The Alzheimer's disease mitochondrial cascade hypothesis.
We first proposed the mitochondrial cascade hypothesis of sporadic Alzheimer's disease (AD) in 2004. Our core assumptions were a person's genes determine baseline mitochondrial function and durability, this durability determines how mitochondria change with advancing age, and critical changes in mitochondrial function initiate other pathologies characteristic of AD. Since then several lines of investigation report data consistent with or supportive of our hypothesis. In particular, AD endophenotype studies suggest a strong maternal genetic contribution, and links between mitochondrial function, tau phosphorylation, and amyloid-beta (Abeta) amyloidosis are increasingly recognized. As predicted, AD therapies designed to reduce Abeta thus far have had at best very limited clinical benefits; our hypothesis identifies alternative therapeutic targets. While placing mitochondria at the apex of an AD cascade certainly remains controversial, it is increasingly accepted by the AD research community that mitochondria play an important role in the late-onset forms of the disease. Even if the mitochondrial cascade hypothesis proves incorrect, considering its assumptions could potentially advance our understanding of sporadic, late-onset AD.
Swerdlow
Russell H
RH
Departments of Neurology and Molecular and Integrative Physiology, University of Kansas School of Medicine, Kansas City, KS, USA. rswerdlow@kumc.edu
Burns
Jeffrey M
JM
Khan
Shaharyar M
SM
D000375:Aging / Q000378:metabolism / Q000473:pathology; D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics; D003576:Electron Transport Complex IV / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008954:Models, Biological
D016229:Amyloid beta-Peptides; D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV