The relative contribution of modifiable and non-modifiable factors for determining cognition in mid-life individuals at risk for late-life Alzheimer's disease

Alzheimers Dement (Amst). 2026 Apr 21;18(2):e70303. doi: 10.1002/dad2.70303. eCollection 2026 Apr-Jun.

ABSTRACT

INTRODUCTION: It remains unknown whether cognitive reserve contributors can protect against dementia from mid-life, in the context of several modifiable and non-modifiable risk factors, including family history and inherited risk for late-life dementia.

METHODS: We leveraged PREVENT Dementia, a large multisite study of healthy mid-life at-risk individuals (N = 700) and used canonical correlation analysis (CCA) to investigate multivariate associations between 13 cognitive tasks, 10 modifiable and four non-modifiable risks, and three reserve contributors.

RESULTS: The CCA identified a significant canonical mode (r = 0.486, p _(FWE) < 0.001) between dementia risk, reserve contributors, and cognition. The key finding was that modifiable stimulating activities showed the strongest positive association with cognition. Depressive symptoms and traumatic brain injury were the top two modifiable risk factors negatively associated with cognition.

DISCUSSION: These results highlight the strong potential of early, cost-effective, and multifactorial dementia prevention interventions that target both modifiable risk reduction and boosting of cognitive reserve from mid-life.

PMID:42023285 | PMC:PMC13097112 | DOI:10.1002/dad2.70303