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1. Levels of Alzheimer's disease blood biomarkers are altered after food intake-A pilot intervention study in healthy adults.

Author

Huber H, Ashton NJ, Schieren A, Montoliu-Gaya L, Molfetta GD, Brum WS, Lantero-Rodriguez J, Grötschel L, Stoffel-Wagner B, Coenen M, Weinhold L, Schmid M, Blennow K, Stehle P, Zetterberg H, and Simon MC

Subjects
Adult, Humans, Pilot Projects, Amyloid beta-Peptides, tau Proteins, Biomarkers, Obesity, Eating, Alzheimer Disease diagnosis
Abstract

Introduction: Blood biomarkers accurately identify Alzheimer's disease (AD) pathophysiology and axonal injury. We investigated the influence of food intake on AD-related biomarkers in cognitively healthy, obese adults at high metabolic risk., Methods: One-hundred eleven participants underwent repeated blood sampling during 3 h after a standardized meal (postprandial group, PG). For comparison, blood was sampled from a fasting subgroup over 3 h (fasting group, FG). Plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), amyloid-beta (Aβ) 42/40, phosphorylated tau (p-tau) 181 and 231, and total-tau were measured via single molecule array assays., Results: Significant differences were found for NfL, GFAP, Aβ42/40, p-tau181, and p-tau231 between FG and PG. The greatest change to baseline occurred for GFAP and p-tau181 (120 min postprandially, p < 0.0001)., Conclusion: Our data suggest that AD-related biomarkers are altered by food intake. Further studies are needed to verify whether blood biomarker sampling should be performed in the fasting state., Highlights: Acute food intake alters plasma biomarkers of Alzheimer's disease in obese, otherwise healthy adults. We also found dynamic fluctuations in plasma biomarkers concentration in the fasting state suggesting physiological diurnal variations. Further investigations are highly needed to verify if biomarker measurements should be performed in the fasting state and at a standardized time of day to improve the diagnostic accuracy., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Published
2023
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2. Low Serum Vitamin D Status Is Associated with Incident Alzheimer's Dementia in the Oldest Old.

Author

Melo van Lent D, Egert S, Wolfsgruber S, Kleineidam L, Weinhold L, Wagner-Thelen H, Stoffel-Wagner B, Bickel H, Wiese B, Weyerer S, Pentzek M, Jessen F, Schmid M, Maier W, Scherer M, Riedel-Heller SG, Ramirez A, and Wagner M

Subjects
Aged, 80 and over, Humans, Aged, beta Carotene, Prospective Studies, Vitamins, Vitamin D, Vitamin A, Tocopherols, Alzheimer Disease epidemiology, Alzheimer Disease etiology, Dementia epidemiology, Dementia etiology, Vitamin D Deficiency complications, Vitamin D Deficiency epidemiology
Abstract

Background. Vitamins A, D and E and beta-carotene may have a protective function for cognitive health, due to their antioxidant capacities. Methods. We analyzed data from 1334 non-demented participants (mean age 84 years) from the AgeCoDe study, a prospective multicenter-cohort of elderly general-practitioner patients in Germany, of whom n = 250 developed all-cause dementia and n = 209 developed Alzheimer’s dementia (AD) during 7 years of follow-up. We examined whether concentrations of vitamins A (retinol), D (25-hydroxycholecalciferol) and E (alpha-tocopherol) and beta-carotene, would be associated with incident (AD) dementia. Results. In our sample, 33.7% had optimum vitamin D concentrations (≥50 nmol/L). Higher concentrations of vitamin D were associated with lower incidence of all-cause dementia and AD (HR 0.99 (95%CI 0.98; 0.99); HR0.99 (95%CI 0.98; 0.99), respectively). In particular, subjects with vitamin D deficiency (25.3%, <25 nmol/L) were at increased risk for all-cause dementia and AD (HR1.91 (95%CI 1.30; 2.81); HR2.28 (95%CI 1.47; 3.53), respectively). Vitamins A and E and beta-carotene were unrelated to (AD) dementia. Conclusions. Vitamin D deficiency increased the risk to develop (AD) dementia. Our study supports the advice for monitoring vitamin D status in the elderly and vitamin D supplementation in those with vitamin D deficiency. We observed no relationships between the other vitamins with incident (AD) dementia, which is in line with previous observational studies.

Published
2022
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3. New insights into the genetic etiology of Alzheimer's disease and related dementias.

Author

Bellenguez C, Küçükali F, Jansen IE, Kleineidam L, Moreno-Grau S, Amin N, Naj AC, Campos-Martin R, Grenier-Boley B, Andrade V, Holmans PA, Boland A, Damotte V, van der Lee SJ, Costa MR, Kuulasmaa T, Yang Q, de Rojas I, Bis JC, Yaqub A, Prokic I, Chapuis J, Ahmad S, Giedraitis V, Aarsland D, Garcia-Gonzalez P, Abdelnour C, Alarcón-Martín E, Alcolea D, Alegret M, Alvarez I, Álvarez V, Armstrong NJ, Tsolaki A, Antúnez C, Appollonio I, Arcaro M, Archetti S, Pastor AA, Arosio B, Athanasiu L, Bailly H, Banaj N, Baquero M, Barral S, Beiser A, Pastor AB, Below JE, Benchek P, Benussi L, Berr C, Besse C, Bessi V, Binetti G, Bizarro A, Blesa R, Boada M, Boerwinkle E, Borroni B, Boschi S, Bossù P, Bråthen G, Bressler J, Bresner C, Brodaty H, Brookes KJ, Brusco LI, Buiza-Rueda D, Bûrger K, Burholt V, Bush WS, Calero M, Cantwell LB, Chene G, Chung J, Cuccaro ML, Carracedo Á, Cecchetti R, Cervera-Carles L, Charbonnier C, Chen HH, Chillotti C, Ciccone S, Claassen JAHR, Clark C, Conti E, Corma-Gómez A, Costantini E, Custodero C, Daian D, Dalmasso MC, Daniele A, Dardiotis E, Dartigues JF, de Deyn PP, de Paiva Lopes K, de Witte LD, Debette S, Deckert J, Del Ser T, Denning N, DeStefano A, Dichgans M, Diehl-Schmid J, Diez-Fairen M, Rossi PD, Djurovic S, Duron E, Düzel E, Dufouil C, Eiriksdottir G, Engelborghs S, Escott-Price V, Espinosa A, Ewers M, Faber KM, Fabrizio T, Nielsen SF, Fardo DW, Farotti L, Fenoglio C, Fernández-Fuertes M, Ferrari R, Ferreira CB, Ferri E, Fin B, Fischer P, Fladby T, Fließbach K, Fongang B, Fornage M, Fortea J, Foroud TM, Fostinelli S, Fox NC, Franco-Macías E, Bullido MJ, Frank-García A, Froelich L, Fulton-Howard B, Galimberti D, García-Alberca JM, García-González P, Garcia-Madrona S, Garcia-Ribas G, Ghidoni R, Giegling I, Giorgio G, Goate AM, Goldhardt O, Gomez-Fonseca D, González-Pérez A, Graff C, Grande G, Green E, Grimmer T, Grünblatt E, Grunin M, Gudnason V, Guetta-Baranes T, Haapasalo A, Hadjigeorgiou G, Haines JL, Hamilton-Nelson KL, Hampel H, Hanon O, Hardy J, Hartmann AM, Hausner L, Harwood J, Heilmann-Heimbach S, Helisalmi S, Heneka MT, Hernández I, Herrmann MJ, Hoffmann P, Holmes C, Holstege H, Vilas RH, Hulsman M, Humphrey J, Biessels GJ, Jian X, Johansson C, Jun GR, Kastumata Y, Kauwe J, Kehoe PG, Kilander L, Ståhlbom AK, Kivipelto M, Koivisto A, Kornhuber J, Kosmidis MH, Kukull WA, Kuksa PP, Kunkle BW, Kuzma AB, Lage C, Laukka EJ, Launer L, Lauria A, Lee CY, Lehtisalo J, Lerch O, Lleó A, Longstreth W Jr, Lopez O, de Munain AL, Love S, Löwemark M, Luckcuck L, Lunetta KL, Ma Y, Macías J, MacLeod CA, Maier W, Mangialasche F, Spallazzi M, Marquié M, Marshall R, Martin ER, Montes AM, Rodríguez CM, Masullo C, Mayeux R, Mead S, Mecocci P, Medina M, Meggy A, Mehrabian S, Mendoza S, Menéndez-González M, Mir P, Moebus S, Mol M, Molina-Porcel L, Montrreal L, Morelli L, Moreno F, Morgan K, Mosley T, Nöthen MM, Muchnik C, Mukherjee S, Nacmias B, Ngandu T, Nicolas G, Nordestgaard BG, Olaso R, Orellana A, Orsini M, Ortega G, Padovani A, Paolo C, Papenberg G, Parnetti L, Pasquier F, Pastor P, Peloso G, Pérez-Cordón A, Pérez-Tur J, Pericard P, Peters O, Pijnenburg YAL, Pineda JA, Piñol-Ripoll G, Pisanu C, Polak T, Popp J, Posthuma D, Priller J, Puerta R, Quenez O, Quintela I, Thomassen JQ, Rábano A, Rainero I, Rajabli F, Ramakers I, Real LM, Reinders MJT, Reitz C, Reyes-Dumeyer D, Ridge P, Riedel-Heller S, Riederer P, Roberto N, Rodriguez-Rodriguez E, Rongve A, Allende IR, Rosende-Roca M, Royo JL, Rubino E, Rujescu D, Sáez ME, Sakka P, Saltvedt I, Sanabria Á, Sánchez-Arjona MB, Sanchez-Garcia F, Juan PS, Sánchez-Valle R, Sando SB, Sarnowski C, Satizabal CL, Scamosci M, Scarmeas N, Scarpini E, Scheltens P, Scherbaum N, Scherer M, Schmid M, Schneider A, Schott JM, Selbæk G, Seripa D, Serrano M, Sha J, Shadrin AA, Skrobot O, Slifer S, Snijders GJL, Soininen H, Solfrizzi V, Solomon A, Song Y, Sorbi S, Sotolongo-Grau O, Spalletta G, Spottke A, Squassina A, Stordal E, Tartan JP, Tárraga L, Tesí N, Thalamuthu A, Thomas T, Tosto G, Traykov L, Tremolizzo L, Tybjærg-Hansen A, Uitterlinden A, Ullgren A, Ulstein I, Valero S, Valladares O, Broeckhoven CV, Vance J, Vardarajan BN, van der Lugt A, Dongen JV, van Rooij J, van Swieten J, Vandenberghe R, Verhey F, Vidal JS, Vogelgsang J, Vyhnalek M, Wagner M, Wallon D, Wang LS, Wang R, Weinhold L, Wiltfang J, Windle G, Woods B, Yannakoulia M, Zare H, Zhao Y, Zhang X, Zhu C, Zulaica M, Farrer LA, Psaty BM, Ghanbari M, Raj T, Sachdev P, Mather K, Jessen F, Ikram MA, de Mendonça A, Hort J, Tsolaki M, Pericak-Vance MA, Amouyel P, Williams J, Frikke-Schmidt R, Clarimon J, Deleuze JF, Rossi G, Seshadri S, Andreassen OA, Ingelsson M, Hiltunen M, Sleegers K, Schellenberg GD, van Duijn CM, Sims R, van der Flier WM, Ruiz A, Ramirez A, and Lambert JC

Subjects
Genome-Wide Association Study, Humans, tau Proteins genetics, Alzheimer Disease genetics, Alzheimer Disease pathology, Cognitive Dysfunction psychology
Abstract

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele., (© 2022. The Author(s).)

Published
2022
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4. Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Author

de Rojas I, Moreno-Grau S, Tesi N, Grenier-Boley B, Andrade V, Jansen IE, Pedersen NL, Stringa N, Zettergren A, Hernández I, Montrreal L, Antúnez C, Antonell A, Tankard RM, Bis JC, Sims R, Bellenguez C, Quintela I, González-Perez A, Calero M, Franco-Macías E, Macías J, Blesa R, Cervera-Carles L, Menéndez-González M, Frank-García A, Royo JL, Moreno F, Huerto Vilas R, Baquero M, Diez-Fairen M, Lage C, García-Madrona S, García-González P, Alarcón-Martín E, Valero S, Sotolongo-Grau O, Ullgren A, Naj AC, Lemstra AW, Benaque A, Pérez-Cordón A, Benussi A, Rábano A, Padovani A, Squassina A, de Mendonça A, Arias Pastor A, Kok AAL, Meggy A, Pastor AB, Espinosa A, Corma-Gómez A, Martín Montes A, Sanabria Á, DeStefano AL, Schneider A, Haapasalo A, Kinhult Ståhlbom A, Tybjærg-Hansen A, Hartmann AM, Spottke A, Corbatón-Anchuelo A, Rongve A, Borroni B, Arosio B, Nacmias B, Nordestgaard BG, Kunkle BW, Charbonnier C, Abdelnour C, Masullo C, Martínez Rodríguez C, Muñoz-Fernandez C, Dufouil C, Graff C, Ferreira CB, Chillotti C, Reynolds CA, Fenoglio C, Van Broeckhoven C, Clark C, Pisanu C, Satizabal CL, Holmes C, Buiza-Rueda D, Aarsland D, Rujescu D, Alcolea D, Galimberti D, Wallon D, Seripa D, Grünblatt E, Dardiotis E, Düzel E, Scarpini E, Conti E, Rubino E, Gelpi E, Rodriguez-Rodriguez E, Duron E, Boerwinkle E, Ferri E, Tagliavini F, Küçükali F, Pasquier F, Sanchez-Garcia F, Mangialasche F, Jessen F, Nicolas G, Selbæk G, Ortega G, Chêne G, Hadjigeorgiou G, Rossi G, Spalletta G, Giaccone G, Grande G, Binetti G, Papenberg G, Hampel H, Bailly H, Zetterberg H, Soininen H, Karlsson IK, Alvarez I, Appollonio I, Giegling I, Skoog I, Saltvedt I, Rainero I, Rosas Allende I, Hort J, Diehl-Schmid J, Van Dongen J, Vidal JS, Lehtisalo J, Wiltfang J, Thomassen JQ, Kornhuber J, Haines JL, Vogelgsang J, Pineda JA, Fortea J, Popp J, Deckert J, Buerger K, Morgan K, Fließbach K, Sleegers K, Molina-Porcel L, Kilander L, Weinhold L, Farrer LA, Wang LS, Kleineidam L, Farotti L, Parnetti L, Tremolizzo L, Hausner L, Benussi L, Froelich L, Ikram MA, Deniz-Naranjo MC, Tsolaki M, Rosende-Roca M, Löwenmark M, Hulsman M, Spallazzi M, Pericak-Vance MA, Esiri M, Bernal Sánchez-Arjona M, Dalmasso MC, Martínez-Larrad MT, Arcaro M, Nöthen MM, Fernández-Fuertes M, Dichgans M, Ingelsson M, Herrmann MJ, Scherer M, Vyhnalek M, Kosmidis MH, Yannakoulia M, Schmid M, Ewers M, Heneka MT, Wagner M, Scamosci M, Kivipelto M, Hiltunen M, Zulaica M, Alegret M, Fornage M, Roberto N, van Schoor NM, Seidu NM, Banaj N, Armstrong NJ, Scarmeas N, Scherbaum N, Goldhardt O, Hanon O, Peters O, Skrobot OA, Quenez O, Lerch O, Bossù P, Caffarra P, Dionigi Rossi P, Sakka P, Mecocci P, Hoffmann P, Holmans PA, Fischer P, Riederer P, Yang Q, Marshall R, Kalaria RN, Mayeux R, Vandenberghe R, Cecchetti R, Ghidoni R, Frikke-Schmidt R, Sorbi S, Hägg S, Engelborghs S, Helisalmi S, Botne Sando S, Kern S, Archetti S, Boschi S, Fostinelli S, Gil S, Mendoza S, Mead S, Ciccone S, Djurovic S, Heilmann-Heimbach S, Riedel-Heller S, Kuulasmaa T, Del Ser T, Lebouvier T, Polak T, Ngandu T, Grimmer T, Bessi V, Escott-Price V, Giedraitis V, Deramecourt V, Maier W, Jian X, Pijnenburg YAL, Kehoe PG, Garcia-Ribas G, Sánchez-Juan P, Pastor P, Pérez-Tur J, Piñol-Ripoll G, Lopez de Munain A, García-Alberca JM, Bullido MJ, Álvarez V, Lleó A, Real LM, Mir P, Medina M, Scheltens P, Holstege H, Marquié M, Sáez ME, Carracedo Á, Amouyel P, Schellenberg GD, Williams J, Seshadri S, van Duijn CM, Mather KA, Sánchez-Valle R, Serrano-Ríos M, Orellana A, Tárraga L, Blennow K, Huisman M, Andreassen OA, Posthuma D, Clarimón J, Boada M, van der Flier WM, Ramirez A, Lambert JC, van der Lee SJ, and Ruiz A

Subjects
Age of Onset, Aged, Aged, 80 and over, Alzheimer Disease epidemiology, Alzheimer Disease pathology, Amyloid beta-Protein Precursor genetics, Amyloid beta-Protein Precursor metabolism, Apolipoproteins E genetics, Case-Control Studies, Cohort Studies, Datasets as Topic, Female, Follow-Up Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Heterozygote, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment methods, Risk Factors, Alzheimer Disease genetics, Multifactorial Inheritance
Abstract

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.

Published
2021
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5. Eicosapentaenoic Acid Is Associated with Decreased Incidence of Alzheimer's Dementia in the Oldest Old.

Author

Melo van Lent D, Egert S, Wolfsgruber S, Kleineidam L, Weinhold L, Wagner-Thelen H, Maier W, Jessen F, Ramirez A, Schmid M, Scherer M, Riedel-Heller SG, and Wagner M

Subjects
Activities of Daily Living, Aged, 80 and over, Alzheimer Disease blood, Dementia blood, Dementia epidemiology, Fatty Acids blood, Fatty Acids, Omega-3 blood, Fatty Acids, Omega-6 blood, Fatty Acids, Unsaturated blood, Female, Germany epidemiology, Humans, Incidence, Longitudinal Studies, Male, Phospholipids blood, Proportional Hazards Models, Prospective Studies, Alzheimer Disease epidemiology, Eicosapentaenoic Acid blood
Abstract

Background: Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) may have different effects on cognitive health due to their anti- or pro-inflammatory properties., Methods: We aimed to prospectively examine the relationships between n-3 and n-6 PUFA contents in serum phospholipids with incident all-cause dementia and Alzheimer's disease dementia (AD). We included 1264 non-demented participants aged 84 ± 3 years from the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe) multicenter-cohort study. We investigated whether fatty acid concentrations in serum phospholipids, especially eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), linoleic acid (LA), dihomo-γ-linolenic acid (DGLA), and arachidonic acid (AA), were associated with risk of incident all-cause dementia and AD., Results: During the follow-up window of seven years, 233 participants developed dementia. Higher concentrations of EPA were associated with a lower incidence of AD (hazard ratio (HR) 0.76 (95% CI 0.63; 0.93)). We also observed that higher concentrations of EPA were associated with a decreased risk for all-cause dementia (HR 0.76 (95% CI 0.61; 0.94)) and AD (HR 0.66 (95% CI 0.51; 0.85)) among apolipoprotein E ε4 (APOE ε4) non-carriers but not among APOE ε4 carriers. No other fatty acids were significantly associated with AD or dementia., Conclusions: Higher concentrations of EPA were associated with a lower risk of incident AD. This further supports a beneficial role of n-3 PUFAs for cognitive health in old age.

Published
2021
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6. PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment.

Author

Kleineidam L, Chouraki V, Próchnicki T, van der Lee SJ, Madrid-Márquez L, Wagner-Thelen H, Karaca I, Weinhold L, Wolfsgruber S, Boland A, Martino Adami PV, Lewczuk P, Popp J, Brosseron F, Jansen IE, Hulsman M, Kornhuber J, Peters O, Berr C, Heun R, Frölich L, Tzourio C, Dartigues JF, Hüll M, Espinosa A, Hernández I, de Rojas I, Orellana A, Valero S, Stringa N, van Schoor NM, Huisman M, Scheltens P, Rüther E, Deleuze JF, Wiltfang J, Tarraga L, Schmid M, Scherer M, Riedel-Heller S, Heneka MT, Amouyel P, Jessen F, Boada M, Maier W, Schneider A, González-Pérez A, van der Flier WM, Wagner M, Lambert JC, Holstege H, Sáez ME, Latz E, Ruiz A, and Ramirez A

Subjects
Aged, Aged, 80 and over, Alzheimer Disease genetics, Amyloid beta-Peptides genetics, Biomarkers analysis, Cognition physiology, Disease Progression, Female, Humans, Male, Middle Aged, tau Proteins cerebrospinal fluid, tau Proteins metabolism, Alzheimer Disease pathology, Cognitive Dysfunction genetics, Cognitive Dysfunction pathology, Phospholipase C gamma metabolism
Abstract

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau 181 , total tau, and Aβ 1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau 181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau 181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ 1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.

Published
2020
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7. Prospective Associations between Single Foods, Alzheimer's Dementia and Memory Decline in the Elderly.

Author

Fischer K, Melo van Lent D, Wolfsgruber S, Weinhold L, Kleineidam L, Bickel H, Scherer M, Eisele M, van den Bussche H, Wiese B, König HH, Weyerer S, Pentzek M, Röhr S, Maier W, Jessen F, Schmid M, Riedel-Heller SG, and Wagner M

Subjects
Age Factors, Aged, Aged, 80 and over, Alzheimer Disease diagnosis, Alzheimer Disease epidemiology, Alzheimer Disease prevention & control, Female, Geriatric Assessment, Germany epidemiology, Humans, Incidence, Male, Memory Disorders diagnosis, Memory Disorders epidemiology, Memory Disorders prevention & control, Mental Status and Dementia Tests, Neuropsychological Tests, Prospective Studies, Protective Factors, Risk Factors, Sex Factors, Time Factors, Wine, Alzheimer Disease psychology, Cognition, Cognitive Aging psychology, Food adverse effects, Memory, Memory Disorders psychology
Abstract

Background : Evidence whether single &ldquo;cognitive health&rdquo; foods could prevent cognitive decline is limited. We investigated whether dietary intake of red wine, white wine, coffee, green tea, olive oil, fresh fish, fruits and vegetables, red meat and sausages, assessed by a single-food-questionnaire, would be associated with either incident Alzheimer&rsquo;s dementia (AD) or verbal memory decline. Methods: Participants aged 75+ of the German Study on Aging, Cognition and Dementia in Primary Care Patients (AgeCoDe) cohort were regularly followed over 10 years ( n = 2622; n = 418 incident AD cases). Multivariable-adjusted joint modeling of repeated-measures and survival analysis was used, taking gender and Apolipoprotein E4 ( APOE &epsilon;4) genotype into account as possible effect modifiers. Results : Only higher red wine intake was associated with a lower incidence of AD ( HR = 0.92; P = 0.045). Interestingly, this was true only for men ( HR = 0.82; P < 0.001), while in women higher red wine intake was associated with a higher incidence of AD ( HR = 1.15; P = 0.044), and higher white wine intake with a more pronounced memory decline over time ( HR = &minus;0.13; P = 0.052). Conclusion : We found no evidence for these single foods to be protective against cognitive decline, with the exception of red wine, which reduced the risk for AD only in men. Women could be more susceptible to detrimental effects of alcohol.

Published
2018
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8. PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment

Author

KLEINEIDAM, Luca, Chouraki, Vincent, Próchnicki, Tomasz, van der Lee, Sven, Madrid‑Márquez, Laura, Wagner-Thelen, Holger, Karaca, Ilker, WEINHOLD, Leonie, Wolfsgruber, Steffen, Boland, Anne, Martino Adami, Pamela, Lewczuk, Piotr, POPP, Julius, Brosseron, Frederic, Jansen, Iris, HULSMAN, Marc, Kornhuber, Johannes, Peters, Oliver, Berr, Claudine, Heun, Reinhard, Frölich, Lutz, Tzourio, Christophe, Dartigues, Jean-François, Hüll, Michael, Espinosa, Ana, Hernández, Isabel, de Rojas, Itziar, ORELLANA, Adelina, VALERO, Sergi, STRINGA, Najada, Van Schoor, Natasja, Huisman, Martijn, Scheltens, Philip, For The Alzheimer'S Disease Neuroimaging Initiative, (ADNI), Rüther, Eckart, Deleuze, Jean-François, Wiltfang, Jens, Tarraga, Lluis, Schmid, Matthias, Scherer, Martin, Riedel-Heller, Steffi, Heneka, Michael, Amouyel, Philippe, Jessen, Frank, Boada, Merce, Maier, Wolfgang, Schneider, Anja, González‑Pérez, Antonio, van der Flier, Wiesje, Wagner, Michael, Lambert, Jean-Charles, Holstege, Henne, Saez, Mª Eugenia, Latz, Eicke, Ruiz, Agustin, Ramirez, Alfredo, University Hospital Bonn, Universität zu Köln, German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Epidémiologie et de Santé Publique [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Amsterdam UMC, Vrije Universiteit Amsterdam [Amsterdam] (VU), Centro andaluz de estudios bioinformáticos - Andalusian Bioinformatics Research Centre [Sevilla] (CAEBi), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Universitätsklinikum Erlangen [Erlangen], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), University of Bialystok, Lausanne University Hospital, University hospital of Zurich [Zurich], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Universität Heidelberg [Heidelberg], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Albert-Ludwigs-Universität Freiburg, Universitat Internacional de Catalunya [Barcelona] (UIC), Instituto de Salud Carlos III [Madrid] (ISC), University Medical Center Göttingen (UMG), Universidade de Aveiro, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Universität Leipzig [Leipzig], University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), Open Access funding provided by Projekt DEAL. This publication was funded in part by the German Federal Ministry of Education and Research (BMBF) (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434, grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716, 01ET1006B). Analyses were also funded by the German Federal Ministry of Education and Research (BMBF 01EA1410A) within the project 'Diet-Body-Brain: from epidemiology to evidence-based communication'. Part of the work was funded by the JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A). Part of the analysis was funded by the German Research Foundation (DFG) grant: RA 1971/6-1 to Alfredo Ramirez. Research of the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case–control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). Data collection and sharing for this project were funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, Araclon Biotech, BioClinica, Inc., Biogen, Bristol-Myers Squibb Company, CereSpir, Inc., Cogstate, Eisai Inc., ElanPharmaceuticals, Inc., Eli Lilly and Company, EuroImmun, F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc., Fujirebio, GE Healthcare, IXICO Ltd., Janssen Alzheimer Immunotherapy Research and Development, LLC., Johnson and Johnson Pharmaceutical Research and Development LLC., Lumosity, Lundbeck, Merck and Co., Inc., Meso Scale Diagnostics, LLC., NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals Corporation, Pfizer Inc., Piramal Imaging, Servier, Takeda Pharmaceutical Company, and transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for NeuroImaging at the University of Southern California. The Three-City Study genotyping and analysis was funded by the GENMED Labex, the Joint Programming Initiative on Neurodegenerative Diseases Research (JPND, PERADES project), the Institute Pasteur de Lille, the University of Lille, and the Nord-Pas de Calais Regional Council. This work also benefited from the Lille Métropole Communauté Urbaine Council, the French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to Alzheimer’s disease). In addition, the Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. Additional funding for the 3C Study was also obtained from the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/INSERM 'Cohortes et collections de données biologiques' programme. Lille Génopôle received an unconditional grant from Eisai. Fundacio ACE cohort receives support from the Innovative Medicines Initiative 2 Joint Undertaking which receives support from the European Union’s Horizon 2020 research and innovation programme (ADAPTED Grant No. 115975). A. Ruiz’s research is also supported by Instituto de Salud Carlos III (ISCIII) grants PI13/02434, PI16/01861, and PI19/01301. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de Hacer Europa'), by Fundación bancaria 'La Caixa' and Grifols SA (GR@ACE project). For the Longitudinal Aging Study Amsterdam (LASA) supports was largely obtained from a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The data collection in 2012–2013 was financially supported by the Netherlands Organization for Scientific Research (NWO) in the framework of the project 'New Cohorts of young old in the twenty-first century' (File Number 480-10-014). Genotyping using Axiom-NL array was financially supported by EMGO+ Research Institute. PL was supported by the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no 115372, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution. JW is supported by an Ilídio Pinho professorship and iBiMED (UID/BIM/04501/2013), at the University of Aveiro, Portugal. JP was supported by a grant from the Swiss National Science Foundation (320030L_141179)., Universität zu Köln = University of Cologne, Amsterdam UMC - Amsterdam University Medical Center, Universität Heidelberg [Heidelberg] = Heidelberg University, Universität Leipzig, Alzheimer's Disease Neuroimaging Initiative (ADNI), Kleineidam, L., Karaca, I., Heneka, M.T., Maier, W., Schneider, A., Wagner, M., Chouraki, V., Amouyel, P., Lambert, J.C., Próchnicki, T., Latz, E., van der Lee, S.J., Jansen, I.E., Hulsman, M., Scheltens, P., van der Flier, W.M., Holstege, H., Madrid-Márquez, L., González-Pérez, A., Sáez, M.E., Wagner-Thelen, H., Martino Adami, P.V., Jessen, F., Ramirez, A., Weinhold, L., Schmid, M., Wolfsgruber, S., Brosseron, F., Boland, A., Deleuze, J.F., Lewczuk, P., Kornhuber, J., Popp, J., Peters, O., Berr, C., Heun, R., Frölich, L., Tzourio, C., Dartigues, J.F., Hüll, M., Espinosa, A., Hernández, I., de Rojas, I., Orellana, A., Valero, S., Ruiz, A., Tarraga, L., Boada, M., Stringa, N., van Schoor, N.M., Huisman, M., Rüther, E., Wiltfang, J., Scherer, M., Riedel-Heller, S., Neurology, Human genetics, Epidemiology and Data Science, APH - Aging & Later Life, APH - Societal Participation & Health, Amsterdam Neuroscience - Complex Trait Genetics, APH - Personalized Medicine, APH - Methodology, Sociology, and The Social Context of Aging (SoCA)

Subjects
Apolipoprotein E, Male, pathology [Cognitive Dysfunction], Cognitive decline, genetics [Alzheimer Disease], Disease, SEPIA, pathology [Alzheimer Disease], 0302 clinical medicine, Cognition, genetics [Amyloid beta-Peptides], Medicine, Aged, 80 and over, 0303 health sciences, education.field_of_study, Microglia, physiology [Cognition], Middle Aged, medicine.anatomical_structure, Disease Progression, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], analysis [Biomarkers], Alzheimer’s disease, Amyloid, Phospholipase C gamma 2, Population, tau Proteins, Pathology and Forensic Medicine, PLCG2, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Alzheimer Disease, Humans, Cognitive Dysfunction, ddc:610, education, Mild cognitive impairment, HEALTHY, 030304 developmental biology, Aged, metabolism [Phospholipase C gamma], Original Paper, Amyloid beta-Peptides, TREM2, business.industry, Phospholipase C gamma, genetics [Cognitive Dysfunction], metabolism [tau Proteins], cerebrospinal fluid [tau Proteins], [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Immunology, Neurology (clinical), business, 030217 neurology & neurosurgery, Biomarkers
Abstract

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer’s disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aβ1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.

Published
2020

9. Common variants in Alzheimer's disease and risk stratification by polygenic risk scores

Author

De Rojas, Itziar, Moreno-Grau, Sonia, Tesi, Niccolo, Grenier-Boley, Benjamin, Andrade, Victor, Jansen, Iris E, Pedersen, Nancy L, Stringa, Najada, Zettergren, Anna, Hernández, Isabel, Montrreal, Laura, Antúnez, Carmen, Antonell, Anna, Tankard, Rick M, Bis, Joshua C, Sims, Rebecca, Bellenguez, Céline, Quintela, Inés, González-Perez, Antonio, Calero, Miguel, Franco-Macías, Emilio, Macías, Juan, Blesa, Rafael, Cervera-Carles, Laura, Menéndez-González, Manuel, Frank-García, Ana, Royo, Jose Luís, Moreno, Fermin, Huerto Vilas, Raquel, Baquero, Miquel, Diez-Fairen, Mónica, Lage, Carmen, García-Madrona, Sebastián, García-González, Pablo, Alarcón-Martín, Emilio, Valero, Sergi, Sotolongo-Grau, Oscar, Ullgren, Abbe, Naj, Adam C, Lemstra, Afina W, Benaque, Alba, Pérez-Cordón, Alba, Benussi, Alberto, Rábano, Alberto, Padovani, Alessandro, Squassina, Alessio, De Mendonça, Alexandre, Arias Pastor, Alfonso, Kok, Almar AL, Meggy, Alun, Pastor, Ana Belén, Espinosa, Ana, Corma-Gómez, Anaïs, Martín Montes, Angel, Sanabria, Ángela, DeStefano, Anita L, Schneider, Anja, Haapasalo, Annakaisa, Kinhult Ståhlbom, Anne, Tybjærg-Hansen, Anne, Hartmann, Annette M, Spottke, Annika, Corbatón-Anchuelo, Arturo, Rongve, Arvid, Borroni, Barbara, Arosio, Beatrice, Nacmias, Benedetta, Nordestgaard, Børge G, Kunkle, Brian W, Charbonnier, Camille, Abdelnour, Carla, Masullo, Carlo, Martínez Rodríguez, Carmen, Muñoz-Fernandez, Carmen, Dufouil, Carole, Graff, Caroline, Ferreira, Catarina B, Chillotti, Caterina, Reynolds, Chandra A, Fenoglio, Chiara, Van Broeckhoven, Christine, Clark, Christopher, Pisanu, Claudia, Satizabal, Claudia L, Holmes, Clive, Buiza-Rueda, Dolores, Aarsland, Dag, Rujescu, Dan, Alcolea, Daniel, Galimberti, Daniela, Wallon, David, Seripa, Davide, Grünblatt, Edna, Dardiotis, Efthimios, Düzel, Emrah, Scarpini, Elio, Conti, Elisa, Rubino, Elisa, Gelpi, Ellen, Rodriguez-Rodriguez, Eloy, Duron, Emmanuelle, Boerwinkle, Eric, Ferri, Evelyn, Tagliavini, Fabrizio, Küçükali, Fahri, Pasquier, Florence, Sanchez-Garcia, Florentino, Mangialasche, Francesca, Jessen, Frank, Nicolas, Gaël, Selbæk, Geir, Ortega, Gemma, Chêne, Geneviève, Hadjigeorgiou, Georgios, Rossi, Giacomina, Spalletta, Gianfranco, Giaccone, Giorgio, Grande, Giulia, Binetti, Giuliano, Papenberg, Goran, Hampel, Harald, Bailly, Henri, Zetterberg, Henrik, Soininen, Hilkka, Karlsson, Ida K, Alvarez, Ignacio, Appollonio, Ildebrando, Giegling, Ina, Skoog, Ingmar, Saltvedt, Ingvild, Rainero, Innocenzo, Rosas Allende, Irene, Hort, Jakub, Diehl-Schmid, Janine, Van Dongen, Jasper, Vidal, Jean-Sebastien, Lehtisalo, Jenni, Wiltfang, Jens, Thomassen, Jesper Qvist, Kornhuber, Johannes, Haines, Jonathan L, Vogelgsang, Jonathan, Pineda, Juan A, Fortea, Juan, Popp, Julius, Deckert, Jürgen, Buerger, Katharina, Morgan, Kevin, Fließbach, Klaus, Sleegers, Kristel, Molina-Porcel, Laura, Kilander, Lena, Weinhold, Leonie, Farrer, Lindsay A, Wang, Li-San, Kleineidam, Luca, Farotti, Lucia, Parnetti, Lucilla, Tremolizzo, Lucio, Hausner, Lucrezia, Benussi, Luisa, Froelich, Lutz, Ikram, M Arfan, Deniz-Naranjo, M Candida, Tsolaki, Magda, Rosende-Roca, Maitée, Löwenmark, Malin, Hulsman, Marc, Spallazzi, Marco, Pericak-Vance, Margaret A, Esiri, Margaret, Bernal Sánchez-Arjona, María, Dalmasso, Maria Carolina, Martínez-Larrad, María Teresa, Arcaro, Marina, Nöthen, Markus M, Fernández-Fuertes, Marta, Dichgans, Martin, Ingelsson, Martin, Herrmann, Martin J, Scherer, Martin, Vyhnalek, Martin, Kosmidis, Mary H, Yannakoulia, Mary, Schmid, Matthias, Ewers, Michael, Heneka, Michael T, Wagner, Michael, Scamosci, Michela, Kivipelto, Miia, Hiltunen, Mikko, Zulaica, Miren, Alegret, Montserrat, Fornage, Myriam, Roberto, Natalia, Van Schoor, Natasja M, Seidu, Nazib M, Banaj, Nerisa, Armstrong, Nicola J, Scarmeas, Nikolaos, Scherbaum, Norbert, Goldhardt, Oliver, Hanon, Oliver, Peters, Oliver, Skrobot, Olivia Anna, Quenez, Olivier, Lerch, Ondrej, Bossù, Paola, Caffarra, Paolo, Dionigi Rossi, Paolo, Sakka, Paraskevi, Mecocci, Patrizia, Hoffmann, Per, Holmans, Peter A, Fischer, Peter, Riederer, Peter, Yang, Qiong, Marshall, Rachel, Kalaria, Rajesh N, Mayeux, Richard, Vandenberghe, Rik, Cecchetti, Roberta, Ghidoni, Roberta, Frikke-Schmidt, Ruth, Sorbi, Sandro, Hägg, Sara, Engelborghs, Sebastiaan, Helisalmi, Seppo, Botne Sando, Sigrid, Kern, Silke, Archetti, Silvana, Boschi, Silvia, Fostinelli, Silvia, Gil, Silvia, Mendoza, Silvia, Mead, Simon, Ciccone, Simona, Djurovic, Srdjan, Heilmann-Heimbach, Stefanie, Riedel-Heller, Steffi, Kuulasmaa, Teemu, Del Ser, Teodoro, Lebouvier, Thibaud, Polak, Thomas, Ngandu, Tiia, Grimmer, Timo, Bessi, Valentina, Escott-Price, Valentina, Giedraitis, Vilmantas, Deramecourt, Vincent, Maier, Wolfgang, Jian, Xueqiu, Pijnenburg, Yolande AL, EADB Contributors, GR@ACE Study Group, DEGESCO Consortium, IGAP (ADGC, CHARGE, EADI, GERAD), PGC-ALZ Consortia, Kehoe, Patrick Gavin, Garcia-Ribas, Guillermo, Sánchez-Juan, Pascual, Pastor, Pau, Pérez-Tur, Jordi, Piñol-Ripoll, Gerard, Lopez De Munain, Adolfo, García-Alberca, Jose María, Bullido, María J, Álvarez, Victoria, Lleó, Alberto, Real, Luis M, Mir, Pablo, Medina, Miguel, Scheltens, Philip, Holstege, Henne, Marquié, Marta, Sáez, María Eugenia, Carracedo, Ángel, Amouyel, Philippe, Schellenberg, Gerard D, Williams, Julie, Seshadri, Sudha, Van Duijn, Cornelia M, Mather, Karen A, Sánchez-Valle, Raquel, Serrano-Ríos, Manuel, Orellana, Adelina, Tárraga, Lluís, Blennow, Kaj, Huisman, Martijn, Andreassen, Ole A, Posthuma, Danielle, Clarimón, Jordi, Boada, Mercè, Van Der Flier, Wiesje M, Ramirez, Alfredo, Lambert, Jean-Charles, Van Der Lee, Sven J, and Ruiz, Agustín

Subjects
Aged, 80 and over, Male, Heterozygote, Multifactorial Inheritance, Datasets as Topic, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment, 3. Good health, Cohort Studies, Amyloid beta-Protein Precursor, Apolipoproteins E, Alzheimer Disease, Risk Factors, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Age of Onset, Aged, Follow-Up Studies, Genome-Wide Association Study
Abstract

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: 733051061, 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.

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