Adair, E. | bioRxiv Science

bioRxiv2026

Intrinsic molecular susceptibility underlies selective neuronal vulnerability in the Alzheimer's disease entorhinal cortex

Entorhinal cortex (EC) excitatory neurons are lost early in Alzheimers disease (AD), yet the specific subtype and characteristics contributing to this vulnerability are poorly understood. Combining imaging mass cytometry (206,913 cells; 62 donors) and single nucleus RNA sequencing (42,780 nuclei; 36 donors) of post-mortem EC, we found that calbindin-expressing layer 2-3 excitatory neurons accumulate high phospho-tau burden and are preferentially lost in AD. In non-diseased brains, these neurons exhibit elevated tau-modifying kinase expression (ERK1/2, FYN, ROCK), reduced phosphatase expression (PP2A/B, PP5) and low mitochondrial respiratory capacity which together are predicted to promote high vulnerability to tau pathology. Trajectory analysis resolved progression from homeostasis through DNA damage and proteostatic stress to developmental re-entry and death priming. In silico screening suggested histone deacetylase inhibitors and cyclooxygenase inhibitors as candidate resilience-promoting therapeutics. Our work thus reframes intrinsic features of neuronal identity promoting phospho-tau formation as modifiable determinants of the selective vulnerability of EC calbindin neurons.

neuroscience↗

bioRxiv2026

ABCA7 rs3752231 variant effects on glial responses to amyloid-β and plaque maturation in Alzheimer's disease.

Variants in ABCA7 are among the most consistently replicated genetic risk factors for late-onset Alzheimers disease (AD), yet the cellular mechanisms remain poorly defined. Here, we characterise the impact of the common ABCA7 rs3752231 risk variant on amyloid-{beta} (A{beta}) pathology and glial responses in human post-mortem brain, combining quantitative neuropathology of 4G8-immunostained mid-temporal gyrus from 99 donors (Braak 0-VI) with glial-enriched single-nucleus RNA sequencing from 54 of them. ABCA7 rs3752231 carriers exhibited an increased A{beta} burden and larger plaques with late AD explained by a selective expansion of diffuse plaques and relative reduction in compact plaques, consistent with impaired microglial-mediated plaque maturation. Transcriptional responses to increasing A{beta} burden were largely genotype-specific: non-carriers showed canonical disease-associated microglial activation, including upregulation of complement, phagocytic, and inflammatory pathways, alongside astrocyte responses consistent with preserved synaptic support, while carriers exhibited a distinguishable activation state. Exploratory ligand-receptor analysis identified carrier-specific intercellular signals suggesting non-cell autonomous suppression of microglial phagocytosis. Together, these findings position ABCA7 rs3752231 as a regulator of glial responses to AD pathology, linking a common coding variant to impaired microglial plaque containment and maladaptive astrocyte responses and nominate microglial TREM2 activation and CD33 inhibition and astrocytic EAAT2 induction as candidate therapeutic strategies.

neuroscience↗