Machine learning (ML) has transformed neuroimaging research by enabling accurate predictions and feature extraction from large datasets. In this study, we investigate the application of six ML algorithms (Lasso, relevance vector regression, support vector regression, extreme gradient boosting, category boost, and multilayer perceptron) to predict brain age for middle-aged and older adults, which is a crucial area of research in neuroimaging. Despite the plethora of proposed ML models, there is no clear consensus on how to achieve better performance in brain age prediction for this population. Our study stands out by evaluating the impact of both ML algorithms and image modalities on brain age prediction performance using a large cohort of cognitively normal adults aged 44.6 to 82.3 years old (N = 27,842) with six image modalities. We found that the predictive performance of brain age is more reliant on the image modalities used than the ML algorithms employed. Specifically, our study highlights the superior performance of T1-weighted MRI and diffusion-weighted imaging and demonstrates that multi-modality-based brain age prediction significantly enhances performance compared to unimodality. Moreover, we identified Lasso as the most accurate ML algorithm for predicting brain age, achieving the lowest mean absolute error in both single-modality and multi-modality predictions. Additionally, Lasso also ranked highest in a comprehensive evaluation of the relationship between BrainAGE and the five frequently mentioned BrainAGE-related factors. Notably, our study also shows that ensemble learning outperforms Lasso when computational efficiency is not a concern. Overall, our study provides valuable insights into the development of accurate and reliable brain age prediction models for middle-aged and older adults, with significant implications for clinical practice and neuroimaging research. Our findings highlight the importance of image modality selection and emphasize Lasso as a promising ML algorithm for brain age prediction.

Sustainable cognitive health is heavily influenced by cognitive reserve (CR), which delays cognitive decline or reduces its severity by enhancing cognitive function through life experiences. The main objective of this study is to explore whether CR moderates the relationship between white matter integrity and cognitive function in cognitively intact older adults. A cross-sectional analysis was conducted on 5004 cognitively normal individuals aged 48–80 years from the UK Biobank, utilizing hierarchical regression analysis to estimate CR through five CR proxies and five skeleton-based diffusion measures. The study’s findings revealed that early fluid intelligence had a significant independent and moderating impact on cognitive performance, demonstrating its suitability as an individual CR proxy. Moreover, the composite proxy composed of early fluid intelligence and physical activity showed promise in promoting sustainable cognitive health. Importantly, this study represents one of the most extensive MRI investigations to unveil the substantial moderating effect of CR on the intricate relationship between white matter integrity and cognitive function based on a complete model. Notably, this study employed the NODDI method, which proved more advantageous than DTI in examining this interaction. Overall, this research constitutes a noteworthy and substantive contribution to our current understanding of the complex and intricate relationship between CR, cognitive function, and aging-associated cognitive decline, highlighting the importance of considering CR proxies in promoting sustainable cognitive health in aging populations.

Age-related cognitive decline is a global phenomenon that affects individuals worldwide. The course and extent of this decline are influenced by numerous factors, such as genetics, lifestyle, education, and cognitive engagement. The theory of brain and cognitive reserve/maintenance posits that these factors have a significant impact on the degree of cognitive decline and overall brain health. However, the absence of standardized definitions and measurements for these terms creates ambiguity in research. To address this issue, we utilized a robust and systematic experimental paradigm, employing a considerably large subject pool comprising 17,030 participants from the UK Biobank. Utilizing advanced machine learning methodologies, we were able to accurately quantify both brain maintenance (BM) and cognitive maintenance (CM), making use of six distinct MRI modalities and nine distinct cognitive capabilities. Our study successfully identified several significant features that were meaningfully associated with both BM and CM outcomes. The results of our study demonstrate that lifestyle factors play a significant role in influencing both BM and CM through unique and independent mechanisms. Specifically, our study found that health status is a critical determinant of BM, while diabetes was found to be moderately associated with CM. Furthermore, our study revealed a positive correlation between BM/CM and cognitive reserve. By carefully considering the unique and independent mechanisms that govern both BM and CM, as well as their correlation with cognitive reserve, our study has provided valuable insight into the various strategies that may be leveraged to promote sustainable interventions to enhance cognitive and brain health across the lifespan.