Author Correction: Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Kunkle, Brian W.; Grenier‐Boley, Benjamin; Sims, Rebecca; Bis, Joshua C.; Damotte, Vincent; Naj, Adam C.; Boland, Anne; Vronskaya, Maria; Lee, Sven J. van der; Amlie‐Wolf, Alexandre; Bellenguez, Céline; Frizatti, Aura; Chouraki, Vincent; Martin, Eden R.; Sleegers, Kristel; Badarinarayan, Nandini; Jakobsdóttir, Jóhanna; Hamilton‐Nelson, Kara L.; Moreno‐Grau, Sonia; Olaso, Robert; Raybould, Rachel; Chen, Yuning; Kuzma, Amanda B.; Hiltunen, Mikko; Morgan, Taniesha; Ahmad, Shahzad; Vardarajan, Badri N.; Epelbaum, Jacques; Hoffmann, Per; Boada, Merçé; Beecham, Gary W.; Garnier, Jean-Guillaume; Harold, Denise; Fitzpatrick, Annette L.; Valladares, Otto; Moutet, Marie-Laure; Gerrish, Amy; Smith, Albert V.; Qu, Liming; Bacq, Delphine; Denning, Nicola; Jian, Xueqiu; Zhao, Yi; Zompo, Maria Del; Fox, Nick C.; Choi, Seung-Hoan; Mateo, Ignacio; Hughes, Joseph T.; Adams, Hieab H.H.; Malamon, John; Sánchez-García, Florentino; Patel, Yogen; Brody, Jennifer A.; Dombroski, Beth A.; Naranjo, Maria Candida Deniz; Daniilidou, Makrina; Eiríksdóttir, Guðný; Mukherjee, Shubhabrata; Wallon, David; Uphill, James; Aspelund, Thor; Cantwell, Laura B.; Garzia, Fabienne; Galimberti, Daniela; Hofer, Edith; Butkiewicz, Mariusz; Fin, Bertrand; Scarpini, Elio; Sarnowski, Chloé; Bush, William S.; Meslage, Stéphane; Kornhuber, Johannes; White, Charles C.; Song, Yuenjoo; Barber, Robert C.; Engelborghs, Sebastiaan; Sordon, Sabrina; Voijnovic, Dina; Adams, Perrie M.; Vandenberghe, Rik; Mayhaus, Manuel; Cupples, L. 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De; Lleó, Alberto; Warner, Nick; López, Oscar L.; Ingelsson, Martin; Deloukas, Panos; Cruchaga, Carlos; Graff, Caroline; Gwilliam, Rhian; Fornage, Myriam; Goate, Alison M.; Sánchez‐Juan, Pascual; Kehoe, Patrick Gavin; Amin, Najaf; Ertekin-Taner, Nilifur; Berr, Claudine; Debette, Stéphanie; Love, Seth; Launer, Lenore J.; Younkin, Steven G.; Dartigues, Jean‐François; Corcoran, Chris; Ikram, M. Arfan; Dickson, Dennis W.; Nicolas, Gaël; Campion, Dominique; Tschanz, JoAnn T.; Schmidt, Helena; Hákonarson, Hákon; Clarimón, Jordi; Munger, Ron; Schmidt, Reinhold; Farrer, Lindsay A.; Broeckhoven, Christine Van; O'Donovan, Michael Conlon; DeStefano, Anita L.; Jones, Lesley; Haines, Jonathan L.; Deleuze, Jean‐François; Owen, Michael John; Guðnason, Vilmundur; Mayeux, Richard; Escott‐Price, Valentina; Psaty, Bruce M.; Ramı́rez, Alfredo; Wang, Li-San; Ruiz, Agustín; Duijn, Cornelia M. van; Holmans, Peter; Seshadri, Sudha; Williams, Julie; Amouyel, Philippe; Schellenberg, Gerard D.; Lambert, Jean‐Charles; Pericak‐Vance, Margaret A.

doi:10.1038/s41588-019-0495-7

Cited by 58 publications

(42 citation statements)

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“…In contrast to HD, Alzheimer’s Disease (AD) is highly genetically complex [ 14 – 16 ]. Like HD, AD is also viewed as a proteinopathy, since it is associated with accumulation of amyloid fibrils derived from the Amyloid Precursor Protein (APP).…”

Section: Introductionmentioning

confidence: 99%

Htt is a repressor of Abl activity required for APP-induced axonal growth

Marquilly¹,

Busto²,

Leger

et al. 2021

PLoS Genet

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Huntington’s disease is a progressive autosomal dominant neurodegenerative disorder caused by the expansion of a polyglutamine tract at the N-terminus of a large cytoplasmic protein. The Drosophila huntingtin (htt) gene is widely expressed during all developmental stages from embryos to adults. However, Drosophila htt mutant individuals are viable with no obvious developmental defects. We asked if such defects could be detected in htt mutants in a background that had been genetically sensitized to reveal cryptic developmental functions. Amyloid precursor protein (APP) is linked to Alzheimer’s disease. Appl is the Drosophila APP ortholog and Appl signaling modulates axon outgrowth in the mushroom bodies (MBs), the learning and memory center in the fly, in part by recruiting Abl tyrosine kinase. Here, we find that htt mutations suppress axon outgrowth defects of αβ neurons in Appl mutant MB by derepressing the activity of Abl. We show that Abl is required in MB αβ neurons for their axon outgrowth. Importantly, both Abl overexpression and lack of expression produce similar phenotypes in the MBs, indicating the necessity of tightly regulating Abl activity. We find that Htt behaves genetically as a repressor of Abl activity, and consistent with this, in vivo FRET-based measurements reveal a significant increase in Abl kinase activity in the MBs when Htt levels are reduced. Thus, Appl and Htt have essential but opposing roles in MB development, promoting and suppressing Abl kinase activity, respectively, to maintain the appropriate intermediate level necessary for axon growth.

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Section: Introductionmentioning

confidence: 99%

Htt is a repressor of Abl activity required for APP-induced axonal growth

Marquilly¹,

Busto²,

Leger

et al. 2021

PLoS Genet

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show abstract

“…To be able to investigate the influence of both “total genetic risk” for AD and genetic risk for AD beyond APOE , and to compare our findings with previous studies, all versions were constructed with and without APOE included. Two of the versions were generated based on summary statistics from the most recent AD GWAS including pure AD phenotypes [ 8 ]. SNPs with MAF ≥ 5% were used for selection by linkage disequilibrium (LD)-clumping.…”

Section: Methodsmentioning

confidence: 99%

“…Genetic risk for AD is often studied through the use of polygenic risk scores (PRSs), which allow the calculation of genetic risk based on several genetic variants identified through genome wide association studies (GWASs) [ 8 – 10 ]. PRSs for AD have been shown to predict clinical diagnosis [ 11 ], pathology-confirmed diagnosis [ 12 ], cognitive decline [ 13 ], disease progression [ 14 ], and imaging biomarkers [ 13 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Association between polygenic risk score of Alzheimer’s disease and plasma phosphorylated tau in individuals from the Alzheimer’s Disease Neuroimaging Initiative

et al. 2021

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Background Recent studies suggest that plasma phosphorylated tau181 (p-tau181) is a highly specific biomarker for Alzheimer’s disease (AD)-related tau pathology. It has great potential for the diagnostic and prognostic evaluation of AD, since it identifies AD with the same accuracy as tau PET and CSF p-tau181 and predicts the development of AD dementia in cognitively unimpaired (CU) individuals and in those with mild cognitive impairment (MCI). Plasma p-tau181 may also be used as a biomarker in studies exploring disease pathogenesis, such as genetic or environmental risk factors for AD-type tau pathology. The aim of the present study was to investigate the relation between polygenic risk scores (PRSs) for AD and plasma p-tau181. Methods Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) was used to examine the relation between AD PRSs, constructed based on findings in recent genome-wide association studies, and plasma p-tau181, using linear regression models. Analyses were performed in the total sample (n = 818), after stratification on diagnostic status (CU (n = 236), MCI (n = 434), AD dementia (n = 148)), and after stratification on Aβ pathology status (Aβ positives (n = 322), Aβ negatives (n = 409)). Results Associations between plasma p-tau181 and APOE PRSs (p = 3e−18–7e−15) and non-APOE PRSs (p = 3e−4–0.03) were seen in the total sample. The APOE PRSs were associated with plasma p-tau181 in all diagnostic groups (CU, MCI, and AD dementia), while the non-APOE PRSs were associated only in the MCI group. The APOE PRSs showed similar results in amyloid-β (Aβ)-positive and negative individuals (p = 5e−5–1e−3), while the non-APOE PRSs were associated with plasma p-tau181 in Aβ positives only (p = 0.02). Conclusions Polygenic risk for AD including APOE was found to associate with plasma p-tau181 independent of diagnostic and Aβ pathology status, while polygenic risk for AD beyond APOE was associated with plasma p-tau181 only in MCI and Aβ-positive individuals. These results extend the knowledge about the relation between genetic risk for AD and p-tau181, and further support the usefulness of plasma p-tau181 as a biomarker of AD.

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“…Albeit, these hits were not replicated in genome-wide association studies (GWAS) [139]. Additionally, SORL1 variation is genetically linked to AD in several GWAS and is a retromer cargo [140][141][142][143]. Further, a collection of 891 genes that are connected to the endolysosomal and autophagy network as a whole are diffusely associated with AD…”

Section: Retromer Dysfunction Is a Common Feature Of Several Neurodegmentioning

confidence: 99%

Retromer dysfunction at the nexus of tauopathies

et al. 2021

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Tauopathies define a broad range of neurodegenerative diseases that encompass pathological aggregation of the microtubuleassociated protein tau. Although tau aggregation is a central feature of these diseases, their underlying pathobiology is remarkably heterogeneous at the molecular level. In this review, we summarize critical differences that account for this heterogeneity and contrast the physiological and pathological functions of tau. We focus on the recent understanding of its prion-like behavior that accounts for its spread in the brain. Moreover, we acknowledge the limited appreciation about how upstream cellular changes influence tauopathy. Dysfunction of the highly conserved endosomal trafficking complex retromer is found in numerous tauopathies such as Alzheimer's disease, Pick's disease, and progressive supranuclear palsy, and we discuss how this has emerged as a major contributor to various aspects of neurodegenerative diseases. In particular, we highlight recent investigations that have elucidated the contribution of retromer dysfunction to distinct measures of tauopathy such as tau hyperphosphorylation, aggregation, and impaired cognition and behavior. Finally, we discuss the potential benefit of targeting retromer for modifying disease burden and identify important considerations with such an approach moving toward clinical translation.

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Author Correction: Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Cited by 58 publications

References 0 publications

Htt is a repressor of Abl activity required for APP-induced axonal growth

Htt is a repressor of Abl activity required for APP-induced axonal growth

Association between polygenic risk score of Alzheimer’s disease and plasma phosphorylated tau in individuals from the Alzheimer’s Disease Neuroimaging Initiative

Retromer dysfunction at the nexus of tauopathies

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