Polygenic Hazard Score Associated Multimodal Brain Networks Along the Alzheimer's Disease Continuum.

Kaicheng Li,Vince D Calhoun,Shile Qi,Zening Fu,Xiao Luo,Peiyu Huang,Xiaopei Xu,Minming Zhang,Qingze Zeng

doi:10.3389/fnagi.2021.725246

Abstract

BackgroundLate-onset Alzheimer’s disease (AD) is a polygenic neurodegenerative disease. Identifying the neuroimaging phenotypes behind the genetic predisposition of AD is critical to the understanding of AD pathogenesis. Two major questions which previous studies have led to are: (1) should the general “polygenic hazard score” (PHS) be a good choice to identify the individual genetic risk for AD; and (2) should researchers also include inter-modality relationships in the analyses considering these may provide complementary information about the AD etiology.MethodsWe collected 88 healthy controls, 77 patients with mild cognitive impairment (MCI), and 22 AD patients to simulate the AD continuum included from the ADNI database. PHS-guided multimodal fusion was used to investigate the impact of PHS on multimodal brain networks in AD-continuum by maximizing both inter-modality association and reference-modality correlation. Fractional amplitude of low frequency fluctuations, gray matter (GM) volume, and amyloid standard uptake value ratios were included as neuroimaging features. Eventually, the changes in neuroimaging features along AD continuum were investigated, and relationships between cognitive performance and identified PHS associated multimodal components were established.ResultsWe found that PHS was associated with multimodal brain networks, which showed different functional and structural impairments under increased amyloid deposits. Notably, along with AD progression, functional impairment occurred before GM atrophy, amyloid deposition started from the MCI stage and progressively increased throughout the disease continuum.ConclusionPHS is associated with multi-facets of brain impairments along the AD continuum, including cognitive dysfunction, pathological deposition, which might underpin the AD pathogenesis.

Highlights

Late-onset Alzheimer’s disease (LOAD) is the most common form of dementia, whose morbidity and progression is largely associated with the risk genes (Escott-Price and Jones, 2017)
Along with AD progression, functional impairment occurred before gray matter (GM) atrophy, amyloid deposition started from the mild cognitive impairment (MCI) stage and progressively increased throughout the disease continuum
polygenic hazard score” (PHS) is associated with multi-facets of brain impairments along the AD continuum, including cognitive dysfunction, pathological deposition, which might underpin the AD pathogenesis

Summary

Introduction

Late-onset Alzheimer’s disease (LOAD) is the most common form of dementia, whose morbidity and progression is largely associated with the risk genes (Escott-Price and Jones, 2017). Genome-wide associated studies (GWAS) have identified multiple AD risk genes, including apolipoprotein E (APOE) ε4, CLU, BIN1, PICALM, MS4A, ABCA7, and CR1 (Lambert et al, 2013; Desikan et al, 2015) These genetic variants were involved in the downstream molecular pathways and affect the AD pathological substances, like amyloid production and clearance, highlighting the importance of genetic variants in AD pathogenesis. SORL1 showed association with hippocampal atrophy (Cuenco et al, 2008) and functional connectivity impairments (Shen et al, 2017) Another APOE major genetic variant, namely APOE ε2 allele is related to a reduced risk of AD seems to confer a protective effect against AD (Reiman et al, 2020). Two major questions which previous studies have led to are: (1) should the general “polygenic hazard score” (PHS) be a good choice to identify the individual genetic risk for AD; and (2) should researchers include inter-modality relationships in the analyses considering these may provide complementary information about the AD etiology

Methods

Results

Discussion

Conclusion