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

Abstract

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.

Keywords: Alzheimer’s disease; functional connectivity; genetic risk; neuroimaging genetics; precision medicine.

Figure 1

Main Effects of Genetic Risk Factors for AD on Brain Functional Connectivity in Cognitively Normal Individuals. Schematic illustration of the main networks influenced by genetic variations in cognitively intact individuals. Mutations in the APOE or CLU genes affect the functional connectivity of (i) the anterior DMN (red), including the anterior cingulate and the middle prefrontal cortices; (ii) the poster DMN (blue), including the posterior cingulate cortex, the precuneus, the inferior parietal lobe, and the retrosplenial cortex; and (iii) the hippocampus (green). By contrast, BIN1 and PICALM genetic variations seem to affect essentially the hippocampal connectivity. AD, Alzheimer’s disease. This figure is a derivative of the work created by Vivid Apps and AXS Biomedical Animation Studio for Cold Spring Harbor Laboratory DNA Learning Center (https://www.dnalc.org/resources/3dbrain.html).

Figure 2

Main Effects of Genetic Risk Factors for AD on Brain Functional Connectivity in Presymptomatic Individuals. In presymptomatic individuals, genetic effects of APP, PSEN1, PSEN2, and APOE were shown in the resting-state functional connectivity of the posterior DMN (blue). In addition, while APP, PSEN2, and APOE influence the anterior DMN (red), PSEN1 mutations affect the temporal lobe (purple). APOE variants affect functional connectivity as well, in sensorimotor, auditory and salience networks (not shown). AD, Alzheimer’s disease. This figure is a derivative of the work created by Vivid Apps and AXS Biomedical Animation Studio for Cold Spring Harbor Laboratory DNA Learning Center (https://www.dnalc.org/resources/3dbrain.html).

Figure 3

Main Effects of Genetic Risk Factors for AD on Brain Functional Connectivity in AD Dementia Individuals. Neuroimaging genetics results in AD dementia patients are still controversial. However, functional alterations at rest resulted in the posterior DMN (blue) in AD diseased individuals with PSEN1 mutations, and in the anterior DMN (red) in APOE ε 4 carriers. Abbreviation: AD, Alzheimer’s disease. This figure is a derivative of the work created by Vivid Apps and AXS Biomedical Animation Studio for Cold Spring Harbor Laboratory DNA Learning Center (https://www.dnalc.org/resources/3dbrain.html).