin‐1 mutation E280A (PS1‐E280A) presents wide clinical and neuropathological variabilities. We characterized clinically and neuropathologically PS1‐E280A focusing in cerebellar involvement and compared it with early‐onset sporadic Alzheimer's disease (EOSAD). Twelve E280A brains and 12 matched EOSAD brains were analyzed for beta‐amyloid and hyperphosphorylated tau (pTau) morphology, beta‐amyloid subspecies 1–40, 1–42 levels, pTau levels, and expression of stress kinases in frontal cortex and cerebellum. The data were correlated to clinical and genetic findings. We observed higher beta‐amyloid load, beta‐amyloid 1–42 and pTau concentrations in frontal cortex of PS1‐E280A compared with EOSAD. High beta‐amyloid load was found in the cerebellum of PS1‐E280A and EOSAD patients. In PS1‐E280A, beta‐amyloid localized to the molecular and Purkinje cell layers, whereas EOSAD showed them in Purkinje and granular cell layers. Surprisingly, 11 out of 12 PS1‐E280A patients showed deposition of pTau in the cerebellum. Also, seven out of 12 PS1‐E280A patients presented cerebellar ataxia. We conclude that deposition of beta‐amyloid in the cerebellum is prominent in early‐onset AD irrespective of genetic or sporadic origin. The presence of pTau in cerebellum in PS1‐E280A underscores the relevance of cerebellar involvement in AD and might be correlated to clinical phenotype.