Re-emphasizing early Alzheimer’s disease pathology starting in select entorhinal neurons, with a special focus on mitophagy

The entorhinal-hippocampal system contains distinct networks subserving declarative memory. This is selectively vulnerable to changes of ageing and pathological processes. entorhinal cortex (EC) a pivotal component this memory since it serves as the interface between neocortex hippocampus. EC heavily affected by proteinopathies Alzheimer's disease (AD). These appear in stereotypical spatiotemporal manner include increased levels intracellular amyloid-beta A? (iA?), parenchymal deposition plaques, neurofibrillary tangles (NFTs) containing abnormally processed Tau. Increased iA? formation NFTs are seen very early on population neurons belonging layer II (EC LII), recent evidence leads us believe that made up highly energy-demanding reelin-positive (RE+) projection neurons. Mitochondria fundamental energy supply, metabolism, plasticity Evidence from AD postmortem brain tissues supports notion mitochondrial dysfunction one initial events AD, likely take place RE + LII Here we review discuss these notions, anchored anatomy formulate hypothesis attempting explain vulnerability NFTs. We attempt link impaired clearance signaling involving both apolipoprotein 4 reelin, argue for their relevance specifically during prodromal stages AD. future studies interactions holds promise advance our understanding etiology provide new ideas drug development.