Michael D Greicius's research while affiliated with University of Camerino and other places

Publications (176)

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Background and Objectives Exome sequencing (ES) and genome sequencing (GS) are expected to be critical to further elucidate the missing genetic heritability of Alzheimer disease (AD) risk by identifying rare coding and/or noncoding variants that contribute to AD pathogenesis. In the United States, the Alzheimer Disease Sequencing Project (ADSP) has...
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Importance: The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missen...
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Importance: Characterization of early tau deposition in individuals with preclinical Alzheimer disease (AD) is critical for prevention trials that aim to select individuals at risk for AD and halt the progression of disease. Objective: To evaluate the prevalence of cortical tau positron emission tomography (PET) heterogeneity in a large cohort o...
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Background Genetic variants within the APOE locus may modulate Alzheimer’s disease (AD) risk independently or in conjunction with APOE *2/3/4 genotypes. Identifying such variants and mechanisms would importantly advance our understanding of APOE pathophysiology and provide critical guidance for AD therapies aimed at APOE . The APOE locus however re...
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Objectives The F386L PSEN1 variant has been reported in 1 Japanese family with limited clinical information. We aimed to prove that F386L is pathogenic by demonstrating that it segregates with early-onset Alzheimer disease (AD). Methods Eight individuals in a South Asian family provided DNA for genetic testing and underwent a neurologic examinatio...
Preprint
Using genome-wide association data, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s (PD) or Alzheimer’s (AD) disease versus controls across ancestry groups. A shared genetic association was observed across diseases at rs601945 (PD: odds ratio (OR)=0.84; 95% confidence interval, [0.80; 0.88]; p=2.2...
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We describe the clinical and neuropathologic features of patients with Lewy body spectrum disorder (LBSD) carrying a nonsense variant, c.604C>T; p.R202X, in the glucocerebrosidase 1 (GBA) gene. While this GBA variant is causative for Gaucher’s disease, the pathogenic role of this mutation in LBSD is unclear. Detailed neuropathologic evaluation was...
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Using genome-wide association data, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's (PD) or Alzheimer's (AD) disease versus controls across ancestry groups. A shared genetic association was observed across diseases at rs601945 (PD: odds ratio (OR)=0.84; 95% confidence interval, [0.80; 0.88]; p=2.2...
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Recent advances in genome sequencing and imputation technologies provide an exciting opportunity to comprehensively study the contribution of genetic variants to complex phenotypes. However, our ability to translate genetic discoveries into mechanistic insights remains limited at this point. In this paper, we propose an efficient knockoff-based met...
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Background: APOE*4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and is highly pleiotropic, such that it may be considered as a biological factor that can affect overall genetic risk for AD. To advance our understanding of the genetic architecture of AD, we sought to perform the largest APOE*4-stratified genome-wide...
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Background: Damaging rare variants in the TREM2, SORL1 and ABCA7 genes have been associated with an increased risk of developing Alzheimer's Disease (AD) with odds ratios that were not observed since the identification of the main AD genetic risk factor, the APOE-ε4 allele. Here, we aimed to identify additional AD-associated genes by investigating...
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Background: The increased risk of Alzheimer's Disease (AD) with age is well established. However, genome-wide association studies of AD have often wrongly accounted for this known effect by covarying by age using age-at-onset for cases and age-at-last-exam for controls. In most scenarios, this leads to controls being on average older than cases an...
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Background: Among Alzheimer's Disease (AD) tier 1 genes, BIN1 shows the greatest sex-biased expression in GTEx RNASeq, notably in brain tissues. Fine-mapping studies suggest that the BIN1 locus harbors at least two independent risk variants. Method: We considered a region ±200kb around BIN1 and performed sex-stratified analyses to identify genom...
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Background: Rare variants are hypothesized to contribute greatly to the "missing heritability" in AD. APOE*4 is the strongest genetic risk factor for late-onset AD. As such, older, cognitively normal APOE*4 carriers may harbor rare protective variants. We prioritized candidate variants in families based on their segregation with protected APOE*4 c...
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Knockoff-based methods have become increasingly popular due to their enhanced power for locus discovery and their ability to prioritize putative causal variants in a genome-wide analysis. However, because of the substantial computational cost for generating knockoffs, existing knockoff approaches cannot analyze millions of rare genetic variants in...
Preprint
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Whole-exome sequencing (WES) and whole-genome sequencing (WGS) are expected to be critical to further elucidate the missing genetic heritability of Alzheimer’s disease (AD) risk by identifying rare coding and/or noncoding variants that contribute to AD pathogenesis. In the United States, the Alzheimer’s Disease Sequencing Project (ADSP) has taken a...
Preprint
Full-text available
Background: Genetic variants within the APOE locus may modulate Alzheimer′s disease (AD) risk independently or in conjunction with APOE*2/3/4 genotypes. Identifying such variants and mechanisms would importantly advance our understanding of APOE pathophysiology and provide critical guidance for AD therapies aimed at APOE. The APOE locus however rem...
Preprint
Full-text available
BACKGROUND The APOE gene has two common missense variants that greatly impact the risk of late-onset Alzheimer's disease (AD). Here we examined the risk of a third APOE missense variant, R145C, that is rare in European-Americans but present in 4% of African-Americans and always in phase with APOE ϵ3. METHODS In this study, we included 11,790 indivi...
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Major surgery is often complicated by postoperative neurocognitive disorder. Affected patients exhibit problems with memory and executive function, similar to deficits seen in Alzheimer disease (AD).¹,2 A critical question is whether surgery can exacerbate or unmask latent pathophysiology underlying the development of AD.
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Extreme longevity in humans has a strong genetic component, but whether this involves genetic variation in the same longevity pathways as found in model organisms is unclear. Using whole-exome sequences of a large cohort of Ashkenazi Jewish centenarians to examine enrichment for rare coding variants, we found most longevity-associated rare coding v...
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The recent US Food and Drug Administration (FDA) approval of aducanumab for the treatment of Alzheimer disease triggered both praise and criticism from various advocacy groups, but a more important decision regarding the drug—whether to pay for it—will now need to be undertaken by the federal government. This next decision offers a window into both...
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PurposeIn vivo measurement of the spatial distribution of neurofibrillary tangle pathology is critical for early diagnosis and disease monitoring of Alzheimer’s disease (AD).Methods Forty-nine participants were scanned with 18F-PI-2620 PET to examine the distribution of this novel PET ligand throughout the course of AD: 36 older healthy controls (H...
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The analysis of whole-genome sequencing studies is challenging due to the large number of rare variants in noncoding regions and the lack of natural units for testing. We propose a statistical method to detect and localize rare and common risk variants in whole-genome sequencing studies based on a recently developed knockoff framework. It can (1) p...
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Evaluating gene by environment (G$\times$E) interaction under an additive risk model (i.e. additive interaction) has gained wider attention. Recently, statistical tests have been proposed for detecting additive interaction that utilize an assumption on G-E independence to boost power, which do not rely on restrictive genetic models such as dominant...
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Background Many Alzheimer’s disease (AD) genetic association studies disregard age or incorrectly account for it, hampering variant discovery. Methods Using simulated data, we compared the statistical power of several models: logistic regression on AD diagnosis adjusted and not adjusted for age; linear regression on a score integrating case-contro...
Preprint
Full-text available
The analysis of whole-genome sequencing studies is challenging due to the large number of rare variants in noncoding regions and the lack of natural units for testing. We propose a statistical method to detect and localize rare and common risk variants in whole-genome sequencing studies based on a recently developed knockoff framework. It can (1) p...
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Objective: To examine whether amyloid PET in CN individuals that were screened for the Anti-Amyloid in Asymptomatic AD (A4) study differed across self-identified, non-Hispanic White and Black (NHW and NHB) groups. Methods: We examined 3689 NHW and 144 NHB that passed initial screening for the A4 study and underwent amyloid PET. The effect of rac...
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Objective Identify genetic variants on the X‐chromosome associated with Parkinson's disease (PD) risk. Methods We performed an X‐chromosome‐wide association study (XWAS) of PD risk by meta‐analyzing results from sex‐stratified analyses. To avoid spurious associations, we designed a specific harmonization pipeline for the X‐chromosome and focused o...
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Prior work in late-onset Alzheimer’s disease (LOAD) has resulted in discrepant findings as to whether recent consanguinity and outbred autozygosity are associated with LOAD risk. In the current study, we tested the association between consanguinity and outbred autozygosity with LOAD in the largest such analysis to date, in which 20 LOAD GWAS datase...
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KLOTHO*VS heterozygosity (KL*VSHET+) was recently shown to be associated with reduced risk of Alzheimer’s disease (AD) in APOE*4 carriers. Additional studies suggest that KL*VSHET+ protects against amyloid burden in cognitively normal older subjects, but sample sizes were too small to draw definitive conclusions. We performed a well-powered meta-an...
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State-of-the-art rare variant association testing methods aggregate the contribution of rare variants in biologically relevant genomic regions to boost statistical power. However, testing single genes separately does not consider the complex interaction landscape of genes, nor the downstream effects of non-synonymous variants on protein structure a...
Preprint
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Introduction Many Alzheimer's disease (AD) genetic association studies disregard age or incorrectly account for it, hampering variant discovery. Method Using simulated data, we compared the statistical power of several models: logistic regression on AD diagnosis adjusted and not adjusted for age; linear regression on a score integrating case-contro...
Preprint
Full-text available
Objective Identify genetic variants on the X-chromosome associated with Parkinson’s disease (PD) risk. Methods We performed an X-chromosome-wide association study (XWAS) of PD risk by meta-analyzing results from sex-stratified analyses. To avoid spurious associations, we designed a specific harmonization pipeline for the X-chromosome and focused o...
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Posterior cortical atrophy (PCA) is a rare early‐onset form of dementia, typically due to Alzheimer’s disease (PCA‐AD) characterised by predominant deficits of higher‐order visual functions, with relatively preserved memory, verbal fluency and insight with respect to typical, amnestic AD (tAD). A prior genetic study by Schott et al. (2016) investig...
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Primary progressive aphasia (PPA) is a syndrome of progressive language impairment caused by neurodegenerative disease. We previously showed using seed‐based connectivity analysis that connectivity between three language network regions is decreased in PPA. Furthermore, we showed selective connectivity disruptions corresponding to grammar, repetiti...
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Microstructural tissue alterations in Alzheimer disease (AD) contribute to decreased fractional anisotropy (FA) in white matter (Sexton et al. 2011), which may be secondary to tau‐based neurodegeneration that starts in the medial temporal lobe (MTL). Here, we show that tau accumulation in the entorhinal and perirhinal cortices (ERC/PRC) – the first...
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Common genetic polymorphisms identified by genome wide association explain less than half the genetic variance of Alzheimer’s disease (AD). Rare genetic mutations with larger effect sizes than common variants are expected to contribute to this missing heritability. We developed an extreme phenotype filtering‐based approach to identify rare candidat...
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Are there genetic variants in the APOE locus that alter APOE4‐related risk for AD? Do these putative variants exert their effect through altering availability of the APOE protein? With these questions in mind, we investigated whether the APOE splice quantitative trait loci (sQTL; variants that alter post‐transcriptional splicing) affect risk for AD...
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Klotho‐VS heterozygosity (KL‐VSHET) has been linked to increased longevity and decreased rate of cognitive decline. In Alzheimer’s disease (AD), KL‐VSHET was recently shown to decrease both AD risk and amyloid burden, specifically, in APOE4+ controls of Northwestern European descent within the age range of 60 to 80 years (Belloy et al., 2020). We i...
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Aducanumab recently underwent two large phase III clinical trials that were stopped prematurely by the sponsor Biogen. One trial was trending positive while the other showed no benefits from aducanumab. Post hoc analyses led the sponsor to assert that there was a sufficient efficacy signal to justify a new drug application as a treatment for Alzhei...
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The amygdala is one of the most widely connected structures in the primate brain and plays a key role in social and emotional behavior. Here, we present the first genome-wide association study (GWAS) of whole-brain resting-state amygdala networks to discern whether connectivity in these networks could serve as an endophenotype for social behavior....
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Several statistical methods have been proposed for testing gene(G)-environment(E) interactions under additive risk models using genome-wide association study data. However, these approaches have strong assumptions on underlying genetic models such as dominant or recessive effects that are known to be less robust when the true genetic model is unkno...
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Question: Does Klotho-VS heterozygosity protect against Alzheimer disease (AD) in individuals who carry APOE4? Findings: In this study, associations were evaluated across 22 AD cohorts (n = 20 928), 3 longitudinal cohorts (n = 3008), and 4 cohorts collecting β-amyloid measurements (cerebrospinal fluid, n = 556; brain, n = 251). In individuals who...
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Alzheimer’s disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function1. However, little is known about the contribution of the adaptive immune response in Alzheimer’s disease2. Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer’s di...
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Phonemic paraphasias are thought to reflect phonological (post-semantic) deficits in language production. Here we present evidence that phonemic paraphasias in non-semantic primary progressive aphasia (PPA) may be associated with taxonomic interference. Agrammatic and logopenic PPA patients and control participants performed a word-to-picture visua...
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Background: State-of-the-art rare variant association testing methods aggregate the contribution of rare variants in biologically relevant genomic regions to boost statistical power. However, testing single genes separately does not consider the complex interaction landscape of genes, nor the downstream effects of non-synonymous variants on protein...
Article
Alzheimer’s disease (AD) is considered a polygenic disorder. This view is clouded, however, by lingering uncertainty over how to treat the quasi “monogenic” role of apolipoprotein E (APOE). The APOE4 allele is not only the strongest genetic risk factor for AD, it also affects risk for cardiovascular disease, stroke, and other neurodegenerative diso...
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Purpose To reduce radiotracer requirements for amyloid PET/MRI without sacrificing diagnostic quality by using deep learning methods. Materials and Methods Forty data sets from 39 patients (mean age ± standard deviation [SD], 67 years ± 8), including 16 male patients and 23 female patients (mean age, 66 years ± 6 and 68 years ± 9, respectively), wh...
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Identifying genetic risk factors underpinning different aspects of Alzheimer's disease has the potential to provide important insights into pathogenesis. Moving away from simple case-control definitions, there is considerable interest in using quantitative endophenotypes, such as those derived from imaging as outcome measures. Previous genome-wide...
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Introduction: Cognitive change in people at risk of Alzheimer's disease (AD) such as subjective memory complainers is highly variable across individuals. Methods: We used latent class growth modeling to identify distinct classes of nonlinear trajectories of cognitive change over 2 years follow-up from 265 subjective memory complainers individual...
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Mitochondrial crista structure partitions vital cellular reactions and is precisely regulated by diverse cellular signals. Here, we show that, in Drosophila, mitochondrial cristae undergo dynamic remodeling among distinct subcellular regions and the Parkinson's disease (PD)-linked Ser/Thr kinase PINK1 participates in their regulation. Mitochondria...
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Objectives: A reduction in glucose metabolism in the posterior cingulate cortex (PCC) predicts conversion to Alzheimer's disease (AD) and tracks disease progression, signifying its importance in AD. We aimed to use decline in PCC glucose metabolism as a proxy for the development and progression of AD to discover common genetic variants associated...
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Altered brain connectivity has been described in people with Parkinson's disease and in response to dopaminergic medications. However, it is unclear whether dopaminergic medications primarily ‘normalize’ disease related connectivity changes or if they induce unique alterations in brain connectivity. Further, it is unclear how these disease- and med...