Targeting neural reserve in dementia

David Bennett has an interesting proposal for future AD/dementia trials. He points out that a large percentage of persons diagnosed with AD actually have mixed pathology, and that solving each of those pathologies with an individual agent is going to be difficult and costly. Instead, he proposes that if one were to target neural reserve — i.e., resilience against dementia — that might be a more tractable strategy.

[C]onsider neural reserve as a therapeutic endpoint. There is no evolutionary pressure to create systems that protect the brain from any brain pathology of old age, let alone different systems that offer protection from different pathologies. Thus, finding that myriad factors alter the trajectory of cognitive decline agnostic to underlying brain pathologies is expected. A hypothetical therapeutic agent that targets neural reserve could be used to offset any and likely all common brain pathologies that alter cognition.

I guess the main problem with this proposal is that it might be harder to find this sort of an all-encompassing pro-cognitive aging agent. If it’s easily available as an exogenous chemical and has a strong effect, why didn’t natural selection already sculpt our brain so that it — or its effects — would be present? I disagree that there is prima facie no evolutionary pressure for this, given the potential importance of kin selection in our evolutionary history.

But that’s just speculation and Bennett’s strategy deserves serious consideration, especially given the series of failures of AD clinical trials.

In terms of already available agents, my immediate thought is nootropics — drugs that are meant to boost one’s cognition. Some of the top nootropics that are commonly discussed are caffeine, nicotine, and modafinil. Caffeine has been shown to be protective against dementia in the epidemiologic studies you read about in the news every week. A very small trial of modafinil (n = 23) was not helpful for apathy in AD. Nicotine has been fairly widely studied in AD but its efficacy is still not clear. All of them deserve more attention, but it’s difficult to fund these trials because generic versions of all of them are now available.