Cholinergic Hub Vulnerability in Typical and Atypical Alzheimer’s Disease Presentations

Abstract

AbstractBackgroundThe nucleus basalis of Meynert (nbM) is a critical hub that supplies cholinergic input throughout the cortex. Prior to even entorhinal cortex involvement, the nbM is observed to be vulnerable to tau pathology. Neuropathologic and neuroimaging studies provide strong evidence suggesting evaluation of nbM volume may be highly informative as an early biomarker of Alzheimer’s disease.MethodThe relevant AD biomarker literature with neuropathologic validation will be highlighted. Data will be provided from the FLorida Autopsied Multi‐Ethnic (FLAME) series of neuropathologically diagnosed AD cases. To enhance translational neuropathologic studies of the nbM, differences in neuronal density will be compared in the context of both typical and atypical (non‐memory) clinical presentations of AD using digital pathology to quantify nbM neurons in the postmortem tissue.ResultIn the FLAME series, we observed greater nbM neuronal loss in individuals with atypical clinical presentations (median=23/mm2) compared to typical AD dementia (median=26; p=0.002). Atypical clinical variants will be compared to provide a didactic learning experience, in addition to discussing the nbM’s influence on cortical tangle accumulation. Moreover, we will emphasize the paradoxical nature of greater nbM neuronal loss in young‐onset AD (median=21) compared to late‐onset AD (median=28; p<0.001).ConclusionEvaluation of cholinergic hub vulnerability may greatly inform our understanding of clinical heterogeneity in AD and provide key insight into early biomarker interpretation.