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. ### Competing Interest Statement The authors have declared no competing interest.

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