Entorhinal cortex layer II neurons are ground-zero for AD tau pathology, yet the molecular explanation for this selective vulnerability remains elusive. Candidate mechanisms include high calcium oscillation frequency, dense perforant path connectivity to hippocampus, low mitochondrial spare capacity, or unique expression of tau isoforms and kinases.
Why do entorhinal cortex layer II stellate neurons die first in AD? Their unique electrophysiological properties, grid cell function, and high metabolic demand may contribute, but the molecular basis of selective vulnerability is unknown.