Abstract
The slow, progressive accumulation of pathology characteristic of Alzheimer's disease is the principal determinant of cognitive decline leading to dementia. Risk-reduction strategies during midlife focus on raising the clinical threshold for the appearance of cognitive symptoms and on reducing the extent of Alzheimer pathology. Best available evidence suggests an approach based on three, conceptually distinct strategies. (1) Raise the threshold for cognitive symptoms by improving brain health. To achieve this goal, the tactic is to reduce cerebrovascular risks mediated by hypertension, diabetes, cigarette smoking, and hyperlipidemia. (2) Raise the threshold for cognitive symptoms by enhancing cognitive reserve. Here, tactics focus on mental stimulation associated with occupation, leisure activities and social engagement. (3) Reduce the burden of Alzheimer pathology. The most promising tactic toward this end is regular aerobic exercise. Tactics in support of strategies to reduce cognitive impairment due to Alzheimer pathology are not yet substantiated by robust, consistent clinical trial evidence. There is pressing need for well-designed pragmatic trials to provide stronger evidence on preventive strategies for late-life cognitive decline and dementia.