Disentangling accelerated cognitive decline from the normal aging process and unraveling its genetic components: A neuroimaging-based deep learning approach

BACKGROUND: The progressive cognitive decline that is an integral component of AD unfolds in tandem with the natural aging process. Neuroimaging features have demonstrated the capacity to distinguish cognitive decline changes stemming from typical brain aging and Alzheimer’s disease between different chronological points. METHODS: We developed a deep-learning framework based on dual-loss Siamese ResNet network to extract fine-grained information from the longitudinal structural magnetic resonance imaging (MRI) data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. We then conducted genome-wide association studies (GWAS) and post-GWAS analyses to reveal the genetic basis of AD-related accelerated cognitive decline. RESULTS: We used our model to process data from 1,313 individuals, training it on 414 cognitively normal people and predicting cognitive assessment for all participants. In our analysis of accelerated cognitive decline GWAS, we identified two genome-wide significant loci: APOE locus (chromosome 19 p13.32) and rs144614292 (chromosome 11 p15.1). Variant rs144614292 (G>T) has not been reported in previous AD GWA studies. It is within the intronic region of NELL1, which is expressed in neuron and plays a role in controlling cell growth and differentiation. In addition, MUC7 and PROL1/OPRPNon chromosome 4 were significant at the gene level. The cell-type-specific enrichment analysis and functional enrichment of GWAS signals highlighted the microglia and immune-response pathways. Furthermore, we found that the cognitive decline slope GWAS was positively correlated with previous AD GWAS. CONCLUSION: Our deep learning model was demonstrated effective on extracting relevant neuroimaging features and predicting individual cognitive decline. We reported a novel variant (rs144614292) within the NELL1 gene. Our approach has the potential to disentangle accelerated cognitive decline from the normal aging process and to determine its related genetic factors, leveraging opportunities for early intervention.