The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives.
Ten years ago we first proposed the Alzheimer's disease (AD) mitochondrial cascade hypothesis. This hypothesis maintains that gene inheritance defines an individual's baseline mitochondrial function; inherited and environmental factors determine rates at which mitochondrial function changes over time; and baseline mitochondrial function and mitochondrial change rates influence AD chronology. Our hypothesis unequivocally states in sporadic, late-onset AD, mitochondrial function affects amyloid precursor protein (APP) expression, APP processing, or beta amyloid (Aβ) accumulation and argues if an amyloid cascade truly exists, mitochondrial function triggers it. We now review the state of the mitochondrial cascade hypothesis, and discuss it in the context of recent AD biomarker studies, diagnostic criteria, and clinical trials. Our hypothesis predicts that biomarker changes reflect brain aging, new AD definitions clinically stage brain aging, and removing brain Aβ at any point will marginally impact cognitive trajectories. Our hypothesis, therefore, offers unique perspective into what sporadic, late-onset AD is and how to best treat it.
Departments of Neurology and Molecular and Integrative Physiology, and the University of Kansas Alzheimer's Disease Center, University of Kansas School of Medicine, Kansas City, KS, USA; Department of Biochemistry and Molecular Biology, University of Kansas School of Medicine, Kansas City, KS, USA. Electronic address: rswerdlow@kumc.edu.
Russell H
RH
Swerdlow
Departments of Neurology and Molecular and Integrative Physiology, and the University of Kansas Alzheimer's Disease Center, University of Kansas School of Medicine, Kansas City, KS, USA.
Jeffrey M
JM
Burns
Gencia Corporation, Charlottesville, VA, USA.
Shaharyar M
SM
Khan
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D015398:Signal Transduction
D015415:Biomarkers
Aging; Alzheimer's disease; Amyloid; Brain; Dementia; Mitochondria