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Pathology is not destiny. So say the more than 1200 brains autopsied so far as part of the Rush Memory and Aging Project and the Religious Orders Study, a pair of massive prospective studies that have tracked the cognitive status of nearly 3000 elders for about 2 decades (Bennett DA et al. Curr Alzheimer Res. 2012;9:646-663, and Bennett DA et al. Curr Alzheimer Res. 2012;9:628-645).
Autopsies showed that some mentally spry participants had extensive signs of cellular neuropathologies such as Lewy bodies or those related to Alzheimer or vascular disease. But others with substantial cognitive decline in their later years had few signs of these cellular abnormalities, explained David Bennett, MD, director of the Rush Alzheimer’s Disease Center at Rush University in Chicago and lead investigator of the studies. In fact, these overt cellular pathologies accounted for only about half of the cognitive decline documented, revealing a disconnect with the study participants’ cognitive status. (Boyle PA et al. Ann Neurol. 2013;74:478-489).
Instead, certain behavioral factors appeared to modify the association between cellular pathologies and cognitive decline, explaining some of the discrepancy. Other work has since similarly implicated behavioral modifiers such as exercise, social interaction, conscientiousness, and sense of purpose in cognitive resilience (Wilson RS et al. Neurology. 2013;81:314-321, Wilson RS et al. Psychol Aging. 2015;30:74-80, and Windsor TD et al. Dev Psychol. 2015;51:975-986).
“The data suggest we need to think more broadly about potential therapeutic targets,” Bennett said during an interview. Currently, the vast majority of public and private funding is spent on therapeutic trials for cognitive decline in Alzheimer disease, but even if successful treatments were developed, only about one-third of age-related cognitive decline would be eliminated, noted Bennett.
Instead, he argued the focus should be on prevention that taps into the brain’s own defense mechanisms. The National Institutes of Health and the National Institute on Aging have committed $12 million to boosting research into brain resilience in 2016 and recently issued a call for proposals (http://1.usa.gov/1MIrrrR).
“Identifying drugs that target protective mechanisms agnostic of [disease] pathology is of the highest value,” he said.