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

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. This study was carried out in accordance with the Regional Ethics Committee and Imperial College Use of Human Tissue guidelines. This study was carried out in accordance with the Regional Ethics Committee and Imperial College Use of Human Tissue guidelines. Cases were selected based first on neuropathological diagnosis (non-disease control [NDC] or AD) from UK brain banks (London Neurodegenerative Diseases Brain Bank [King’s College London], Newcastle Brain Tissue Resource, Queen’s Square Brain Bank [University College London], Manchester Brain Bank, Oxford Brain Bank and South West Dementia Brain Bank [University of Bristol]. We excluded cases with clinical or pathological evidence for small vessel disease, stroke, cerebral amyloid angiopathy, diabetes, Lewy body pathology (TDP-43), or other neurological diseases. Where the information was available, cases were selected with a post mortem delay of less than 49 hours. The final cohort was formed of non-diseased controls (Braak 0-II; 16 samples) and early (Braak III-IV; 4 samples) and late (Braak V-VI; 33 samples) AD human post-mortem FFPE middle temporal gyrus (MTG) samples. Of these, 5 controls and 10 late AD donors carried the AD high-risk R62H TREM2 variant, while 2 controls and 8 late AD donors carried the R47H variant. *************************************************************** All raw data are submitted on Synapse.org under the accession id syn54083444 and is available upon completing the Data User Agreement. ***************************************************************