Intracellular accumulation of amyloid-ß is a marker of selective neuronal vulnerability in Alzheimer's disease

Nat Commun. 2025 Jun 4;16(1):5189. doi: 10.1038/s41467-025-60328-w.

ABSTRACT

Defining how amyloid-β and pTau together lead to neurodegeneration is fundamental to understanding Alzheimer's disease (AD). We used imaging mass cytometry to identify neocortical neuronal subtypes lost with AD in post-mortem brain middle temporal gyri from non-diseased and AD donors. Here we showed that L5,6 RORB⁺FOXP2⁺ and L3,5,6 GAD1⁺FOXP2⁺ neurons, which accumulate amyloid-β intracellularly from early Braak stages, are selectively vulnerable to degeneration in AD, while L3 RORB⁺GPC5⁺ neurons, which accumulate pTau but not amyloid-β, are not lost even at late Braak stages. We discovered spatial associations between activated microglia and these vulnerable neurons and found that vulnerable RORB⁺FOXP2⁺ neuronal transcriptomes are enriched selectively for pathways involved in inflammation and glycosylation and, with progression to AD, also protein degradation. Our results suggest that the accumulation of intraneuronal amyloid-β, which is associated with glial inflammatory pathology, may contribute to the initiation of degeneration of these vulnerable neurons.

PMID:40467545 | DOI:10.1038/s41467-025-60328-w