Mechanisms of resilience to autosomal dominant Alzheimer's disease via oligogenic modulation of rare variants in the entorhinal cortex

Two PSEN1 E280A carriers have presented extreme protection against autosomal dominant Alzheimers disease (ADAD), with over two decades of delay for dementia onset. One of them, a male heterozygous for the RELN-COLBOS protective variant showed increased neuronal density in the entorhinal cortex 1. We conducted a deep phenotyping and genotyping study of the entorhinal cortex in protected and unprotected PSEN1 E280A cases, sporadic AD, and non-demented controls. We used single nuclei and spatial transcriptomics, whole genome sequencing, and candidate genotype-associated expression changes (GAEC) analysis. Our results showed unique neuronal and oligodendrocytic populations in the male RELN-COLBOS patient. Unique RELN positive inhibitory interneurons were enriched in cortical Layer I, while unique abundant ADAMTSL1 positive excitatory neurons were distributed in Layers II/III and Layer Va. These neurons and mature myelinated oligodendrocytes benefitted from increased expression of LRP6 receptor, functioning as a non-canonical receptor for the mutated Reelin protein encoded by RELN-COLBOS. Finally, GAEC and pathway enrichment analyses suggested that other mutations enhanced RELN-COLBOS effects in oligodendrocytes in the male RELN-COLBOS patient, explaining the phenotypic differences with his sister, a RELN-COLBOS carrier with no evident protection from ADAD. Our findings suggest that extreme deviations of the PSEN1 E280A phenotype are more likely attributed to oligogenic effects, including simultaneous mutations occurring in genes including ITGA2, involved in single molecular pathways, such as the Integrins / Focal Adhesion pathway, as potential disease modifiers for Alzheimers disease (AD).