Genetic, Transcriptome, Proteomic, and Epidemiological Evidence for Blood-Brain Barrier Disruption and Polymicrobial Brain Invasion as Determinant Factors in Alzheimer’s Disease

Carter, Chris J.

The AD genes are enriched in global GWAS datasets relating to pathogen diversity, suggesting that some have been selected for pathogen resistance rather that susceptibility. This is supported by the old age of AD patients, indicating survival from the many infections that contribute to mortality in the younger population. APOE4 variants protect against malaria and hepatitis C, and immune/inflammatory gain of function applies to APOE4, CR1, TREM2, and presenilin variants, supporting this contention. Logically, any gene variant increasing the production of the anti-microbial peptide A␤ in response to pathogens might also be considered as beneficial in evolutionary terms. Gene networks involved in innate immunity, inflammation and pathogen defense have been subject to positive selection pressure, although many arms of these networks are cytotoxic (for example, cytokines or free radicals), and evolution has involved a considerable trade-off between diseases/infections prevented by and tissue damage caused by excessive immune activation or inflammatory processes [276, 277] . The same might therefore apply to the toxic effects of A␤ in the brain, particularly if, as in old age, pathogens normally barred from access can infiltrate a defective BBB.