Version 1
: Received: 28 March 2023 / Approved: 28 March 2023 / Online: 28 March 2023 (08:24:53 CEST)
Version 2
: Received: 21 April 2023 / Approved: 23 April 2023 / Online: 23 April 2023 (02:50:35 CEST)
Lardelli, M. An Alternative View of Familial Alzheimer’s Disease Genetics. Journal of Alzheimer’s Disease 2023, 1–27, doi:10.3233/jad-230313.
Lardelli, M. An Alternative View of Familial Alzheimer’s Disease Genetics. Journal of Alzheimer’s Disease 2023, 1–27, doi:10.3233/jad-230313.
Lardelli, M. An Alternative View of Familial Alzheimer’s Disease Genetics. Journal of Alzheimer’s Disease 2023, 1–27, doi:10.3233/jad-230313.
Lardelli, M. An Alternative View of Familial Alzheimer’s Disease Genetics. Journal of Alzheimer’s Disease 2023, 1–27, doi:10.3233/jad-230313.
Abstract
A probabilistic and parsimony-based view of available genetics data is presented to argue that Hardy and Higgins’ amyloid cascade hypothesis is valid but is commonly misinterpreted to support, incorrectly, the primacy of the amyloid beta peptide (Aβ) in driving Alzheimer’s disease pathogenesis. Similar means are used to argue that the pathological effects of familial Alzheimer’s disease mutations in the genes PSEN1 and PSEN2 are not exerted directly via changes in APP cleavage to produce different ratios of Aβ length. Instead, increase in the activity of the bCTF (C99) fragment of APP is likely 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 (IRE). Familial Alzheimer’s disease (fAD) mutations in PSEN1 and PSEN2 likely affect the stability of presenilin holoprotein and/or γ-secretase multimers with consequences for γ-secretase activity and other important cellular functions. 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. Aβ production is enhanced and distorted by oxidative stress and accumulates due to decreased lysosomal function. It may act as a disease-associated molecular pattern (DAMP) enhancing oxidative stress-driven neuroinflammation during the cognitive phase of the disease. We also discuss fascinating, but largely ignored, data on presenilin biology that may be important in understanding presenilins’ central role in familial Alzheimer’s disease.
Medicine and Pharmacology, Neuroscience and Neurology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
