Fig. 8. MTG cells impacted by AD, predominantly localizing to superficial layers, can be organized into two epochs: an early and a late phase.

a, Diagram illustrating cortical columns with actual neuronal reconstruction from vulnerable populations (from donors without AD) organized according to early (top) and late (bottom) disease epochs. During the early epoch, superficial Sst, Sncg and Lamp5 interneurons were lost. In the late epoch, most lost neurons localized superficially (L2/3 IT, Pvalb and Vip), with the addition of deep cortical and striatum-projecting L5 IT neurons. b, First box, the dynamic changes associated with AD progression can be organized into early and late epochs. In the early epoch, the first neuropathological event is an increase in the size of sparse Aβ plaques, subsequently followed by an exponential aggregation of both pTau and plaque burden. A decrease in NeuN⁺ cells occurs throughout. Second box, supragranular interneurons (Sst, Sncg, Lamp5) are lost early on. During this period, genes encoding the ETC complex, and ribosomal proteins, are downregulated broadly across neurons, except in the vulnerable Sst interneurons. In the latter cells, there is a strong downregulation of ubiquitin ligases and kinases. Later on, not only inhibitory cells (Pvalb and Vip) are lost but also long-range-projecting pyramidal neurons (L2/3 IT and L5 IT). Third and fourth boxes, nonneuronal cells accompany these changes with the early emergence of DAMs and an increase in protoplasmic astrocytes, while myelinating oligodendrocytes decrease their abundance. Concurrently, DAMs upregulate inflammatory and plaque-inducing genes, while OPCs attempt to compensate for oligodendrocyte loss by upregulating their OPC differentiating genes. Later, OPC cells are impacted and lost while myelination genes in oligodendrocytes are downregulated. The cohort demographics can be found in Supplementary Table 1. Schematics created using Biorender.com.