Single Nucleotide Polymorphisms in Alzheimer’s Disease Risk Genes Are Associated with Intrinsic Connectivity in Middle Age

Background: It is critical to identify individuals at risk for Alzheimer’s disease (AD) earlier in the disease time course, such as middle age and preferably well prior to the onset of clinical symptoms, when intervention efforts may be more successful. Genome-wide association and candidate gene studies have identified single nucleotide polymorphisms (SNPs) in APOE, CLU, CR1, PICALM, and SORL1 that confer increased risk of AD. Objective: In the current study, we investigated the associations between SNPs in these genes and resting-state functional connectivity within the default mode network (DMN), frontoparietal network (FPN), and executive control network (ECN) in healthy, non-demented middle-aged adults (age 40 –60; N = 123; 74 females). Methods: Resting state networks of interest were identified through independent components analysis using a template-matching procedure and individual spatial maps and time courses were extracted using dual regression. Results: Within the posterior DMN, functional connectivity was associated with CR1 rs1408077 and CLU rs9331888 polymorphisms (p’s < 0.05). FPN connectivity was associated with CR1 rs1408077, CLU rs1136000, SORL1 rs641120, and SORL1 rs689021 (p’s < 0.05). Functional connectivity within the ECN was associated with the CLU rs11136000 (p < 0.05). There were no APOE- or PICALM-related differences in any of the networks investigated (p’s > 0.05). Conclusion: This is the first demonstration of the relationship between intrinsic network connectivity and AD risk alleles in CLU, CR1, and SORL1 in healthy, middle-aged adults. These SNPs should be considered in future investigations aimed at identifying potential preclinical biomarkers for AD.