Shanks_2026_Alzheimers.Dement_22_e71380

The cholinergic neurons of the basal forebrain are among the most vulnerable cell types to age- and Alzheimer's disease-related dysfunction and neurodegeneration. However, the biological bases of basal forebrain cholinergic vulnerability (the why) and the temporal sequence (the how) have yet to be fully resolved. In this review, we summarize multi-disciplinary evidence to present a lifespan staging model of basal forebrain cholinergic vulnerability, which outlines how converging biological stressors position these neurons to fail. We trace the origins of basal forebrain cholinergic vulnerability from evolutionary and neurodevelopmental pressures, which ultimately interact with midlife stressors to culminate in two divergent trajectories of cholinergic aging: resilient and vulnerable. Lastly, we highlight that the branch point in cholinergic aging trajectories may serve as a critical window for intervention if sensitive, specific, and clinically scalable in vivo cholinergic biomarkers can be developed.