Structural Covariance Network as an Endophenotype in Alzheimer's Disease-Susceptible Single-Nucleotide Polymorphisms and the Correlations With Cognitive Outcomes.

Hsin-I Chang,Kuo-Lun Huang,Chen-Chang Lee,Shih-Wei Hsu,Wen-Neng Chang,Jung-Lung Hsu,Chi-Wei Huang,Shih-Jen Tsai,Chiung-Chih Chang,Yu-Tzu Chang,Shu-Hua Huang

doi:10.3389/fnagi.2021.721217

Abstract

The cognitive manifestations of Alzheimer’s disease (AD) are related to brain network degeneration, and genetic differences may mediate network degeneration. Several AD-susceptible loci have been reported to involve amyloid or tau cascades; however, their relationships with gray matter (GM) volume and cognitive outcomes have yet to be established. We hypothesized that single-nucleotide polymorphism genotype groups may interact with apolipoprotein E4 (ApoE4) status or independently exert an effect on cognitive outcomes. We also hypothesized that GM structural covariance networks (SCNs) may serve as an endophenotype of the genetic effect, which, in turn, may be related to neurobehavior test scores. Gray matter SCNs were constructed in 324 patients with AD using T1 magnetic resonance imaging with independent component analysis (ICA). We assessed the effects of 15 genetic loci (rs9349407, rs3865444, rs670139, rs744373, rs3851179, rs11136000, rs3764650, rs610932, rs6887649, rs7849530, rs4866650, rs3765728, rs34011, rs6656401, and rs597668) using additive, recessive, and dominant models on cognitive outcomes. Statistical analysis was performed to explore the independent role of each locus, interactions with ApoE4 status, and relationships to GM ICA network intensity score. For outcome measures, we used the Mini-Mental State Examination (MMSE), Cognitive Abilities Screening Instrument (CASI) total score, and short-term memory (STM) subscores, adjusted for the covariates of education, disease duration, and age. Clinically, the CD2AP G allele showed a protective role in MMSE, 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 subscores independent of ApoE4 status. Three loci showed synergic interactions with ApoE4: BIN 1, MS4A6A, and FTMT. Of the 15 meaningful ICA components, 5 SCNs (anterior and posterior hippocampus, right temporal, left thalamus, default mode network) showed relationships with general cognitive performance, in which only the ApoE4 and MS4A6A genotype groups were independently related to the hippocampus network. The genetic loci MS4A6A, BIN1, CLU, CR1, BIN1, PICALM, and FGF1 influenced the networks independently or in synergy. This study suggests that AD-susceptible loci may each exert clinical significance independently through interactions with ApoE4 status or through SCNs as an endophenotype and that this effect is associated with the cognitive outcomes.

Highlights

The National Institutes on Aging-Alzheimer’s Association (NIAAA) criteria (Jack et al, 2018) incorporate diagnostic biomarkers in the definition of Alzheimer’s disease (AD), and the key pathology is the presence of amyloid plaque and neurofibrillary tangles
Using the Mini-Mental State Examination (MMSE), CASI total score, or short-term memory (STM) subscore as dependent variables, we explored the interactions between the susceptible single-nucleotide polymorphism (SNP) and ApoE4 status (ApoE4 carriers and nonE4 carriers) using a linear regression model, with education, age, and duration of disease as covariates
Short-term memory is the salient feature in AD, and we found three additional SNPs that showed interactions with the ApoE4 gene: BIN 1, MS4A6A, and FTMT (Table 4 and Supplementary Figure 1)

Summary

Introduction

The National Institutes on Aging-Alzheimer’s Association (NIAAA) criteria (Jack et al, 2018) incorporate diagnostic biomarkers in the definition of Alzheimer’s disease (AD), and the key pathology is the presence of amyloid plaque and neurofibrillary tangles. The synergic effect of the ApoE4 allele with other genetic loci has been reported in previous studies (Mahley, 1988), which showed that overall pathological cascades may influence neuropsychiatric outcomes (Hall et al, 2014). The mechanisms by which ApoE influences the pathogenesis of AD have been proposed, including a role in the clearance of amyloid (Koistinaho et al, 2004; Shi et al, 2017; Ringland et al, 2020). Whether this is via interactions between APoE4 and amyloid- or tau-related SNPs remains to be explored

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Results

Conclusion