ABSTRACT Importance Both cognitive reserve and modifiable lifestyle behaviors are associated with dementia risk. The effect of early lifestyle behaviors and cognitive reserve on late midlife brain aging could inform early identification and risk reduction of future dementia. Objective Determine associations of young adult cognitive reserve, early midlife lifestyle behaviors, and the reserve-by-lifestyle interaction on late midlife brain age. Examine the relationship between mild cognitive impairment (MCI) and brain age. Design Participants were from the nationally representative Vietnam Era Twin Study of Aging (VETSA). Cognitive reserve was assessed at median age 20 years (IQR=1.38) with the Armed Forces Qualification Test (AFQT). Lifestyle behaviors (smoking, alcohol consumption, and social engagement) were assessed at median age 41 (IQR=5.00). Structural brain imaging conducted at median age 69 (IQR=4.74) was used to construct predicted brain age difference scores (PBAD=chronological age minus predicted brain age) and MCI was ascertained. Setting In-person cognitive testing (ages 20 and 69); mailed survey (age 41); structural MRI, MCI diagnosis at University of California, San Diego (age 69). Participants 431 community-dwelling men. Exposures AFQT; self-reported health and lifestyle behaviors. Main outcomes and measures PBAD scores; MCI. Results In fully adjusted mixed linear models, age 20 cognitive reserve and the age 41 lifestyle composite were associated with age 69 PBAD [t (104)=2.62, p=0.01, 95%CI 0.874, 6.285; t (104)=3.37, p=0.001, 95%CI 0.583, 2.249 respectively] as was the reserve-by-lifestyle interaction [t (104) = −2.29, p=0.02, 95%CI −2.330, −0.167]. Unfavorable lifestyle predicted more advanced brain age, but only for those with lower young adult cognitive reserve. The MCI group had more advanced brain age (F (2,130) = 3.13; p=0.05). Conclusions and relevance Favorable lifestyle behaviors promoted resistance to accelerated brain aging 3 decades later for those with lower young adult cognitive reserve. High reserve appeared to be protective regardless of lifestyle. The association with MCI suggests that advanced PBAD scores reflect poorer brain integrity, although it is unclear if PBAD is related to Alzheimer’s dementia specifically. Lower cognitive reserve increases risk for dementia, but early lifestyle modification may promote healthier brain aging and dementia risk reduction, particularly in those with lower reserve. Study Type Cohort Study Key Points Question Do modifiable lifestyle behaviors in early midlife predict later accelerated brain aging and is that association moderated by cognitive reserve? Findings A lifestyle composite of smoking, alcohol consumption and social engagement at age 41 was associated with estimated brain age in late midlife. There was a significant moderation effect whereby more unfavorable lifestyle behaviors predicted more advanced brain aging, but only in those with low-to-moderate cognitive reserve. Meaning Favorable lifestyle behaviors appear to be protective for brain integrity especially among those with lower cognitive reserve. Early midlife efforts at prevention could be prioritized among those with lower cognitive reserve.

Associations between Early Midlife Lifestyle Behaviors, Young Adult Cognitive Reserve and Advanced Predicted Brain Age in Late Midlife