Characterizing the structural covariance network in AD-susceptible single nucleotide polymorphisms and the correlations with cognitive outcomes

Abstract BackgroundThe clinical manifestations of Alzheimer disease (AD) are related to brain network degeneration, while genetic differences may mediate network change patterns. A number of AD-susceptible loci have been reported using genome-wide association studies, however, how they modulate intracerebral volume and relationships to cognitive outcomes remains to be established. We hypothesized that different genotype groups may modulate large-scale brain networks independently or interact with apolipoprotein E4 (ApoE4) status to determine neurobehavior test scores.MethodsGray matter structural covariance networks were constructed in 324 patients with AD using T1 magnetic resonance imaging with independent component analysis (ICA). We assessed 15 genetic loci (rs9349407, rs3865444, rs670139, rs744373, rs3851179, rs11136000, rs3764650, rs610932, rs6887649, rs7849530, rs4866650, rs3765728, rs34011, rs6656401, rs597668) using the additive, recessive and dominant model on clinical outcomes. Statistical analysis was performed to explore the independent role of each locus, interactions with ApoE4 status, and relationships to brain ICA network integrity score. We used Cognitive Abilities Screening Instrument (CASI) total score or short-term memory (STM) subscore as the major outcome factors, adjusted for covariates of education, disease duration and age.ResultsClinically, the CD2AP G allele showed a protective role in CASI-total and CASI-STM scores independently or via interactions with non-ApoE4 status, while the CR1 A genotype group was associated with lower STM independently of ApoE4 status. Three loci showed synergic interactions with ApoE4: BIN 1 T allele and MS4A6A G allele with non-ApoE4 status, and FTMT G allele with ApoE4 status. The network integrity scores revealed 9 significant ICA networks (anterior and posterior hippocampus, right temporal, right or left thalamus, inferior cerebellum, medial cerebellum, default mode network, frontal attention network) that correlated with cognitive scores, in which only the ApoE4 and MS4A6A genotype group was independently related to the hippocampus network. Genetic loci of MS4A6A, BIN1, CD2AP, CD33, CLU, BIN1, P73, EXOC3L2, CR1 and MS4AE4 exerted network influence independently or via interactions with ApoE4 status.ConclusionsThis study suggests that AD-susceptible loci may exert clinical significance independently, through interactions with ApoE4 status or by modulating ICA networks to determine cognitive outcomes.