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Abstract Background Alzheimer’s disease (AD) is a complex neurodegenerative disorder and the most common type of dementia. AD is characterized by a decline of cognitive function and brain atrophy, and is highly heritable with estimated heritability ranging from 60 to 80 $$\%$$ % . The most straightforward and widely used strategy to identify AD genetic basis is to perform genome-wide association study (GWAS) of the case-control diagnostic status. These GWAS studies have identified over 50 AD related susceptibility loci. Recently, imaging genetics has emerged as a new field where brain imaging measures are studied as quantitative traits to detect genetic factors. Given that many imaging genetics studies did not involve the diagnostic outcome in the analysis, the identified imaging or genetic markers may not be related or specific to the disease outcome. Results We propose a novel method to identify disease-related genetic variants enriched by imaging endophenotypes, which are the imaging traits associated with both genetic factors and disease status. Our analysis consists of three steps: (1) map the effects of a genetic variant (e.g., single nucleotide polymorphism or SNP) onto imaging traits across the brain using a linear regression model, (2) map the effects of a diagnosis phenotype onto imaging traits across the brain using a linear regression model, and (3) detect SNP-diagnosis association via correlating the SNP effects with the diagnostic effects on the brain-wide imaging traits. We demonstrate the promise of our approach by applying it to the Alzheimer’s Disease Neuroimaging Initiative database. Among 54 AD related susceptibility loci reported in prior large-scale AD GWAS, our approach identifies 41 of those from a much smaller study cohort while the standard association approaches identify only two of those. Clearly, the proposed imaging endophenotype enriched approach can reveal promising AD genetic variants undetectable using the traditional method. Conclusion We have proposed a novel method to identify AD genetic variants enriched by brain-wide imaging endophenotypes. This approach can not only boost detection power, but also reveal interesting biological pathways from genetic determinants to intermediate brain traits and to phenotypic AD outcomes. 

Brain imaging genetics examines associations between imaging quantitative traits (QTs) and genetic factors such as single nucleotide polymorphisms (SNPs) to provide important insights into the pathogenesis of Alzheimer’s disease (AD). The individual level SNP-QT signals are high dimensional and typically have small effect sizes, making them hard to be detected and replicated. To overcome this limitation, this work proposes a new approach that identifies high-level imaging genetic associations through applying multigraph clustering to the SNP-QT association maps. Given an SNP set and a brain QT set, the association between each SNP and each QT is evaluated using a linear regression model. Based on the resulting SNP-QT association map, five SNP–SNP similarity networks (or graphs) are created using five different scoring functions, respectively. Multigraph clustering is applied to these networks to identify SNP clusters with similar association patterns with all the brain QTs. After that, functional annotation is performed for each identified SNP cluster and its corresponding brain association pattern. We applied this pipeline to an AD imaging genetic study, which yielded promising results. For example, in an association study between 54 AD SNPs and 116 amyloid QTs, we identified two SNP clusters with one responsible for amyloid beta clearances and the other regulating amyloid beta formation. These high-level findings have the potential to provide valuable insights into relevant genetic pathways and brain circuits, which can help form new hypotheses for more detailed imaging and genetics studies in independent cohorts. 

Abstract INTRODUCTIONAlzheimer's disease (AD) initiates years prior to symptoms, underscoring the importance of early detection. While amyloid accumulation starts early, individuals with substantial amyloid burden may remain cognitively normal, implying that amyloid alone is not sufficient for early risk assessment. METHODSGiven the genetic susceptibility of AD, a multi‐factorial pseudotime approach was proposed to integrate amyloid imaging and genotype data for estimating a risk score. Validation involved association with cognitive decline and survival analysis across risk‐stratified groups, focusing on patients with mild cognitive impairment (MCI). RESULTSOur risk score outperformed amyloid composite standardized uptake value ratio in correlation with cognitive scores. MCI subjects with lower pseudotime risk score showed substantial delayed onset of AD and slower cognitive decline. Moreover, pseudotime risk score demonstrated strong capability in risk stratification within traditionally defined subgroups such as early MCI, apolipoprotein E (APOE) ε4+ MCI,APOEε4– MCI, and amyloid+ MCI. DISCUSSIONOur risk score holds great potential to improve the precision of early risk assessment. HighlightsAccurate early risk assessment is critical for the success of clinical trials.A new risk score was built from integrating amyloid imaging and genetic data.Our risk score demonstrated improved capability in early risk stratification.