Midlife interventions are critical in prevention, delay, or improvement of Alzheimer's disease and vascular cognitive impairment and dementia.

The basic strategy for focusing exclusively on genetically identified targets for intervening in late life dementias was formulated 30 years ago.  Three decades and billions of dollars later, all efforts at disease-modifying interventions have failed.  Over that same period, evidence has accrued pointing to dementias as late-life clinical phenotypes that begin as midlife pathologies.  Effective prevention therefore may need to begin in midlife, in order to succeed. No current interventions are sufficiently safe to justify their use in midlife dementia prevention trials.  Observational studies could be informative in testing the proposal that amyloid imaging and ε genotype can predict those who are highly likely to develop Alzheimer's disease and in whom higher risk interventions might be justifiable. A naturally occurring, diet-responsive cognitive decline syndrome occurs in canines that closely resembles human Alzheimer's.  Canine cognitive dysfunction could be useful in estimating how early intervention must begin in order to succeed.  This model may also help identify and assess novel targets and strategies.  New approaches to dementia prevention are urgently required, since none of the world's economies can sustain the costs of caring for this epidemic of brain failure that is devastating half of the over 85-year-olds globally.