Brain reserve, cognitive reserve, and education are thought to protect against late-life cognitive decline, but these variables have not been directly compared to one another in the same model, using future cognitive and functional decline as outcomes. We sought to determine whether the influence of these protective factors on executive function (EF) and daily function decline was dependent upon Alzheimer’s disease (AD) pathology severity, as measured by the total tau to beta-amyloid (T-τ/Aβ1-42) ratio in cerebrospinal fluid (CSF).

Participants were 1201 older adult volunteers in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. Brain reserve was defined using a composite index of structural brain volumes (total brain matter, hippocampus, and white matter hyperintensity). Cognitive reserve was defined as the variance in episodic memory performance not explained by brain integrity and demographics.

At higher levels of T-τ/Aβ1-42, brain and cognitive reserve predicted slower decline in EF. Only brain reserve attenuated decline at lower levels of T-τ/Aβ1-42. Education had no independent association with cognitive decline.

These results point to a hierarchy of protection against aging- and disease-associated cognitive decline. When pathology is low, only structural brain integrity predicts rate of future EF decline. The ability of cognitive reserve to predict future EF decline becomes stronger as CSF biomarker evidence of AD increases. Although education is typically thought of as a proxy for cognitive reserve, it did not show any protective effects on cognition after accounting for brain integrity and the residual cognitive reserve index.