Mitochondria, Diabetes, and Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease as well as the leading cause of dementia (1,2). Identification of disease-causing mutations in the amyloid precursor protein, presenilin 1, and presenilin 2 has unraveled the molecular basis of some forms of familial AD, but the etiology and pathogenesis of sporadic AD remain elusive and controversial. Epidemiological data suggest that diabetes increases the risk of developing AD (2–4). These data are corroborated by clinical and laboratory findings. Indeed, diabetic subjects show signs of cognitive dysfunction, leukoariosis, and more severe hippocampal atrophy than control subjects (5). In addition, neuritic plaques and neurofibrillary tangles, the pathological hallmarks of AD, accumulate more abundantly in the brains of diabetic patients relative to control subjects. The association between diabetes and AD pathology seems even stronger among carriers of the apolipoprotein E ε4 allele, a variant that by itself carries an increased risk for AD (6).

The hyperglycemia and hyperinsulinemia that may accompany the preclinical syndrome of type 2 diabetes may play a role in the pathogenesis of AD. In particular, elevated levels of insulin, which crosses the blood-brain barrier, may compete with amyloid β for the insulin-degrading enzyme. This enzyme has …