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Background  Late-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.    Methods  We 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.    Results  We 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.    Conclusion  PHS is associated with multi-facets of brain impairments along the AD continuum, including cognitive dysfunction, pathological deposition, which might underpin the AD pathogenesis.

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