Abstract
<jats:title>Abstract</jats:title> <jats:p> Two <jats:italic>PSEN1 E280A</jats:italic> carriers have presented extreme protection against autosomal dominant Alzheimer’s disease (ADAD), with over two decades of delay for dementia onset. One of them, a male heterozygous for the <jats:italic>RELN-COLBOS</jats:italic> protective variant showed increased neuronal density in the entorhinal cortex <jats:sup>1</jats:sup> . We conducted a deep phenotyping and genotyping study of the entorhinal cortex in protected and unprotected <jats:italic>PSEN1</jats:italic> 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 <jats:italic>RELN-COLBOS</jats:italic> 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 <jats:italic>RELN-COLBOS</jats:italic> . Finally, GAEC and pathway enrichment analyses suggested that other mutations enhanced <jats:italic>RELN-COLBOS</jats:italic> effects in oligodendrocytes in the male <jats:italic>RELN-COLBOS</jats:italic> patient, explaining the phenotypic differences with his sister, a <jats:italic>RELN-COLBOS</jats:italic> carrier with no evident protection from ADAD. Our findings suggest that extreme deviations of the <jats:italic>PSEN1 E280A</jats:italic> 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 Alzheimer’s disease (AD). </jats:p>