Intra-cellular accumulation of amyloid is a marker of selective neuronal vulnerability in Alzheimer’s disease

ABSTRACT Characterisation of vulnerable neurons that die earliest with Alzheimer’s disease (AD) could provide rationale treatment targets to slow or prevent neurodegeneration. We used imaging mass cytometry to identify the neuronal sub-types lost earliest in AD and explored associated mechanisms with paired single nuclear transcriptomics in post-mortem middle temporal gyri from diseased donors. We found L5-6 RORB + and L3-6 GAD1 + neurons show the greatest loss in AD. These neuronal subtypes also accumulated β-amyloids intracellularly. By contrast, pTau + tangles progressively formed in a distinct L3 RORB + GPC5 + subtype that appeared resilient. Both astrocytes and microglia expressed reactive phenotype markers with AD and reactive microglia were spatially associated with vulnerable neurons. RORB + neuronal sub-types accumulating either amyloids or pTau showed increased expression of autophagy-related genes. In conclusion, we identified layer- and neuronal subtype-specific loss with AD that suggest intrinsic autophagy-related defects associated with intracellular accumulation of β-amyloids, rather than pTau, may initiate early neurodegeneration.