Brain Blindness Versus Eye Blindness: Genetic and Molecular Connections Between Alzheimer's Disease and Visual...

Visual dysfunctions were observed among Alzheimer's disease (AD) patients, including posterior cortical degeneration, retinal abnormalities, or coexisting ocular disease. Posterior cortical atrophy (PCA) is a clinical syndrome characterized by progressive higher-order visual impairment and is most frequently associated with AD pathology, although other neurodegenerative causes may be possible. Pathogenic variants in PSEN1 and PSEN2 were reported in individual cases of PCA and may support a possible monogenic contribution to selected early-onset posterior phenotypes. By contrast, variants and common AD risk genes, including GRN, MAPT, TREM2, BIN1, PICALM, ABCA7, and APOE E4 allele, represented broader genetic associations whose specific contribution to posterior cortical vulnerability remains incompletely defined. These forms of evidence should be interpreted separately. Genome-wide association studies identified overlapping loci associated with AD and glaucoma, including loci on chromosome 11 involving MTCH2, NDUFS3, and SPI1. This overlap reflected shared genetic susceptibility, pleiotropy, or putative convergent biological pathways involving mitochondrial function, immune regulation, and cellular stress. However, shared loci and pathway associations did not establish direct signaling, anatomical communication, or a causal relationship between brain and ocular tissues. The opposing tissue-specific effects reported for APOE further indicated that data in the brain may not be extrapolated to the retina. Future studies should clarify the cell-specific effects, causal direction, and clinical significance of shared genetic factors using well-characterized cohorts and tissue-specific experimental models. Overall, current evidence supported the partially overlapping genetic and cellular mechanisms in AD and selected ocular disorders, while further studies should be needed on the biological relationship between the brain and eye.