Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 20, Issue -, Pages S265-S279Publisher
IOS PRESS
DOI: 10.3233/JAD-2010-100339
Keywords
Alzheimer's disease; amyloid-beta; cytochrome oxidase; endophenotype; mitochondria; mitochondrial DNA
Categories
Funding
- National Institutes of Health [AG022407, AG026374, AG029615, K23NS058252, EY018474]
- University of Kansas General Clinical Research Center [M01RR023940]
- NATIONAL CENTER FOR RESEARCH RESOURCES [M01RR023940] Funding Source: NIH RePORTER
- NATIONAL EYE INSTITUTE [R21EY018474] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [K23NS058252] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R03AG026374, R21AG029615, R01AG022407] Funding Source: NIH RePORTER
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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 (A beta) amyloidosis are increasingly recognized. As predicted, AD therapies designed to reduce A beta 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.
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