Highlights + APOE4 women with family history of AD had greater brain aging than men. Non-modifiable risk factors interact with modifiable ones to decrease brain aging. Higher BMI was associated with less brain aging in +APOE4 women. Sex differences in APOE status on brain aging were found in physical activity. Greater physical activity was associated with less brain aging in +APOE4 men.

A functional gradient has been proposed across the medial temporal lobes (MTL) such that the anterior MTL is thought to support processing of individual items (e.g., item memory and complex object perception), whereas the posterior MTL is thought to support item-context retrieval (e.g., source memory). Whereas functional imaging studies have provided evidence supporting this anatomical organization, results from structural analyses remain inconclusive. The current study examined the relationship between volume of MTL regions of interest (ROIs), and performance on a source memory task and a fine-grain complex object perception task, in healthy young adults (mean age = 21.5, range = 18-29). Using a semiautomated procedure, we segmented the parahippocampal and perirhinal cortices (PHC, PRC), posteromedial and anterolateral entorhinal cortices (pmERC, alERC), and posterior and anterior hippocampus (postHC, antHC) on high-resolution T2-weighted MRIs. Regional volumes were computed as proportions of intracranial volume, and as posterior-anterior volumetric ratios (PHC: PRC, pmERC:alERC, postHC:antHC). Partial-least squares regressions were applied to predict source and item memory, and perceptual discrimination accuracy, based on ROI and ratio volumes. In our ROI regressions, we found that postHC volume was positively correlated with a latent factor predicting source memory, and PRC and antHC volumes were negatively correlated to this latent factor. In our ratio regressions, we observed an effect relating the posterior-anterior distribution of gray matter across the MTL with source memory. Our results demonstrate differential associations between anterior and posterior MTL and source memory performance. Findings from this study highlight the importance of considering patterns of structure-behavior associations in the neurobiology of episodic memory.

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Background Determining the effect of AD risk factors on brain aging in healthy middle‐aged and older women, compared to men, is critical for understanding whether there are sex differences in the pathways towards AD in cognitively intact, at risk adults. The goal of this study was to use an elastic net regression model to predict the effect of family history of AD [+FH] and the APOE‐e4 [+APOE4] genotype on brain age gap (BAG) in cognitively normal women and men. Method This cross‐sectional study used T1‐weighted structural MRIs from the Dallas Lifespan Brain Study (DLBS), South Asian Lifespan Dataset (SALD), Montreal Memory and Aging Lifespan Study (MMALS), and Pre‐symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer’s Disease (PREVENT‐AD) cohorts. Data were collected from multiple sites: Dallas, USA (DLBS); Chonqing, China (SALD); Montreal, Canada (MMALS and PREVENT‐AD). 1067 cognitively normal adults (18‐89 years; 697 [65%] women) were randomly split into train and test sets. In the train set: 596 unknown FH (uFH) participants (mean [SD] age = 47.39 [18.46] years, 63% women); in the test set: 251 uFH (47.50 [19.15] years, 64% women) and 220 +FH participants (61.53 [6.04] years, 72% women). BAG, was measured as the difference between Predicted Age, estimated by the elastic net model, and Chronological Age. Result The age prediction model applied to the test set revealed greater BAG deviations in the +FH cohort compared to the uFH cohort (31% vs. 74% of the age variance, respectively; MAE = 8.22 years). A significant interaction was observed between FH status and Sex: +FH women had more advanced brain aging compared to +FH men. APOE genotype interacted with Sex in the +FH group: +APOE4 women had more positive BAG than +APOE4 men. In a sub‐cohort of individuals with AD risk factors, we observed sex differences in the role of modifiable factors of Body Mass Index and physical activity in preserving brain aging. Conclusion AD risk factors have more negative consequences to brain aging in cognitively normal women with family history than men with family history, but that modifiable factors can interact with genetic factors to potentially protect against brain aging.