Towards a multimodal neuroimaging-based risk score for mild cognitive impairment by combining clinical studies with a large (N>37000) population-based study

Alzheimer's disease (AD) is the most common form of age-related dementia, leading to a decline in memory, reasoning, and social skills. While numerous studies have investigated the genetic risk factors associated with AD, less attention has been given to identifying a brain imaging-based measure of AD risk. This study introduces a novel approach to assess mild cognitive impairment MCI, as a stage before AD, risk using neuroimaging data, referred to as a brain-wide risk score (BRS), which incorporates multimodal brain imaging. To begin, we first categorized participants from the Open Access Series of Imaging Studies (OASIS)-3 cohort into two groups: controls (CN) and individuals with MCI. Next, we computed structure and functional imaging features from all the OASIS data as well as all the UK Biobank data. For resting functional magnetic resonance imaging (fMRI) data, we computed functional network connectivity (FNC) matrices using fully automated spatially constrained independent component analysis. For structural MRI data we computed gray matter (GM) segmentation maps. We then evaluated the similarity between each participant's neuroimaging features from the UK Biobank and the difference in the average of those features between CN individuals and those with MCI, which we refer to as the brain-wide risk score (BRS). Both GM and FNC features were utilized in determining the BRS. We first evaluated the differences in the distribution of the BRS for CN vs MCI within the OASIS-3 (using OASIS-3 as the reference group). Next, we evaluated the BRS in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (using OASIS-3 as the reference group), showing that the BRS can differentiate MCI from CN in an independent data set. Subsequently, using the sMRI BRS, we identified 10 distinct subgroups and similarly, we identified another set of 10 subgroups using the FNC BRS. For sMRI and FNC we observed results that mutually validate each other, with certain aspects being complementary. For the unimodal analysis, sMRI provides greater differentiation between MCI and CN individuals than the fMRI data, consistent with prior work. Additionally, by utilizing a multimodal BRS approach, which combines both GM and FNC assessments, we identified two groups of subjects using the multimodal BRS scores. One group exhibits high MCI risk with both negative GM and FNC BRS, while the other shows low MCI risk with both positive GM and FNC BRS. Moreover, in the UKBB we have 46 participants diagnosed with AD showed FNC and GM patterns similar to those in high-risk groups, defined in both unimodal and multimodal BRS. Finally, to ensure the reproducibility of our findings, we conducted a validation analysis using the ADNI as an additional reference dataset and repeated the above analysis. The results were consistently replicated across different reference groups, highlighting the potential of FNC and sMRI-based BRS in early Alzheimer's detection.