A lifespan staging model of basal forebrain cholinergic vulnerability

Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine

Abstract 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) and the temporal sequence (the) 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. Highlights Basal forebrain cholinergic neurons (BFCNs) are vulnerable to aging and disease. The causes and temporal staging of BFCN vulnerability have yet to be fully resolved. A lifespan staging model of BFCN vulnerability is presented. Evolutionary and developmental pressures on BFCNs interact with midlife stressors. BFCN vulnerability culminates in resilient and vulnerable aging trajectories. bullet alz71380-list-0001 highlights