Reviewer 3 (Public Review): The (Limited?) Utility of Brain Age as a Biomarker for Capturing Cognitive Decline

Abstract

For decades, neuroscientists have been on a quest to search for a biomarker that can help capture age-related cognitive decline. One well-known candidate is Brain Age, or a predicted value based on machine-learning models built to predict chronological age from brain MRI data. Here we aim to formally evaluate the utility of Brain Age as a biomarker for capturing cognitive decline. Using 504 aging participants (36-100 years old) from the Human Connectome Project in Aging, we created 26 age-prediction models for Brain Age based on different combinations of MRI modalities. We first tested how much Brain Age from these age-prediction models added to what we had already known from a person’s chronological age in capturing cognitive decline. Based on the commonality analyses, we found a large degree of overlap between Brain Age and chronological age, so much so that, at best, Brain Age could uniquely add only around 1.6% in explaining variation in cognitive decline. Next, the age-prediction models that performed better at predicting chronological age did NOT necessarily create better Brain Age for capturing cognitive decline over and above chronological age. Instead, better-performing age-prediction models created Brain Age that overlapped larger with chronological age, up to around 29% out of 32%, in explaining cognitive decline, thus not improving the models’ ability to capture cognitive decline. Lastly, unlike Brain Age, Brain Cognition, or a predicted value based on machine-learning models built to predict cognitive abilities from brain MRI data, provided much higher unique effects. Brain Cognition added over 11% to explain variation in cognitive decline beyond chronological age, leading to around a 1/3-time improvement of the total variation explained. Accordingly, while demonstrating the limited utility of Brain Age, we provided a solution to improve our ability to use brain MRI data as a biomarker for cognitive decline.