From stress to Alzheimer's: A circuit-based framework for prefrontal cognitive dysfunction.

Impairments in working memory and cognitive flexibility are early and consistent features of both Alzheimer's disease (AD) and stress. These functions depend critically on prefrontal cortical (PFC) circuits, which are particularly vulnerable to neuromodulatory and pathological insults. Recent studies suggest that stress and AD do not simply act globally, but instead converge on specific molecular and cellular targets within distinct neural populations. Notably, both chronic stress and Alzheimer's disease models exhibit dysregulation of synaptic signaling via NR2B-containing NMDA receptors and aberrant GSK-3β activation. These changes often emerge in a cell-type-specific manner, affecting excitatory pyramidal neurons and vulnerable interneuron subtypes such as SST+, PV+, and VIP + cells. The resulting imbalance in excitation and inhibition disrupts the integrity of prefrontal circuits, impairing adaptive behavior. This review synthesizes evidence across molecular, cellular, and circuit levels to outline a framework in which stress and AD pathology converge on shared vulnerable pathways. Understanding how specific cell populations mediate this vulnerability may lead to targeted strategies for enhancing cognitive resilience in neurodegenerative and stress-related disorders.