CHMP2B p.Ala30Ser Variant in Biomarker-Confirmed Early-Onset Alzheimer Disease: A Potential Endolysosomal Disease...

Endolysosomal dysfunction has been increasingly implicated in the pathogenesis of neurodegenerative diseases. The charged multivesicular body protein 2B (CHMP2B) gene encodes a component of the endosomal sorting complexes required for transport (ESCRT-III), which regulates endosomal trafficking, multivesicular body formation, and autophagosome-lysosome fusion. Mutations in CHMP2B are classically associated with autosomal dominant frontotemporal dementia. Here, we report a 59-year-old woman with biomarker-confirmed Alzheimer disease (AD) (A+T+N+) carrying a heterozygous CHMP2B c.90C>T (p.Ala30Ser) variant identified by targeted exome sequencing after negative testing for APP, APOE, PSEN1, and PSEN2. The patient presented with progressive episodic memory impairment and spatial disorientation over 3 years. Brain MRI showed prominent posterior cortical atrophy, and cerebrospinal fluid biomarkers demonstrated decreased Aβ42 and elevated phosphorylated and total tau levels consistent with AD pathology. Dysfunction of CHMP2B-mediated endolysosomal pathways may impair intracellular protein degradation and influence tau clearance mechanisms. This observation suggests that rare variants in endolysosomal pathway genes may contribute to AD pathophysiology.