Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease.Fil: Dalmasso, Maria Carolina. Gobierno de la Provincia de la Pampa. Ministerio Publico. Laboratorio de Genetica Forense.; Argentina. Universitat zu Köln; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Confluencia; ArgentinaFil: de Rojas, Itziar. Universitat Internacional de Catalunya; España. Instituto de Salud Carlos Iii (isciii); EspañaFil: Moreno Grau, Sonia. Universitat Internacional de Catalunya; España. Instituto de Salud Carlos Iii (isciii); EspañaFil: Tesi, Niccolo. Vrije Universiteit Amsterdam; Países Bajos. Delft University of Technology; Países BajosFil: Grenier Boley, Benjamin. Universite Lille; FranciaFil: Andrade, Victor. Universitat zu Köln; Alemania. Universitat Bonn; AlemaniaFil: Pedersen, Nancy L.. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Stringa, Najada. University of Amsterdam; Países BajosFil: Zettergren, Anna. University of Gothenburg; SueciaFil: Hernández, Isabel. Universitat Internacional de Catalunya; España. Instituto de Salud Carlos Iii (isciii); EspañaFil: Montrreal, Laura. Universitat Internacional de Catalunya; EspañaFil: Antúnez, Carmen. Hospital Clínico Universitario Virgen de la Arrixaca; EspañaFil: Antonell, Anna. Universidad de Barcelona; EspañaFil: Tankard, Rick M.. Murdoch University; AustraliaFil: Bis, Joshua C.. University of Washington; Estados UnidosFil: Sims, Rebecca. Cardiff University; Reino UnidoFil: Bellenguez, Céline. Universite Lille; FranciaFil: Quintela, Inés. Universidad de Santiago de Compostela; EspañaFil: González Perez, Antonio. Centro Andaluz de Estudios Bioinformáticos; EspañaFil: Calero, Miguel. Instituto de Salud Carlos Iii (isciii); España. Fundación Reina Sofia; EspañaFil: Franco Macías, Emilio. Universidad de Sevilla; EspañaFil: Macías, Juan. Hospital Universitario de Valme; EspañaFil: Blesa, Rafael. Instituto de Salud Carlos Iii (isciii); España. Universitat Autònoma de Barcelona; EspañaFil: Cervera Carles, Laura. Instituto de Salud Carlos Iii (isciii); España. Universitat Autònoma de Barcelona; EspañaFil: Menéndez González, Manuel. Universidad de Oviedo; EspañaFil: Frank García, Ana. Instituto de Salud Carlos Iii (isciii); España. Universidad Autónoma de Madrid; España. Instituto de Investigacion del Hospital de la Paz.; España. Hospital Universitario La Paz; EspañaFil: Royo, Jose Luís. Universidad de Málaga; EspañaFil: Moreno, Fermin. Instituto de Salud Carlos Iii (isciii); España. Hospital Universitario Donostia; España. Instituto Biodonostia; EspañaFil: Huerto Vilas, Raquel. Hospital Universitari Santa Maria de Lleida; España. Institut de Recerca Biomedica de Lleida; EspañaFil: Baquero, Miquel. Hospital Universitari i Politècnic La Fe; Españ

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer’s disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (p = 4.22 × 10−20) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease.</p

Rare missense variant (R251G) on APOE counterbalances the Alzheimer’s disease risk associated with APOE-ε4

Background Despite decades of research, the mechanisms linking APOE to Alzheimer’s disease (AD) remain poorly understood. Finding additional risk variants at the APOE locus, beyond the common APOE-ε2 and APOE-ε4 alleles, may help elucidate how APOE is involved in the disease. Method Association with case-control status was tested in a sequenced discovery sample (Stage 1) and followed-up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (Stages 2+3) (Table 1). Stage 1 included 37,409 non-unique participants of European or Admixed-European ancestry, with 11,868 cases and 11,934 controls passing analysis inclusion criteria. In Stages 2+3, 475,473 participants were considered across 8 cohorts, of which 56,029 cases, 28,484 proxy-AD cases, and 328,372 healthy-controls passed inclusion criteria, and were of European ancestry. Result Two missense variants were associated with a two to three-fold decreased AD risk: R251G (odds ratio, 0.44; 95% confidence interval [CI], 0.33-0.59; P = 4.7×10-8) and V236E (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9×10-6) (Table 2, Figures 1, 2). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared to non-carriers (Table 3). Conclusion We identified a novel variant associated with AD, R251G, which mitigates the ε4 associated AD risk, and confirmed the protective effect of the V236E variant. The location of the variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here, suggest that protein chemistry and functional assays of these variants have the potential to identify novel pathways for drug development

Association of Rare APOE Missense Variants V236E and R251G with Risk of Alzheimer Disease

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 missense variants in addition to APOE ϵ2 and APOE ϵ4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly. Objective: To determine whether rare missense variants on APOE are associated with AD risk. Design, Setting, and Participants: Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 included 37409 nonunique participants of European or admixed European ancestry, with 11868 individuals with AD and 11934 controls passing analysis inclusion criteria. In stages 2 and 3, 475473 participants were considered across 8 cohorts, of which 84513 individuals with AD and proxy-AD and 328372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021. Main Outcomes and Measures: In primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were estimated with age at onset using linear mixed-model regression and risk of conversion to AD using competing-risk regression. Results: A total of 544384 participants were analyzed in the primary case-control analysis; 312476 (57.4%) were female, and the mean (SD; range) age was 64.9 (15.2; 40-110) years. Two missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ϵ4 (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10-8) and APOE ϵ3 (V236E) (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10-6). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared with noncarriers. Conclusions and Relevance: In this genetic association study, a novel variant associated with AD was identified: R251G always coinherited with ϵ4 on the APOE gene, which mitigates the ϵ4-associated AD risk. The protective effect of the V236E variant, which is always coinherited with ϵ3 on the APOE gene, was also confirmed. The location of these variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here suggest that protein chemistry and functional assays of these variants should be pursued, as they have the potential to guide drug development targeting APOE.

Association of rare APOE missense variants V236E and R251G with risk of Alzheimer disease

© 2022 American Medical Association. All rights reserved.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 missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly. Objective: To determine whether rare missense variants on APOE are associated with AD risk. Design, setting, and participants: Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 included 37 409 nonunique participants of European or admixed European ancestry, with 11 868 individuals with AD and 11 934 controls passing analysis inclusion criteria. In stages 2 and 3, 475 473 participants were considered across 8 cohorts, of which 84 513 individuals with AD and proxy-AD and 328 372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76 195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021. Main outcomes and measures: In primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were estimated with age at onset using linear mixed-model regression and risk of conversion to AD using competing-risk regression. Results: A total of 544 384 participants were analyzed in the primary case-control analysis; 312 476 (57.4%) were female, and the mean (SD; range) age was 64.9 (15.2; 40-110) years. Two missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ε4 (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10-8) and APOE ε3 (V236E) (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10-6). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared with noncarriers. Conclusions and relevance: In this genetic association study, a novel variant associated with AD was identified: R251G always coinherited with ε4 on the APOE gene, which mitigates the ε4-associated AD risk. The protective effect of the V236E variant, which is always coinherited with ε3 on the APOE gene, was also confirmed. The location of these variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here suggest that protein chemistry and functional assays of these variants should be pursued, as they have the potential to guide drug development targeting APOE.info:eu-repo/semantics/publishedVersio

Protective association of HLA-DRB1*04 subtypes in neurodegenerative diseases implicates acetylated tau PHF6 sequences

Background Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS) and other neurodegenerative diseases are responsible for considerable morbidity and mortality. With incidence rising with aging, these also represent a growing societal challenge. Pathophysiology involves accumulation of tau (neurofibrillary tangles) and Amyloid-β-rich (amyloid plaques) aggregates in AD, α-synuclein-rich aggregates (Lewy bodies) in PD and TDP-43 aggregates in ALS, although co-presence of these aggregates may occur. Consensus is also growing that tau may also play a key role in PD and ALS. Method Using genome-wide association data, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with PD or Alzheimer’s AD disease versus controls across ancestry groups. Result A shared genetic association was observed across diseases at rs601945 (PD: odds ratio (OR)=0.84; 95% confidence interval, [0.80; 0.88]; p=2.2x10-13; AD: OR=0.91[0.89; 0.93]; p=1.8x10-22), and with a protective HLA association recently reported in ALS. Hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03, and absent for HLA-DRB1*04:05. The same signal was associated with decreased neurofibrillary tangles (but not neuritic plaque density) in postmortem brains and was more strongly associated with tau levels than Aβ42 levels in the cerebrospinal fluid. Finally, protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, but only when acetylated at K311, a modification central to aggregation. Conclusion An HLA-DRB1*04-mediated adaptive immune response, potentially against tau, decreases PD, AD and ALS risk, offering the possibility of new therapeutic avenues