Concerns about memory often increase with age and have been suggested as a precursor to impending memory impairment or dementia. However, subjective memory concern (SMC) has also been shown to reflect an individual’s trait-like tendency to worry about memory, which is more strongly linked to negative affect than to objective memory performance. Despite behavioral evidence supporting a trait-like dimension of SMC, its neuroanatomical underpinnings remain underexplored. In 477 community-dwelling dementia-free men (56–72 years old), we investigated the association between SMC and cortical mean diffusivity (cMD)—a diffusion MRI-based metric of gray matter microstructural integrity—generating a brain-wide map of their association. Self-report trait anxiety and depressive symptoms were collected, along with objective memory scores based on three neuropsychological tasks for which brain maps of their association with cMD were also generated. Finally, we conducted spatial correlational analyses to compare the spatial patterns of these brain association maps to assess whether there were significant spatial resemblances between each. We found that the gray matter integrity correlates of SMC spatially resembled those of depressive symptoms and trait anxiety but not those of objective memory. The spatial correspondences between gray matter integrity correlates of negative affect measures and SMC were significantly stronger than those between SMC and objective memory. Together, these results suggest a neuroanatomical basis of trait-like SMC, which should be distinguished from state-related SMC that may be a precursor of objective memory deficits in research and clinical settings.

The amyloid cascade hypothesis predicts that amyloid-beta (Aβ) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between Aβ40 and Aβ42 and total Tau (t-Tau) plasma biomarkers. Plasma Aβ40, Aβ42, t-Tau, and neurofilament light chain (NFL) were measured in 1,035 men (mean = 67.0 years) using Simoa immunoassays. Genetically informative twin modeling tested the direction of causation between Aβs and t-Tau. No clear evidence that Aβ40 or Aβ42 directly causes t-Tau was observed. Instead, the alternative causal hypotheses also fit the data well. In contrast, exploratory analyses suggested a causal impact of the Aβ biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL. Plasma Aβ40 or Aβ42 do not appear to have a direct causal impact on t-Tau, though our use of total rather than phosphorylated tau was a limitation. In contrast, Aβ biomarkers appeared to causally impact NFL in cognitively unimpaired men in their late 60 s.

Little is known about the genetics of hippocampal volume change during later life. The degree to which genetic risk for Alzheimer’s disease (AD) contributes to hippocampal volume change prior to AD onset is also unclear. We estimated the heritability of hippocampal volume change, as well as the contribution of APOE genotype and AD polygenic risk. Data were obtained from the Vietnam Era Twin Study of Aging. A latent change model was used to characterize baseline hippocampal volume and volume change across two waves. Average ages at each wave were61.9 years (SD=2.6) and 67.5 years (SD=2.6), and the average interval was 5.6 years (SD=0.5). Baseline hippocampal volume and volume change were highly heritable, .83 (95% CI: .72-.91) and .87 (95% CI: .50-1.23) respectively. APOE was not associated with baseline volume or volume change. An AD polygenic score without APOE was positively associated with baseline hippocampal volume, and negatively associated volume change. Results indicate that hippocampal volume change during later life is highly heritable and is partially related to AD

Objective:US forces used Agent Orange (AO) during the Vietnam War and continued to store/test it at other locations after the war. AO is a powerful herbicide including dioxin, a highly toxic ingredient classified as a human carcinogen. The National Academies of Sciences, Engineering, and Medicine periodically review the literature on the health effects of AO exposure (AOE) and concluded in 2018 that there is sufficient evidence linking AO with a wide range of adverse health outcomes, including neurologic disorders (e.g., Parkinson’s disease). The VA has a list of medical disorders considered presumptive conditions related to AOE. More recently, AOE has been linked to a nearly double risk compared to those without AOE for receiving a dementia diagnosis. To our knowledge, no one has investigated the association of AOE to mild cognitive impairment (MCI), a condition thought to precede dementia.Participants and Methods:We examined men in three waves of the Vietnam Era Twin Study of Aging (VETSA). In wave 3, participants self-reported yes/no to the question of whether they ever had prolonged or serious AOE. MCI was diagnosed by the Jak-Bondi approach. Impairment was defined as 2+ tests within a cognitive domain that were more than 1.5 standard deviations below normative means after adjusting for premorbid cognitive ability. In mixed effects models, we tested the effect of AOE on MCI status. Models were adjusted for age, ethnicity, and non-independence within twin pairs.Results:In wave 3, 12.6% (230) of 1167 participants reported AOE. Those with AOE data had mean ages of 51.1 (wave 1), 56.0 (wave 2), and 61.4 (wave 3). Those with data on both AOE and MCI numbered 861 (wave 1), 900 (wave 2), 1121 (wave 3), and 766 had AOE and MCI at all waves. AOE was significantly related to wave 2 MCI (p < .001), but not to waves 1 and 3 MCI. AOE was significantly associated with the number of time points at which someone met criteria for MCI (p = .011). Analyses were conducted on six cognitive domains used to diagnose MCI, using available participants per wave. At all 3 waves, AOE was significantly associated with lower scores in processing speed (p = .003, p = .004, p = .005, respectively), working memory (p < .001, p = .002, p = .008) and nearly significant at all waves for executive dysfunction (p < .001, p < .001, p = .050). There were two other significant associations [wave 2 memory (p = .038), wave 3 fluency (p = .024)]. The semantic fluency cognitive domain was unrelated to AOE in all waves.Conclusions:AOE was consistently associated with lower processing speed, working memory, and executive dysfunction in males ages 51-61. It was also associated with the number of time points at which one met criteria for MCI in that age range, and with MCI in the mid-fifties. Findings support the idea of a risk for greater cognitive decline in those exposed to AO earlier in their lives, and with a risk for developing MCI.

INTRODUCTION:Despite their increased application, the heritability of Alzheimer's disease (AD)-related blood-based biomarkers remains unexplored. METHODS:Plasma amyloid beta 40 (Aβ40), Aβ42, the Aβ42/40 ratio, total tau (t-tau), and neurofilament light (NfL) data came from 1035 men 60 to 73 years of age (μ = 67.0, SD = 2.6). Twin models were used to calculate heritability and the genetic and environmental correlations between them. RESULTS:Additive genetics explained 44% to 52% of Aβ42, Aβ40, t-tau, and NfL. The Aβ42/40 ratio was not heritable. Aβ40 and Aβ42 were genetically near identical (rg  = 0.94). Both Aβ40 and Aβ42 were genetically correlated with NfL (rg  = 0.35 to 0.38), but genetically unrelated to t-tau. DISCUSSION:Except for Aβ42/40, plasma biomarkers are heritable. Aβ40 and Aβ42 share mostly the same genetic influences, whereas genetic influences on plasma t-tau and NfL are largely unique in early old-age men. The absence of genetic associations between the Aβs and t-tau is not consistent with the amyloid cascade hypothesis.

The amyloid-tau-neurodegeneration (ATN) framework has led to an increased focus on Alzheimer’s disease (AD) biomarkers. The cost and invasiveness of obtaining biomarkers via cerebrospinal fluid has motivated efforts to develop sensitive blood-based biomarkers. Although AD is highly heritable, the biometric genetic and environmental etiology of blood-based biomarkers has never been explored. We therefore, analyzed plasma beta-amyloid (Aβ40, Aβ42, Aβ42/40), total tautau (t-tautau), and neurofilament light (NFL) biomarkers in a sample of 1,050 men aged 60 to 73 years (m=68.2, SD=2.5) from the Vietnam Era Twin Study of Aging (VETSA). Unlike Aβ and tautau, NFL does not define AD; however, as a biomarker of neurodegeneration it serves as the N component in the ATN framework. Univariate estimates suggest that familial aggregation in Aβ42, Aβ42/40, t-tau, and NFL is entirely explained by additive genetic influences accounting for 40%-58% of the total variance. All remaining variance is associated with unshared or unique environmental influences. For Aβ40, a additive genetic (31%), shared environmental (44%), and unshared environmental (25%) influences contribute to the total variance. In the more powerful multivariate analysis of Aβ42, Aβ40, t-tau, and NFL, heritability estimates range from 32% to 58%. Aβ40 and Aβ42 are statistically genetically identical (r g = 1.00, 95%CI = 0.92,1.00) and are also moderately environmentally correlated (r e = 0.66, 95%CI = 0.59, 0.73). All other genetic and environmental associations were non-significant or small. Our results suggest that plasma biomarkers are heritable and that Aβ40 and Aβ42 share the same genetic influences, whereas the genetic influences on plasma t-tau and NFL are mostly unique and uncorrelated with plasma Aβ in early old-age men.

Magnetic resonance imaging data are being used in statistical models to predicted brain ageing (PBA) and as biomarkers for neurodegenerative diseases such as Alzheimer’s Disease. Despite their increasing application, the genetic and environmental etiology of global PBA indices is unknown. Likewise, the degree to which genetic influences in PBA are longitudinally stable and how PBA changes over time are also unknown. We analyzed data from 734 men from the Vietnam Era Twin Study of Aging with repeated MRI assessments between the ages 51–72 years. Biometrical genetic analyses “twin models” revealed significant and highly correlated estimates of additive genetic heritability ranging from 59 to 75%. Multivariate longitudinal modeling revealed that covariation between PBA at different timepoints could be explained by a single latent factor with 73% heritability. Our results suggest that genetic influences on PBA are detectable in midlife or earlier, are longitudinally very stable, and are largely explained by common genetic influences.

Abstract Objective: To determine associations of alcohol use with cognitive aging among middle-aged men. Method: 1,608 male twins (mean 57 years at baseline) participated in up to three visits over 12 years, from 2003–2007 to 2016–2019. Participants were classified into six groups based on current and past self-reported alcohol use: lifetime abstainers, former drinkers, very light (1–4 drinks in past 14 days), light (5–14 drinks), moderate (15–28 drinks), and at-risk drinkers (>28 drinks in past 14 days). Linear mixed-effects regressions modeled cognitive trajectories by alcohol group, with time-based models evaluating rate of decline as a function of baseline alcohol use, and age-based models evaluating age-related differences in performance by current alcohol use. Analyses used standardized cognitive domain factor scores and adjusted for sociodemographic and health-related factors. Results: Performance decreased over time in all domains. Relative to very light drinkers, former drinkers showed worse verbal fluency performance, by –0.21 SD (95% CI –0.35, –0.07), and at-risk drinkers showed faster working memory decline, by 0.14 SD (95% CI 0.02, –0.20) per decade. There was no evidence of protective associations of light/moderate drinking on rate of decline. In age-based models, light drinkers displayed better memory performance at advanced ages than very light drinkers (+0.14 SD; 95% CI 0.02, 0.20 per 10-years older age); likely attributable to residual confounding or reverse association. Conclusions: Alcohol consumption showed minimal associations with cognitive aging among middle-aged men. Stronger associations of alcohol with cognitive aging may become apparent at older ages, when cognitive abilities decline more rapidly.

BACKGROUND AND AIMS:Smoking is associated with increased risk for brain aging/atrophy and dementia. Few studies have examined early associations with brain aging. This study aimed to measure whether adult men with a history of heavier smoking in early mid-life would have older than predicted brain age 16-28 years later. DESIGN:Prospective cohort observational study, utilizing smoking pack years data from average age 40 (early mid-life) predicting predicted brain age difference scores (PBAD) at average ages 56, 62 (later mid-life) and 68 years (early old age). Early mid-life alcohol use was also evaluated. SETTING:Population-based United States sample. PARTICIPANTS/CASES:Participants were male twins of predominantly European ancestry who served in the United States military between 1965 and 1975. Structural magnetic resonance imaging (MRI) began at average age 56. Subsequent study waves included most baseline participants; attrition replacement subjects were added at later waves. MEASUREMENTS:Self-reported smoking information was used to calculate pack years smoked at ages 40, 56, 62, and 68. MRIs were processed with the Brain-Age Regression Analysis and Computation Utility software (BARACUS) program to create PBAD scores (chronological age-predicted brain age) acquired at average ages 56 (n = 493; 2002-08), 62 (n = 408; 2009-14) and 68 (n = 499; 2016-19). FINDINGS:In structural equation modeling, age 40 pack years predicted more advanced age 56 PBAD [β = -0.144, P = 0.012, 95% confidence interval (CI) = -0.257, -0.032]. Age 40 pack years did not additionally predict PBAD at later ages. Age 40 alcohol consumption, but not a smoking × alcohol interaction, predicted more advanced PBAD at age 56 (β = -0.166, P = 0.001, 95% CI = -0.261, -0.070) with additional influences at age 62 (β = -0.115, P = 0.005, 95% CI = -0.195, -0.036). Age 40 alcohol did not predict age 68 PBAD. Within-twin-pair analyses suggested some genetic mechanism partially underlying effects of alcohol, but not smoking, on PBAD. CONCLUSIONS:Heavier smoking and alcohol consumption by age 40 appears to predict advanced brain aging by age 56 in men.

Despite their increasing application, the genetic and environmental etiology of global predicted brain ageing (PBA) indices is unknown. Likewise, the degree to which genetic influences in PBA are longitudinally stable and how PBA changes over time are also unknown. We analyzed data from 734 men from the Vietnam Era Twin Study of Aging with repeated MRI assessments between the ages 52 to 72 years. Biometrical genetic analyses revealed significant and highly correlated estimates of additive genetic heritability ranging from 59% to 75%. Multivariate longitudinal modelling revealed that covariation between PBA at different timepoints could be explained by a single latent factor with 73% heritability. Our results suggest that genetic influences on PBA are detectable in midlife or earlier, are longitudinally very stable, and are largely explained by common genetic influences.

BACKGROUND:Clarifying the relationship between depression symptoms and cardiometabolic and related health could clarify risk factors and treatment targets. The objective of this study was to assess whether depression symptoms in midlife are associated with the subsequent onset of cardiometabolic health problems.METHODS:The study sample comprised 787 male twin veterans with polygenic risk score data who participated in the Harvard Twin Study of Substance Abuse ('baseline') and the longitudinal Vietnam Era Twin Study of Aging ('follow-up'). Depression symptoms were assessed at baseline [mean age 41.42 years (s.d. = 2.34)] using the Diagnostic Interview Schedule, Version III, Revised. The onset of eight cardiometabolic conditions (atrial fibrillation, diabetes, erectile dysfunction, hypercholesterolemia, hypertension, myocardial infarction, sleep apnea, and stroke) was assessed via self-reported doctor diagnosis at follow-up [mean age 67.59 years (s.d. = 2.41)].RESULTS:Total depression symptoms were longitudinally associated with incident diabetes (OR 1.29, 95% CI 1.07-1.57), erectile dysfunction (OR 1.32, 95% CI 1.10-1.59), hypercholesterolemia (OR 1.26, 95% CI 1.04-1.53), and sleep apnea (OR 1.40, 95% CI 1.13-1.74) over 27 years after controlling for age, alcohol consumption, smoking, body mass index, C-reactive protein, and polygenic risk for specific health conditions. In sensitivity analyses that excluded somatic depression symptoms, only the association with sleep apnea remained significant (OR 1.32, 95% CI 1.09-1.60).CONCLUSIONS:A history of depression symptoms by early midlife is associated with an elevated risk for subsequent development of several self-reported health conditions. When isolated, non-somatic depression symptoms are associated with incident self-reported sleep apnea. Depression symptom history may be a predictor or marker of cardiometabolic risk over decades.

We examined the influence of lifestyle on brain aging after nearly 30 years, and tested the hypothesis that young adult general cognitive ability (GCA) would moderate these effects. In the community-dwelling Vietnam Era Twin Study of Aging (VETSA), 431 largely non-Hispanic white men completed a test of GCA at mean age 20. We created a modifiable lifestyle behavior composite from data collected at mean age 40. During VETSA, MRI-based measures at mean age 68 included predicted brain age difference (PBAD), Alzheimer's disease (AD) brain signature, and abnormal white matter scores. There were significant main effects of young adult GCA and lifestyle on PBAD and the AD signature (ps ≤ 0.012), and a GCA-by-lifestyle interaction on both (ps ≤ 0.006). Regardless of GCA level, having more favorable lifestyle behaviors predicted less advanced brain age and less AD-like brain aging. Unfavorable lifestyles predicted advanced brain aging in those with lower age 20 GCA, but did not affect brain aging in those with higher age 20 GCA. Targeting early lifestyle modification may promote dementia risk reduction, especially among lower reserve individuals.

Because longitudinal studies of aging typically lack cognitive data from earlier ages, it is unclear how general cognitive ability (GCA) changes throughout the life course. In 1173 Vietnam Era Twin Study of Aging (VETSA) participants, we assessed young adult GCA at average age 20 and current GCA at 3 VETSA assessments beginning at average age 56. The same GCA index was used throughout. Higher young adult GCA and better GCA maintenance were associated with stronger specific cognitive abilities from age 51 to 73. Given equivalent GCA at age 56, individuals who had higher age 20 GCA outperformed those whose GCA remained stable in terms of memory, executive function, and working memory abilities from age 51 to 73. Thus, paradoxically, despite poorer maintenance of GCA, high young adult GCA still conferred benefits. Advanced predicted brain age and the combination of elevated vascular burden and APOE-ε4 status were associated with poorer maintenance of GCA. These findings highlight the importance of distinguishing between peak and current GCA for greater understanding of cognitive aging.

Neuroimaging signatures based on composite scores of cortical thickness and hippocampal volume predict progression from mild cognitive impairment to Alzheimer's disease. However, little is known about the ability of these signatures among cognitively normal adults to predict progression to mild cognitive impairment. Towards that end, a signature sensitive to microstructural changes that may predate macrostructural atrophy should be useful. We hypothesized that: (i) a validated MRI-derived Alzheimer's disease signature based on cortical thickness and hippocampal volume in cognitively normal middle-aged adults would predict progression to mild cognitive impairment; and (ii) a novel grey matter mean diffusivity signature would be a better predictor than the thickness/volume signature. This cohort study was part of the Vietnam Era Twin Study of Aging. Concurrent analyses compared cognitively normal and mild cognitive impairment groups at each of three study waves (ns = 246-367). Predictive analyses included 169 cognitively normal men at baseline (age = 56.1, range = 51-60). Our previously published thickness/volume signature derived from independent data, a novel mean diffusivity signature using the same regions and weights as the thickness/volume signature, age, and an Alzheimer's disease polygenic risk score were used to predict incident mild cognitive impairment an average of 12 years after baseline (follow-up age= 67.2, range= 61-71). Additional analyses adjusted for predicted brain age difference scores (chronological age minus predicted brain age) to determine if signatures were Alzheimer-related and not simply ageing-related. In concurrent analyses, individuals with mild cognitive impairment had higher (worse) mean diffusivity signature scores than cognitively normal participants, but thickness/volume signature scores did not differ between groups. In predictive analyses, age and polygenic risk score yielded an area under the curve of 0.74 (sensitivity = 80.00%; specificity = 65.10%). Prediction was significantly improved with addition of the mean diffusivity signature (area under the curve = 0.83; sensitivity =85.00%; specificity = 77.85%; P= 0.007), but not with addition of the thickness/volume signature. A model including both signatures did not improve prediction over a model with only the mean diffusivity signature. Results held up after adjusting for predicted brain age difference scores. The novel mean diffusivity signature was limited by being yoked to the thickness/volume signature weightings. An independently derived mean diffusivity signature may thus provide even stronger prediction. The young age of the sample at baseline is particularly notable. Given that the brain signatures were examined when participants were only in their 50 s, our results suggest a promising step towards improving very early identification of Alzheimer's disease risk and the potential value of mean diffusivity and/or multimodal brain signatures.

INTRODUCTION:The locus coeruleus (LC) undergoes extensive neurodegeneration in early Alzheimer's disease (AD). The LC is implicated in regulating the sleep-wake cycle, modulating cognitive function, and AD progression. METHODS:Participants were 481 men (ages 62 to 71.7) from the Vietnam Era Twin Study of Aging. LC structural integrity was indexed by neuromelanin-sensitive magnetic resonance imaging (MRI) contrast-to-noise ratio (LCCNR ). We examined LCCNR , cognition, amnestic mild cognitive impairment (aMCI), and daytime dysfunction. RESULTS:Heritability of LCCNR was .48. Participants with aMCI showed greater daytime dysfunction. Lower LCCNR was associated with poorer episodic memory, general verbal fluency, semantic fluency, and processing speed, as well as increased odds of aMCI and greater daytime dysfunction. DISCUSSION:Reduced LC integrity is associated with widespread differences across cognitive domains, daytime sleep-related dysfunction, and risk for aMCI. These findings in late-middle-aged adults highlight the potential of MRI-based measures of LC integrity in early identification of AD risk.

Abstract Objective: Heavy alcohol consumption is associated with poorer cognitive function in older adults. Although understudied in middle-aged adults, the relationship between alcohol and cognition may also be influenced by genetics such as the apolipoprotein (ApoE) ε4 allele, a risk factor for Alzheimer’s disease. We examined the relationship between alcohol consumption, ApoE genotype, and cognition in middle-aged adults and hypothesized that light and/or moderate drinkers (≤2 drinks per day) would show better cognitive performance than heavy drinkers or non-drinkers. Additionally, we hypothesized that the association between alcohol use and cognitive function would differ by ApoE genotype (ε4+ vs. ε4−). Method: Participants were 1266 men from the Vietnam Era Twin Study of Aging (VETSA; M age = 56; range 51–60) who completed a neuropsychological battery assessing seven cognitive abilities: general cognitive ability (GCA), episodic memory, processing speed, executive function, abstract reasoning, verbal fluency, and visuospatial ability. Alcohol consumption was categorized into five groups: never, former, light, moderate, and heavy. Results: In fully adjusted models, there was no significant main effect of alcohol consumption on cognitive functions. However, there was a significant interaction between alcohol consumption and ApoE ε4 status for GCA and episodic memory, such that the relationship of alcohol consumption and cognition was stronger in ε4 carriers. The ε4+ heavy drinking subgroup had the poorest GCA and episodic memory. Conclusions: Presence of the ε4 allele may increase vulnerability to the deleterious effects of heavy alcohol consumption. Beneficial effects of light or moderate alcohol consumption were not observed.

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.