An Alternative View of Familial Alzheimer's Disease Genetics

Probabilistic and parsimony-based arguments regarding available genetics data are used to propose that Hardy and Higgin's amyloid cascade hypothesis is valid but is commonly interpreted too narrowly to support, incorrectly, the primacy of the amyloid-beta peptide (A beta) in driving Alzheimer's disease pathogenesis. Instead, increased activity of the beta CTF (C99) fragment of A beta PP is the critical pathogenic determinant altered by mutations in the APP gene. This model is consistent with the regulation of APP mRNA translation via its 5' iron responsive element. Similar arguments support that the pathological effects of familial Alzheimer's disease mutations in the genes PSEN1 and PSEN2 are not exerted directly via changes inA beta PP cleavage to produce different ratios of A beta length. Rather, these mutations likely act through effects on presenilin holoprotein conformation and function, and possibly the formation and stability of multimers of presenilin holoprotein and/or of the beta secretase complex. All fAD mutations in APP, PSEN1, and PSEN2 likely find unity of pathological mechanism in their actions on endolysosomal acidification and mitochondrial function, with detrimental effects on iron homeostasis and promotion of pseudo-hypoxia being of central importance. A beta production is enhanced and distorted by oxidative stress and accumulates due to decreased lysosomal function. It may act as a disease-associated molecular pattern enhancing oxidative stress-driven neuroinflammation during the cognitive phase of the disease.

Automated summary

Probabilistic and parsimony-based arguments suggest that Hardy and Higgin's amyloid cascade hypothesis is valid but commonly misinterpreted. Mutations in the APP gene alter the activity of the critical pathogenic determinant, the beta CTF fragment of A beta PP. Familial Alzheimer's disease mutations likely affect presenilin holoprotein conformation and function, as well as the formation and stability of multimers of presenilin holoprotein and/or the beta secretase complex. These mutations also impact endolysosomal acidification and mitochondrial function, leading to detrimental effects on iron homeostasis and promoting pseudo-hypoxia. A beta production is increased due to oxidative stress and decreased lysosomal function, leading to enhanced oxidative stress-driven neuroinflammation during the cognitive phase of the disease.