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
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 (Aβ) in driving Alzheimer’s disease pathogenesis. Instead, increased activity of the βCTF (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). 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 in APP cleavage to produce different ratios of Aβ length. Rather, these mutations 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.
Received:
23 April 2023
Commenter:
Michael Lardelli
Commenter's Conflict of Interests:
Author
Comment:
The following revisions were made to the manuscript: - The abstract was revised to increase clarity. - Some minor typos were corrected and the manner in which some ratios are displayed and described was changed to increase clarity. - An error in how this manuscript describes and interprets the data from the Petit et al. 2022 paper (Mol Psychiatry27, 2821-2832) was corrected and analysis of some of the data from the Petit et al. paper was included in a new version of Supplemenatry Data File 1.
Commenter: Michael Lardelli
Commenter's Conflict of Interests: Author
- The abstract was revised to increase clarity.
- Some minor typos were corrected and the manner in which some ratios are displayed and described was changed to increase clarity.
- An error in how this manuscript describes and interprets the data from the Petit et al. 2022 paper (Mol Psychiatry 27, 2821-2832) was corrected and analysis of some of the data from the Petit et al. paper was included in a new version of Supplemenatry Data File 1.
Commenter:
The commenter has declared there is no conflict of interests.
Common & "Incomplete" relative to "complete" cleavage
should actually read,
Common & "complete" relative to "incomplete" cleavage