Affiliations: [a] Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China
| [b] Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA
Correspondence:
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Correspondence to: Dr. Feng Bai, Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China. Tel.: +86 25 83262243; Fax: +86 25 2583285132; E-mail: [email protected].
Abstract: The aim of the study was to investigate the cognitive significance of the changes in default mode network (DMN) during the process of Alzheimer’s disease (AD) and the genetic basis that drives the alteration. Eighty-seven subjects with mild cognitive impairment (MCI) and 131 healthy controls (HC) were employed at baseline, and they had the genetic risk scores (GRS) based on the GWAS-validated AD-related top loci. Eleven MCIs who converted to AD (c-MCIs), 32 subjects who remained stable (nc-MCIs), and 56 HCs participated in the follow-up analyses after an average of 35 months. Decreased functional connectivity (FC) within temporal cortex was identified for MCIs at baseline, which was partially determined by the GRS; moreover, compensations may occur within the frontal-parietal brain to maintain relatively intact cognition. During the follow-ups, c-MCIs exhibited more FC declines within the prefrontal-parietal lobes and parahippocampal gyrus/hippocampus than the HCs and nc-MCIs. The GRS did not significantly vary among the three groups, whereas associations were identified at risky alleles and FC declines in all AD spectra. Interestingly, the influence of APOE ɛ4 varied as the disease progressed; APOE ɛ4 was associated with longitudinal FC decreases only for HCs in the single variance-based analyses and deteriorated DMN integration in nc-MCIs by combining the effects of other loci. However, the GRS without APOE ɛ4 predicted FC decline for converters. It is suggested that the integration of multilocus genetic risk predicted the longitudinal trajectory of DMN and may be used as a clinical strategy to track AD progression.
