MAPT and Alzheimer disease: This study demonstrates that NP-intensive neurons display multifaceted properties associated with AD vulnerability: (1) characterized by heightened metabolic activity and susceptibility to tau hyperphosphorylation; (2) exhibiting disproportionate and site-specific depletion during early AD progression, manifesting in both cognitive and neuropathological alterations; and (3) showing spatial distribution that correlates with AD-vulnerable brain regions under physiological conditions.