Although compromised brain health is a common consequence of aging, cognition varies across individuals and growing evidence shows that diverse genetic and modifiable lifestyle factors influence cognitive function and change in the presence of accumulating neuropathologies (Ahangari et al., 2023, (ADNI), A.s.D.N.I., Alzheimer’s Disease Genetics Consortium (ADGC), A.S.T., 2020, Hayden et al., 2011). Herein lies the promise of studying cognitive resilience, which we operationalize as the change in cognition not explained by common brain pathologies. Therapeutic interventions can extend beyond targeting one or more pathologies to factors associated with cognition irrespective of underlying pathological burden. However, while several risk factors that slow or hasten decline are under investigation, the neural mechanisms of cognitive resilience have not been well-characterized.

Here, we define cognitive resilience as residual variation in person-specific slopes of change not explained by demographics and common neuropathologic indices (Yu et al., 2015). Given that nearly all older adults have some burden of neuropathology at the time of death (Boyle et al., 2018), this definition allows for every individual to have some degree of resilience such that they exhibit either faster or slower rates of decline relative to the average person (Bocancea et al., 2021). Recently, in a proteome-wide study of nearly 400 decedents from the Religious Orders Study and the Rush Memory and Aging Project, we identified eight cortical proteins whose abundance in the dorsolateral prefrontal cortex (DLPFC) was associated with cognitive resilience (Yu et al., 2020). However, the neural mechanisms by which these proteins are associated with cognition independent of neuropathology remain unknown.

The current study examined their association with regional brain volumes, a proxy for brain reserve and atrophy. Specifically, we used deformation-based morphometry (DBM) to identify the spatial patterns of brain structures associated with cognitive resilience and examined associations of brain morphometry with cortical protein levels. Potential associations could reveal the brain regions that underly resilience associated with specific proteins.