Alzheimer's disease and intelligence.

A significant body of evidence has accumulated suggesting that individual variation in intellectual ability, whether assessed directly by intelligence tests or indirectly through proxy measures, is related to risk of developing Alzheimer's disease (AD) in later life. Important questions remain unanswered, however, such as the specificity of risk for AD vs. other forms of dementia, and the specific links between premorbid intelligence and development of the neuropathology characteristic of AD. Lower premorbid intelligence has also emerged as a risk factor for greater mortality across myriad health and mental health diagnoses. Genetic covariance contributes importantly to these associations, and pleiotropic genetic effects may impact diverse organ systems through similar processes, including inefficient design and oxidative stress. Through such processes, the genetic underpinnings of intelligence, specifically, mutation load, may also increase the risk of developing AD. We discuss how specific neurobiologic features of relatively lower premorbid intelligence, including reduced metabolic efficiency, may facilitate the development of AD neuropathology. The cognitive reserve hypothesis, the most widely accepted account of the intelligence-AD association, is reviewed in the context of this larger literature.