Revolution of Resting-State Functional Neuroimaging Genetics in Alzheimer's Disease

The quest to comprehend genetic, biological, and symptomatic heterogeneity underlying Alzheimer's disease (AD) requires a deep understanding of mechanisms affecting complex brain systems. Neuroimaging genetics is an emerging field that provides a powerful way to analyze and characterize intermediate biological phenotypes of AD. Here, we describe recent studies showing the differential effect of genetic risk factors for AD on brain functional connectivity in cognitively normal, preclinical, prodromal, and AD dementia individuals. Functional neuroimaging genetics holds particular promise for the characterization of preclinical populations; target populations for disease prevention and modification trials. To this end, we emphasize the need for a paradigm shift towards integrative disease modeling and neuroimaging biomarker-guided precision medicine for AD and other neurodegenerative diseases. Neural rs-fMRI differences are detectable in CN mutation carriers of APOE, PICALM, CLU, and BIN1 genes across the lifespan. CN individuals carrying risk variants of APOE, PICALM, CLU, or BIN1 and presymptomatic AD individuals showed overlapping rs-fMRI alterations: decreased functional connectivity in the middle and posterior DMN regions, and increased the frontal and lateral DMN areas. No consistent results were reported in AD dementia, despite findings suggest selective alterations in the DMN and in the executive control network. Multimodal biomarker data – including distinct combinations of underlying functional neuroimaging genetics patterns – are standardized and integrated according to the integrative disease modeling (IDM) concept. The PM paradigm applies IDM to translate biomarker-indicated, individual-specific, molecular pathophysiological mechanisms into tailored clinical applications.