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

Two individuals with PSEN1 E280A mutations exhibited remarkable resistance to developing autosomal dominant Alzheimer's disease (ADAD). One male patient, who also carried a protective RELN-COLBOS variant, displayed a significantly higher density of neurons in the entorhinal cortex compared to those with unprotected PSEN1 E280A mutations.

To further investigate the mechanisms behind this resilience, a comprehensive study was conducted on the entorhinal cortex of the protective patient, as well as those with unprotected PSEN1 E280A mutations, sporadic AD cases, and non-demented controls. The study utilized single nuclei and spatial transcriptomics, whole genome sequencing, and candidate genotype-associated expression changes (GAEC) analysis.

The results revealed distinct neuronal and oligodendrocytic populations in the male RELN-COLBOS patient. Notably, unique inhibitory interneurons containing the RELN protein were enriched in cortical Layer I, while abundant excitatory neurons expressing ADAMTSL1 were distributed in Layers II/III and Layer Va. These neurons, along with mature myelinated oligodendrocytes, experienced increased expression of the LRP6 receptor, which functions as a non-canonical receptor for the mutated Reelin protein encoded by RELN-COLBOS.

Furthermore, GAEC and pathway enrichment analyses suggested that additional mutations in genes such as ITGA2, involved in the Integrins / Focal Adhesion pathway, may have amplified the protective effects of RELN-COLBOS on the male patient's neurons, setting him apart from his RELN-COLBOS carrier sister who remained unaffected by ADAD.

These findings indicate that extreme deviations in the PSEN1 E280A phenotype may be primarily due to oligogenic effects, including simultaneous mutations in specific genes contributing to single molecular pathways, potentially serving as disease modifiers for Alzheimer's disease.