Polygenic risk of Alzheimer disease is associated with early- and late-life processes

Mormino, Elizabeth C.; Sperling, Reisa A.; Holmes, Avram J.; Buckner, Randy L.; Jager, Philip L. De; Smoller, Jordan W.; Sabuncu, Mert R.

doi:10.1212/wnl.0000000000002922

Cited by 156 publications

(205 citation statements)

References 42 publications

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“…The minimal amount of statistically significant findings observed when assessing cognitive function is similar to the findings of two studies that concluded that a PRS based on all significant IGAP genes one including and one excluding APOE , was not associated with cognitive function in older non-demented individuals[34, 35]. Two other studies did find associations between cognitive function and an overall PRS using a subset of IGAP genes in general populations; however, removing APOE from the PRS eliminated the statistical significance[36, 37].…”

Section: Discussionsupporting

confidence: 78%

“…It will be crucial to modify these pathway-specific PRSs to reflect new findings in order to improve their predictive ability. One recent successful approach used a large number of the top IGAP SNPs (~16,000) to develop an overall PRS, potentially utilizing many other relevant genetic variants that did not meet statistical significance, and found that it was associated with cognitive function, Aβ deposition, hippocampal volume, and clinical progression[35]. A possible interesting expansion of this approach could be to develop pathway-specific PRSs using this large panel of SNPs and the pathways outlined by the IGAP pathway analysis[6].…”

Section: Discussionmentioning

confidence: 99%

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Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-β Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer’s Disease

Darst

Koscik

Racine

et al. 2016

JAD

118

180

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Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer’s disease (AD)-related biomarkers and cognitive function. Participants were from the Wisconsin Registry for Alzheimer’s Prevention, a longitudinal study of adults who were cognitively asymptomatic at enrollment and enriched for a parental history of AD. Using genes associated with AD in the International Genomics of Alzheimer’s Project’s meta-analysis, we identified clusters of genes that grouped into pathways involved in β-amyloid (Aβ) deposition and neurodegeneration: Aβ clearance, cholesterol metabolism, and immune response. Weighted pathway-specific and overall PRSs were developed and compared to APOE alone. Mixed models were used to assess whether each PRS was associated with cognition in 1,200 individuals, cerebral Aβ deposition measured using amyloid ligand (Pittsburgh compound B) positron emission imaging (PET) in 168 individuals, and cerebrospinal fluid (CSF) Aβ deposition, neurodegeneration, and tau pathology in 111 individuals, with replication performed in an independent sample. We found that PRSs including APOE appeared to be driven by the inclusion of APOE, suggesting that the pathway-specific PRSs used here were not more predictive than an overall PRS or APOE alone. However, pathway-specific PRSs could prove to be useful as more knowledge is gained on the genetic variants involved in specific biological pathways of AD.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-β Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer’s Disease

Darst

Koscik

Racine

et al. 2016

JAD

118

180

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“…Here, these prior observations are expanded on to show that these alterations are also present in early life process. Together, accumulating evidence now suggests that both common and rare variations that confer risk for AD may converge on pathophysiological mechanisms such as alterations in subcortical volumetry in early life [6,8]. Furthermore, there was a negative association between the TREM2 risk allele and volume of putamen.…”

Section: Discussionmentioning

confidence: 99%

Associations between rare microglia‐linked Alzheimer's disease risk variants and subcortical brain volumes in young individuals

Lancaster

2019

Alz & Dem Diag Ass & Dis Mo

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Introduction Recent exome sequencing studies have identified three novel risk variants associated with Alzheimer's disease (AD). However, the mechanisms by which these variants confer risk are largely unknown. Methods In the present study, the impact of these rare coding variants (in ABI3, PLCG2 , and TREM2 ) on all subcortical volumes is determined in a large sample of young healthy individuals (N = 756–765; aged 22–35 years). Results After multiple testing correction ( P CORRECTED < .05), rare variants were associated with basal ganglia volumes ( TREM2 and PLCG2 effects within the putamen and pallidum, respectively). Nominal associations between TREM2 and reduced hippocampal and thalamic volumes were also observed. Discussion Our observations suggest that rare variants in microglia-mediated immunity pathway may contribute to the subcortical alterations observed in AD cases. These observations provide further evidence that genetic risk for AD may influence the volume of subcortical volumes and increase AD risk in early life processes.

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“…Naj et al found that while APOE contributes to 3.9% of variation at age of onset, nine other IGAP SNPs together contribute to additional 1.1% variation [77]. The scores are also associated with clinical progression to AD and can predict progression from healthy controls [70•, 73, 75] or MCI [69] to AD. In addition, there is a relationship between higher score values and worsening behavioral and neuroimaging endophenotypes of the disease [73].…”

Section: Gwasmentioning

confidence: 99%

Genetics of Alzheimer’s Disease: the Importance of Polygenic and Epistatic Components

Raghavan

Tosto

2017

Curr Neurol Neurosci Rep

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Purpose of Review We aimed to summarize the recent advances in genetic findings of Alzheimer’s disease (AD), focusing on traditional single-marker and gene approaches and non-traditional ones, i.e., polygenic and epistatic components. Recent Findings Genetic studies have progressed over the last few decades from linkage to genome-wide association studies (GWAS), and most recently studies utilizing high-throughput sequencing. So far, GWASs have identified several common variants characterized by small effect sizes (besides APOE-ε4). Sequencing has facilitated the study of rare variants with larger effects. Nevertheless, missing heritability for AD remains extensive; a possible explanation might lie in the existence of polygenic and epistatic components. Summary We review findings achieved by single-marker approaches, but also polygenic and epistatic associations. The latter two are critical, yet-underexplored mechanisms. Genes involved in complex diseases are likely regulated by mechanisms and pathways involving many other genes, an aspect potentially missed by traditional approaches.

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Polygenic risk of Alzheimer disease is associated with early- and late-life processes

Cited by 156 publications

References 42 publications

Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-β Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer’s Disease

Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-β Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer’s Disease

Associations between rare microglia‐linked Alzheimer's disease risk variants and subcortical brain volumes in young individuals

Genetics of Alzheimer’s Disease: the Importance of Polygenic and Epistatic Components

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