Publications by authors named "Sonia Moreno-Grau"

33 Publications

Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease.

Mol Psychiatry 2021 Jun 10. Epub 2021 Jun 10.

Neuroscience Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.
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http://dx.doi.org/10.1038/s41380-021-01152-8DOI Listing
June 2021

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

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

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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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

Multiomics integrative analysis identifies allele-specific blood biomarkers associated to Alzheimer's disease etiopathogenesis.

Aging (Albany NY) 2021 Apr 12;13(7):9277-9329. Epub 2021 Apr 12.

Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.

Alzheimer's disease (AD) is the most common form of dementia, currently affecting 35 million people worldwide. Apolipoprotein E (APOE) ε4 allele is the major risk factor for sporadic, late-onset AD (LOAD), which comprises over 95% of AD cases, increasing the risk of AD 4-12 fold. Despite this, the role of APOE in AD pathogenesis is still a mystery. Aiming for a better understanding of APOE-specific effects, the ADAPTED consortium analysed and integrated publicly available data of multiple OMICS technologies from both plasma and brain stratified by haplotype ( and ). Combining genome-wide association studies (GWAS) with differential mRNA and protein expression analyses and single-nuclei transcriptomics, we identified genes and pathways contributing to AD in both APOE dependent and independent fashion. Interestingly, we characterised a set of biomarkers showing plasma and brain consistent protein profiles and opposite trends in and AD cases that could constitute screening tools for a disease that lacks specific blood biomarkers. Beside the identification of APOE-specific signatures, our findings advocate that this novel approach, based on the concordance across OMIC layers and tissues, is an effective strategy for overcoming the limitations of often underpowered single-OMICS studies.
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http://dx.doi.org/10.18632/aging.202950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064208PMC
April 2021

Neuropsychiatric profiles and conversion to dementia in mild cognitive impairment, a latent class analysis.

Sci Rep 2021 03 19;11(1):6448. Epub 2021 Mar 19.

Research Center and Memory Clinic, Fundació ACE, Barcelona Alzheimer Treatment and Research Centre, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya (UIC) - Barcelona, Gran Vía Carles III, 85 bis, bajos, 08028, Barcelona, Spain.

Neuropsychiatric symptoms (NPS) have been recently addressed as risk factors of conversion to Alzheimer's disease (AD) and other dementia types in patients diagnosed with Mild Cognitive Impairment (MCI). Our aim was to determine profiles based on the prominent NPS in MCI patients and to explore the predictive value of these profiles on conversion to specific types of dementia. A total of 2137 MCI patients monitored in a memory clinic were included in the study. Four NPS profiles emerged (classes), which were defined by preeminent symptoms: Irritability, Apathy, Anxiety/Depression and Asymptomatic. Irritability and Apathy were predictors of conversion to dementia (HR = 1.43 and 1.56, respectively). Anxiety/depression class showed no risk effect of conversion when compared to Asymptomatic class. Irritability class appeared as the most discriminant neuropsychiatric condition to identify non-AD converters (i.e., frontotemporal dementia, vascular dementia, Parkinson's disease and dementia with Lewy Bodies). The findings revealed that consistent subgroups of MCI patients could be identified among comorbid basal NPS. The preeminent NPS showed to behave differentially on conversion to dementia, beyond AD. Therefore, NPS should be used as early diagnosis facilitators, and should also guide clinicians to detect patients with different illness trajectories in the progression of MCI.
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http://dx.doi.org/10.1038/s41598-021-83126-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979780PMC
March 2021

Long runs of homozygosity are associated with Alzheimer's disease.

Transl Psychiatry 2021 02 24;11(1):142. Epub 2021 Feb 24.

Dep. of Surgery, Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain.

Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer's disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [β (CI 95%) = 0.070 (0.037-0.104); P = 3.91 × 10; β (CI95%) = 0.043 (0.009-0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.
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http://dx.doi.org/10.1038/s41398-020-01145-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904832PMC
February 2021

Interaction of neuropsychiatric symptoms with APOE ε4 and conversion to dementia in MCI patients in a Memory Clinic.

Sci Rep 2020 11 18;10(1):20058. Epub 2020 Nov 18.

Research Center and Memory Clinic, Fundació ACE Institut Català de Neurociències Aplicades - Universitat Internacional de Catalunya (UIC), Gran Via Carles III, 85 bis., 08028, Barcelona, Spain.

To date, very few studies have been focused on the impact of the convergence of neuropsychiatric symptoms (NPS) and APOE ε4 on the conversion to dementia in patients with Mild Cognitive Impairment patients (MCI), and none has been based in a clinical setting. The objective of the study is to determine the predictive value of additive and multiplicative interactions of NPS and APOE ε4 status on the prediction of incident dementia among MCI patients monitored in a Memory Clinic. 1512 patients (aged 60 and older) with prevalent MCI were followed for a mean of 2 years. Neuropsychiatric symptoms were assessed at baseline using the Neuropsychiatric Inventory Questionnaire. Cox proportional hazards models were calculated. Additive interactions for depression, apathy, anxiety, agitation, appetite, or irritability and a positive ε4 carrier status were obtained, significantly increasing the hazard ratios of incident dementia (HR range 1.3-2.03). Synergistic interactions between NPS and APOE ε4 are identified among MCI patients when predicting incident dementia. The combination of the behavioral status and the genetic trait could be considered a useful strategy to identify the most vulnerable MCI patients to dementia conversion in a Memory Clinic.
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http://dx.doi.org/10.1038/s41598-020-77023-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674479PMC
November 2020

, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts.

Neurology 2020 12 17;95(24):e3288-e3302. Epub 2020 Sep 17.

From the Institute of Neurology (B.C., D.A.K., J.H., P.A.L., R.F.), School of Pharmacy (C.M.), and UCL Movement Disorders Centre (J.H.), University College London; School of Pharmacy (C.M., P.A.L.), University of Reading, Whiteknights; Neurogenetics Laboratory (M.B.-Q., C.W., J.M.P.), National Hospital for Neurology and Neurosurgery, London, UK; Aptima Clinic (Miquel Aguilar), Terrassa; Memory Disorders Unit, Department of Neurology (I.A., M.D.-F., P.P.), University Hospital Mutua de Terrassa, Barcelona; Hospital Universitario Central de Asturias (V.A., M.M.-G.), Oviedo, Spain; NORMENT (O.A.), Institute of Clinical Medicine, University of Oslo, Norway; Regional Neurogenetic Centre (Maria Anfossi, Livia Bernardi, A.C.B., M.E.C., Chiara Cupidi, F.F., Maura Gallo, R.M., N.S.), ASPCZ, Lamezia Terme; Department of Neuroscience, Psychology, Drug Research and Child Health (S.B., B.N., I.P., S.S.), University of Florence; Molecular Markers Laboratory (Luisa Benussi, Giuliano Binetti, R.G.), IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience (D.B.), University of Sheffield, UK; Research Center and Memory Clinic (M.B., I.H., S.M.-G., Agustín Ruiz), Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya (UIC), Barcelona, Spain; Centre for Neurodegenerative Disorders (B.B., A.P.), Department of Clinical and Experimental Sciences, University of Brescia, Italy; Department of Clinical Neurosciences (Lucy Bowns, T.E.C., J.B.R.), Cambridge University, UK; Department of Neurology (Geir Bråthen, S.B.S.), University Hospital of Trondheim, Norway; Dept NVS, Division of Neurogeriatrics (H.-H.C., C.G., B.K., L.Ö.), Karolinska Institutet, Bioclinicum Solna, Sweden; Department of Neurology (J.C., O.D.-I., I.I.-G., A.L.), IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Spain; Anne Rowling Regenerative Neurology Clinic (S.C., G.J.T.H., S.P.) and Centre for Clinical Brain Sciences (S.P.), University of Edinburgh, UK; NeuroGenomics and Informatics, Department of Psychiatry (Carlos Cruchaga), Washington University, St. Louis, MO; Cognitive Impairment Center (M.E.D.B., Maurizio Gallucci) and Immunohematology and Transfusional Medicine Service (E.D., A.V.), Local Health Authority n.2 Marca Trevigiana, Treviso, Italy; Department of Psychiatry and Psychotherapy (J.D.-S., C.R.), School of Medicine, Technical University of Munich, Germany; Department of Neurology (D.F., M.G.K.) and Clinical Institute of Medical Genetics (A.M., B.P.), University Medical Center Ljubljana, Slovenia; Dino Ferrari Center (D.G., Elio Scarpini, M.S.), University of Milan, Italy; Cognitive Neuroscience Lab, Think and Speak Lab (J.H.G.), Shirley Ryan Ability Lab, Chicago, IL; Department of Pathology and Laboratory Medicine (Murray Grossman, EunRan Suh, J.Q.T., V.M.V.D.), Center for Neurodegenerative Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia; UCL Dementia Research Institute (J.H.), London; Reta Lila Weston Institute (J.H.), UCL Queen Square Institute of Neurology, UK; Institute for Advanced Study (J.H.), The Hong Kong University of Science and Technology, China; Royal Edinburgh Hospital (G.J.T.H.), UK; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (E.D.H.), Columbia University, New York, NY; Department of Neurology, Memory and Aging Center (A.K., B.M., J.Y.), University of California, San Francisco; UCL Genomics (M.K., G.K.M., Y.P.), UCL Great Ormond Street Institute of Child Health, London, UK; Geriatric Center Frullone ASL Napoli 1 Centro (G.M.), Napoli, Italy; Department of Neurology (M.O.M., J.v.R., J.C.V.S.), Erasmus Medical Center, Rotterdam, the Netherlands; Rona Holdings (P.M.), Silicon Valley, CA; Newcastle Brain Tissue Resource, Institute of Neuroscience (C.M.M.), Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK; Department of Neurology (C.N.), Skåne University Hospital, Malmö, Sweden; Fondazione Policlinico Universitario A. Gemelli IRCCS (V.N.), Rome, Italy; Division of Neuroscience & Experimental Psychology (S.P.-B., A.M.T.R., S.R., J.C.T.), University of Manchester, UK; Amsterdam University Medical Center (Y.A.L.P.), VU University Medical Center, the Netherlands; Cardiovascular Research Unit (A.A.P.), IRCCS Multimedica, Milan; Neurology I, Department of Neuroscience (I.R., Elisa Rubino), University of Torino; NeurOMICS laboratory (G.M., Antonella Rendina, E.V.), Institute of Biochemistry and Cell Biology (IBBC), CNR Napoli, Italy; Manchester Centre for Clinical Neurosciences (A.M.T.R., J.S., J.C.T.), Salford Royal NHS Trust, Manchester, UK; Tanz Centre for Research in Neurodegenerative Diseases (Ekaterina Rogaeva), University of Toronto, Canada; Department of Biotechnology (B.R.), Jožef Stefan Institute, Ljubljana, Slovenia; Division of Neurology V and Neuropathology (G.R., F.T.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Alzheimer's Disease and Other Cognitive Disorders Unit (R.S.-V.), Hospital Clínic of Barcelona, Spain; Clinical Memory Research Unit, Department of Clinical Sciences Malmö (C.N., A.F.S.), and Division of Clinical Sciences Helsingborg, Department of Clinical Sciences Lund (M.L.W.), Lund University, Sweden; Neurodegenerative Brain Diseases Group (J.V.d.Z., C.V.B.), Center for Molecular Neurology, VIB, Antwerp, Belgium; Medical Research Council Centre for Neuropsychiatric Genetics and Genomics (V.E.-P.), Division of Psychological Medicine and Clinical Neurosciences and Dementia Research Institute, Cardiff University, UK; Instituto de Investigación Sanitaria del Principado de Asturias (V.A.), Oviedo, Asturias; Fundació per la Recerca Biomèdica i Social Mútua Terrassa (I.A., M.D.-F., P.P.), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (M.B., J.C., O.D.-I., I.H., I.I.-G., A.L., S.M.-G., Agustín Ruiz), Instituto de Salud Carlos III, Madrid, Spain; MRC Cognition and Brain Sciences Unit (Lucy Bowns, T.E.C., J.B.R.), Cambridge University, UK; Department of Neuromedicine and Movement Science (Geir Bråthen, S.B.S.), Norwegian University of Science and Technology, Trondheim, Norway; Unit for Hereditary Dementias (H.-H.C., C.G., B.K., L.Ö.), Theme Aging, Karolinska University Hospital, Solna, Sweden; Medical Faculty (D.F., M.G.K.), University of Ljubljana, Slovenia; Fondazione IRCCS Ca'Granda (D.G., Elio Scarpini, M.S.), Ospedale Policlinico, Milan, Italy; Penn Center for Frontotemporal Degeneration (Murray Grossman), Philadelphia, PA; Universidad de Oviedo (M.M.-G.), Asturias, Spain; IRCCS Fondazione Don Carlo Gnocchi (B.N., S.S.), Florence; Istituto di Medicina Genomica (V.N.), Università Cattolica del sacro Cuore, Rome, Italy; Amsterdam Neuroscience (Y.A.L.P.), the Netherlands; Department of Medicine and Surgery (A.A.P.), University of Salerno, Baronissi (SA), Italy; Faculty of Chemistry and Chemical Technology (B.R.), University of Ljubljana, Slovenia; Institud d'Investigacions Biomèdiques August Pi i Sunyer (R.S.-V.), Barcelona, Spain; Department of Biomedical Sciences (J.V.d.Z., C.V.B.), University of Antwerp, Belgium; and Department of Comparative Biomedical Sciences (P.A.L.), The Royal Veterinary College, London, UK.

Objective: We sought to characterize expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.

Methods: We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions.

Results: We found pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [ = 2.17 × 10; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [ = 1.1 × 10; OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy.

Conclusions: Our results indicate correlation between pathogenic expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.
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http://dx.doi.org/10.1212/WNL.0000000000010914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836664PMC
December 2020

Association between retinal thickness and β-amyloid brain accumulation in individuals with subjective cognitive decline: Fundació ACE Healthy Brain Initiative.

Alzheimers Res Ther 2020 03 31;12(1):37. Epub 2020 Mar 31.

Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.

Background: Optical coherence tomography (OCT) of the retina is a fast and easily accessible tool for the quantification of retinal structural measurements. Multiple studies show that patients with Alzheimer's disease (AD) exhibit thinning in several retinal layers compared to age-matched controls. Subjective cognitive decline (SCD) has been proposed as a risk factor for progression to AD. There is little data about retinal changes in preclinical AD and their correlation with amyloid-β (Aβ) uptake.

Aims: We investigated the association of retinal thickness quantified by OCT with Aβ accumulation and conversion to mild cognitive impairment (MCI) over 24 months in individuals with SCD.

Methods: One hundred twenty-nine individuals with SCD enrolled in Fundació ACE Healthy Brain Initiative underwent comprehensive neuropsychological testing, OCT scan of the retina and florbetaben (FBB) positron emission tomography (PET) at baseline (v0) and after 24 months (v2). We assessed the association of sixteen retinal thickness measurements at baseline with FBB-PET status (+/-) and global standardize uptake value ratio (SUVR) as a continuous measure at v0 and v2 and their predictive value on clinical status change (conversion to mild cognitive impairment (MCI)) at v2.

Results: Mean age of the sample was 64.72 ± 7.27 years; 62.8% were females. Fifteen participants were classified as FBB-PET+ at baseline and 22 at v2. Every 1 μm of increased thickness in the inner nasal macular region conferred 8% and 6% higher probability of presenting a FBB-PET+ status at v0 (OR = 1.08, 95% CI = 1.02-1.14, p = 0.007) and v2 (OR = 1.06, 95% CI = 1.02-1.11, p = 0.004), respectively. Inner nasal macular thickness also positively correlated with global SUVR (at v0: β = 0.23, p = 0.004; at v2: β = 0.26, p = 0.001). No retinal measurements were associated to conversion to MCI over 24 months.

Conclusions: Subtle retinal thickness changes in the macular region are already present in SCD and correlate with Aβ uptake.
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http://dx.doi.org/10.1186/s13195-020-00602-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7110730PMC
March 2020

Genetic architecture of neurodegenerative dementias.

Neuropharmacology 2020 05 17;168:108014. Epub 2020 Feb 17.

CIBERNED, Center for Networked Biomedical Research into Neurodegenerative Diseases, Madrid, Spain; Research Center and Memory Clinic, Fundació ACE. Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya (UIC), Barcelona, Spain.

Molecular genetics has been an invaluable tool to help understand the molecular basis of neurodegenerative dementias. In this review, we provide an overview of the genetic architecture underlying some of the most prevalent causes of dementia, including Alzheimer's dementia, frontotemporal lobar degeneration, Lewy body dementia, and prion diseases. We also discuss the complexity of the human genome and how the novel technologies have revolutionized and accelerated the way we screen the variety of our DNA. Finally, we also provide some examples about how this genetic knowledge is being transferred into the clinic through personalized medicine. This article is part of the special issue entitled 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108014DOI Listing
May 2020

Evaluation of macular thickness and volume tested by optical coherence tomography as biomarkers for Alzheimer's disease in a memory clinic.

Sci Rep 2020 01 31;10(1):1580. Epub 2020 Jan 31.

Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain.

Building on previous studies that report thinning of the macula in Alzheimer's disease (AD) and mild cognitive impairment (MCI) patients, the use of optical coherence tomography (OCT) has been proposed as a potential biomarker for AD. However, other studies contradict these results. A total of 930 participants (414 cognitively healthy people, 192 with probable amnestic MCI, and 324 probable AD patients) from a memory clinic were consecutively included in this study and underwent a spectral domain OCT scan (Maestro, Topcon) to assess total macular volume and thickness. Macular width measurements were also taken in several subregions (central, inner, and outer rings) and in layers such as the retinal nerve fiber (RNFL) and ganglion cell (CGL). The study employed a design of high ecological validity, with adjustment by age, education, sex, and OCT image quality. AD, MCI, and control groups did not significantly vary with regard to volume and retinal thickness in different layers. When these groups were compared, multivariate-adjusted analysis disclosed no significant differences in total (p = 0.564), CGL (p = 0.267), RNFL (p = 0.574), and macular thickness and volume (p = 0.380). The only macular regions showing significant differences were the superior (p = 0.040) and nasal (p = 0.040) sectors of the inner macular ring. However, adjustment for multiple comparisons nullified this significance. These results are not supporting existing claims for the usefulness of macular thickness as a biomarker of cognitive impairment in a memory unit. OCT biomarkers for AD should be subject to further longitudinal testing.
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http://dx.doi.org/10.1038/s41598-020-58399-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994670PMC
January 2020

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The [email protected] project.

Alzheimers Dement 2019 10 28;15(10):1333-1347. Epub 2019 Aug 28.

Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain; Department of Surgery, Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain.

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways.

Methods: Genome Research at Fundacio ACE ([email protected]) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, [email protected] series were meta-analyzed with additional genome-wide association study data sets.

Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444.

Discussion: The regulation of vasculature is a prominent causal component of probable AD. [email protected] meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.
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http://dx.doi.org/10.1016/j.jalz.2019.06.4950DOI Listing
October 2019

Genetic markers of lipid metabolism genes associated with low susceptibility to HCV infection.

Sci Rep 2019 06 21;9(1):9054. Epub 2019 Jun 21.

Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Sevilla, Spain.

Due to the relation between lipids and Hepatitis C virus (HCV) life-cycle, we aimed to explore the existence of single nucleotide polymorphisms (SNPs) associated with low susceptibility to HCV-infection within lipid metabolism genes. This was a case-control study in three phases: (I) allelic frequencies of 9 SNPs within 6 genes were compared in 404 HCV-infected patients and 801 population controls; (II) results were validated in 602 HCV-infected individuals and 1352 controls; (III) results were confirmed in 30 HCV-exposed uninfected (EU) individuals. In phase I, only the LDLRAP1-rs4075184-A allele was differentially distributed in patients and controls (358 of 808 alleles [44.3%] and 807 of 1602 alleles [50.3%], respectively) (p = 0.004). In phase II, the A allele frequency was 547 of 1204 alleles (45.4%) in patients and 1326 of 2704 alleles (49.0%) in controls (p = 0.037). This frequency in EU was 36 of 60 alleles (60%), which was higher than that observed in patients from phase I (p = 0.018) and phase II (p = 0.027). The LDLRAP1-mRNA expression was lower in AA carriers than in non-AA carriers (median [Q1-Q3]: 0.85 [0.17-1.75] relative-units [ru] versus 1.71 [1.00-2.73] ru; p = 0.041). Our results suggest that LDLRAP1-rs4075184-A allele is associated with lower susceptibility to HCV-infection and with reduced expression of LDLRAP1-mRNA.
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http://dx.doi.org/10.1038/s41598-019-45389-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588564PMC
June 2019

Visual impairment in aging and cognitive decline: experience in a Memory Clinic.

Sci Rep 2019 06 18;9(1):8698. Epub 2019 Jun 18.

Alzheimer Research Center and Memory Clinic, Fundació ACE Institut Català de Neurociències Aplicades - Universitat Internacional de Catalunya (UIC), Barcelona, Spain.

Visual impairment is common in people living with dementia and regular ophthalmological exams may improve their quality of life. We evaluated visual function in a cohort of elderly individuals and analyzed its association with their degree of cognitive impairment. Participants underwent neurological and neuropsychological exams, neuro-ophthalmological assessment (visual acuity, intraocular pressure, rates of past ophthalmological pathologies, use of ocular correction, treatments and surgeries) and optical coherence tomography (OCT) scan. We analyzed differences in ophthalmological characteristics among diagnostic groups. The final sample of 1746 study participants aged ≥ 50 comprised 229 individuals with Subjective Cognitive Decline (SCD), 695 with mild cognitive impairment (MCI) and 833 with Dementia (Alzheimer disease: n = 660; vascular dementia: n = 92, Lewy body dementia: n = 34; frontotemporal dementia: n = 19 and other: n = 28). Age, gender and education were used as covariates. Patients with Dementia, compared to those with SCD and MCI, presented worse visual acuity (p < 0.001), used less visual correction (p = 0.02 and p < 0.001, respectively) and fewer ophthalmological treatments (p = 0.004 and p < 0.001, respectively) and underwent fewer ocular surgeries (p = 0.009 and p < 0.001, respectively). OCT image quality worsened in parallel to cognitive decline (Dementia vs SCD: p = 0.008; Dementia vs MCI: p < 0.001). No group differences in past ophthalmological disorders or abnormal OCT findings were detected. Efforts should be made to ensure dementia patients undergo regular ophthalmological assessments to correct their visual function in order to improve their quality of life.
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http://dx.doi.org/10.1038/s41598-019-45055-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581941PMC
June 2019

A genome-wide association study on low susceptibility to hepatitis C virus infection (GEHEP012 study).

Liver Int 2019 10 10;39(10):1918-1926. Epub 2019 Jul 10.

Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Sevilla, Spain.

Background: A low proportion of individuals repeatedly exposed to the hepatitis C virus (HCV) remain uninfected. This condition could have a genetic basis but it is not known whether or not it is mainly driven by a high-penetrance common allele.

Objective: To explore whether low susceptibility to HCV infection is mainly driven by a high-penetrance common allele.

Methods: In this genome-wide association study (GWAS), a total of 804 HCV-seropositive individuals and 27 high-risk HCV-seronegative (HRSN) subjects were included. Plink and Magma software were used to carry out single nucleotide polymorphism (SNP)-based and gene-based association analyses respectively.

Results: No SNP nor any gene was associated with low susceptibility to HCV infection after multiple testing correction. However, SNPs previously associated with this trait and allocated within the LDLR gene, rs5925 and rs688, were also associated with this condition in our study under a dominant model (24 out of 27 [88.9%] rs5925-C carriers in the HRSN group vs 560 of 804 [69.6%] rs5925-C carriers in the HCV-seropositive group, P = 0.031, odds ratio [OR] = 3.48; 95% confidence interval [CI] = 1.04-11.58; and 24 out of 27 [88.9%] rs688-T carriers in the HRSN group vs 556 of 804 [69.1%] rs688-T carriers in the HCV-seropositive group, P = 0.028, OR = 3.57, 95% CI = 1.65-11.96).

Conclusions: Low susceptibility to HCV infection does not seem to be mainly driven by a high-penetrant common allele. By contrast, it seems a multifactorial trait where genes such as LDLR could be involved.
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http://dx.doi.org/10.1111/liv.14177DOI Listing
October 2019

A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

Acta Neuropathol 2019 08 27;138(2):237-250. Epub 2019 May 27.

Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.
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http://dx.doi.org/10.1007/s00401-019-02026-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660501PMC
August 2019

GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study.

Sci Rep 2019 05 7;9(1):7013. Epub 2019 May 7.

Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10). One additional genetic locus previously linked to psychosis in Alzheimer's disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10. We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.
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http://dx.doi.org/10.1038/s41598-019-43458-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504850PMC
May 2019

The BDNF SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer's disease.

Mol Psychiatry 2021 02 21;26(2):614-628. Epub 2019 Mar 21.

Fundació ACE, Alzheimer Treatment and Research Center, Barcelona, Spain.

In Alzheimer's disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNF) is associated with worse impact of primary AD pathology (beta-amyloid, Aβ) on neurodegeneration and cognitive decline, rendering BDNF an important modulating factor of cognitive impairment in AD. However, the effect of BDNF on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNF on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNF carriers compared to BDNF homozogytes. BDNF was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNF could be also found in elderly subjects with sporadically occurring Aβ, including a group with subjective cognitive decline (N = 149, FACEHBI study) and a group ranging from preclinical to AD dementia (N = 114, DELCODE study). In both of these independently recruited groups, BDNF was associated with a stronger effect of more abnormal Aβ-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNF is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment.
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http://dx.doi.org/10.1038/s41380-019-0404-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754794PMC
February 2021

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Nat Genet 2019 03 28;51(3):414-430. Epub 2019 Feb 28.

Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya, Barcelona, Spain.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
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http://dx.doi.org/10.1038/s41588-019-0358-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463297PMC
March 2019

Correlations between plasma and PET beta-amyloid levels in individuals with subjective cognitive decline: the Fundació ACE Healthy Brain Initiative (FACEHBI).

Alzheimers Res Ther 2018 11 29;10(1):119. Epub 2018 Nov 29.

Departament de Diagnòstic per la Imatge, Clínica Corachan, Barcelona, Spain.

Background: Peripheral biomarkers that identify individuals at risk of developing Alzheimer's disease (AD) or predicting high amyloid beta (Aβ) brain burden would be highly valuable. To facilitate clinical trials of disease-modifying therapies, plasma concentrations of Aβ species are good candidates for peripheral AD biomarkers, but studies to date have generated conflicting results.

Methods: The Fundació ACE Healthy Brain Initiative (FACEHBI) study uses a convenience sample of 200 individuals diagnosed with subjective cognitive decline (SCD) at the Fundació ACE (Barcelona, Spain) who underwent amyloid florbetaben(F) (FBB) positron emission tomography (PET) brain imaging. Baseline plasma samples from FACEHBI subjects (aged 65.9 ± 7.2 years) were analyzed using the ABtest (Araclon Biotech). This test directly determines the free plasma (FP) and total plasma (TP) levels of Aβ40 and Aβ42 peptides. The association between Aβ40 and Aβ42 plasma levels and FBB-PET global standardized uptake value ratio (SUVR) was determined using correlations and linear regression-based methods. The effect of the APOE genotype on plasma Aβ levels and FBB-PET was also assessed. Finally, various models including different combinations of demographics, genetics, and Aβ plasma levels were constructed using logistic regression and area under the receiver operating characteristic curve (AUROC) analyses to evaluate their ability for discriminating which subjects presented brain amyloidosis.

Results: FBB-PET global SUVR correlated weakly but significantly with Aβ42/40 plasma ratios. For TP42/40, this observation persisted after controlling for age and APOE ε4 allele carrier status (R = 0.193, p = 1.01E-09). The ROC curve demonstrated that plasma Aβ measurements are not superior to APOE and age in combination in predicting brain amyloidosis. It is noteworthy that using a simple preselection tool (the TP42/40 ratio with an empirical cut-off value of 0.08) optimizes the sensitivity and reduces the number of individuals subjected to Aβ FBB-PET scanners to 52.8%. No significant dependency was observed between APOE genotype and plasma Aβ measurements (p value for interaction = 0.105).

Conclusion: Brain and plasma Aβ levels are partially correlated in individuals diagnosed with SCD. Aβ plasma measurements, particularly the TP42/40 ratio, could generate a new recruitment strategy independent of the APOE genotype that would improve identification of SCD subjects with brain amyloidosis and reduce the rate of screening failures in preclinical AD studies. Independent replication of these findings is warranted.
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http://dx.doi.org/10.1186/s13195-018-0444-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267075PMC
November 2018

Exploring Genetic Associations of Alzheimer's Disease Loci With Mild Cognitive Impairment Neurocognitive Endophenotypes.

Front Aging Neurosci 2018 30;10:340. Epub 2018 Oct 30.

Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany.

The role of genetic risk markers for Alzheimer's disease (AD) in mediating the neurocognitive endophenotypes (NEs) of subjects with mild cognitive impairment (MCI) has rarely been studied. The aim of the present study was to investigate the relationship between well-known AD-associated single-nucleotide polymorphisms (SNPs) and individual NEs routinely evaluated during diagnosis of MCI, AD, and other dementias. The Fundació ACE (ACE) dataset, comprising information from 1245 patients with MCI, was analyzed, including the total sample, amnestic MCI (aMCI) ( = 811), and non-amnestic MCI (naMCI) ( = 434). As probable-MCI (Pr-MCI) patients with memory impairment have a higher risk of AD, which could influence the statistical power to detect genetic associations, the MCI phenotype was also stratified into four related conditions: Pr-aMCI ( = 262), Pr-naMCI ( = 76), possible (Pss)-aMCI ( = 549), and Pss-naMCI ( = 358). Validation analyses were performed using data from the German study on Aging, Cognition, and Dementia in primary care patients (AgeCoDe), and the German Dementia Competence Network (DCN). SNP associations with NEs were calculated in PLINK using multivariate linear regression analysis adjusted for age, gender, and education. In the total MCI sample, -ε4 was significantly associated with the memory function NEs "delayed recall (DR)" (β = -0.76, = 4.1 × 10), "learning" (β = -1.35, = 2.91 × 10), and "recognition memory" (β = -0.58, = 9.67 × 10); and with "DR" in the aMCI group (β = -0.36, = 2.96 × 10). These results were confirmed by validation in the AgeCoDe ( = 503) and DCN ( = 583) datasets. -ε4 was also significantly associated with the NE "learning" in individuals classified as having Pss-aMCI (β = -1.37, = 5.82 × 10). Moreover, there was a near study-wide significant association between the locus (rs6448799) and the "backward digits" working memory NE (β = 0.52, = 7.57 × 10) among individuals with Pr-aMCI, while the locus (rs10751667) was significantly associated with the language NE "repetition" (β = -0.19, = 5.34 × 10). Overall, our findings support specific associations of established AD-associated SNPs with MCI NEs.
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http://dx.doi.org/10.3389/fnagi.2018.00340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218590PMC
October 2018

Usefulness of peripapillary nerve fiber layer thickness assessed by optical coherence tomography as a biomarker for Alzheimer's disease.

Sci Rep 2018 11 5;8(1):16345. Epub 2018 Nov 5.

Alzheimer Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.

The use of optical coherence tomography (OCT) has been suggested as a potential biomarker for Alzheimer's Disease based on previously reported thinning of the retinal nerve fiber layer (RNFL) in Alzheimer's disease's (AD) and Mild Cognitive Impairment (MCI). However, other studies have not shown such results. 930 individuals (414 cognitively healthy individuals, 192 probable amnestic MCI and 324 probable AD) attending a memory clinic were consecutively included and underwent spectral domain OCT (Maestro, Topcon) examinations to assess differences in peripapillary RNFL thickness, using a design of high ecological validity. Adjustment by age, education, sex and OCT image quality was performed. We found a non-significant decrease in mean RNFL thickness as follows: control group: 100,20 ± 14,60 µm, MCI group: 98,54 ± 14,43 µm and AD group: 96,61 ± 15,27 µm. The multivariate adjusted analysis revealed no significant differences in mean overall (p = 0.352), temporal (p = 0,119), nasal (p = 0,151), superior (p = 0,435) or inferior (p = 0,825) quadrants between AD, MCI and control groups. These results do not support the usefulness of peripapillary RNFL analysis as a marker of cognitive impairment or in discriminating between cognitive groups. The analysis of other OCT measurements in other retinal areas and layers as biomarkers for AD should be tested further.
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http://dx.doi.org/10.1038/s41598-018-34577-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218495PMC
November 2018

Genome-wide significant risk factors on chromosome 19 and the locus.

Oncotarget 2018 May 15;9(37):24590-24600. Epub 2018 May 15.

Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Univesitat Internacional de Catalunya, Barcelona, Spain.

The apolipoprotein E () gene on chromosome 19q13.32, was the first, and remains the strongest, genetic risk factor for Alzheimer's disease (AD). Additional signals associated with AD have been located in chromosome 19, including (19p13.3) and 19q13.41). The gene has been replicated in most populations. However, the contribution to AD of other signals close to gene remains controversial. Possible explanations for inconsistency between reports include long range linkage disequilibrium (LRLD). We analysed the contribution of and loci to AD risk and explore LRLD patterns across region. To evaluate AD risk conferred by rs4147929:G>A and rs3865444:C>A, we used a large Spanish population (1796 AD cases, 2642 controls). The rs4147929:G>A SNP effect was nominally replicated in the Spanish cohort and reached genome-wide significance after meta-analysis (odds ratio (OR)=1.15, 95% confidence interval (95% CI)=1.12-1.19; = 1.60 x 10). rs3865444:C>A was not associated with AD in the dataset. The meta-analysis was also negative (OR=0.98, 95% CI=0.93-1.04; =0.48). After exploring LRLD patterns between and in several datasets, we found significant LD (D' >0.20; <0.030) between -Ɛ2 and rs3865444C>A in two of five datasets, suggesting the presence of a non-universal long range interaction between these loci affecting to some populations. In conclusion, we provide here evidence of genetic association of the locus in the Spanish population and also propose a plausible explanation for the controversy on the contribution of to AD susceptibility.
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http://dx.doi.org/10.18632/oncotarget.25083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973862PMC
May 2018

Exploring APOE genotype effects on Alzheimer's disease risk and amyloid β burden in individuals with subjective cognitive decline: The FundacioACE Healthy Brain Initiative (FACEHBI) study baseline results.

Alzheimers Dement 2018 05 20;14(5):634-643. Epub 2017 Nov 20.

Departament de Diagnòstic per la Imatge, Clínica Corachan, Barcelona, Spain.

Introduction: Subjective cognitive decline (SCD) has been proposed as a potential preclinical stage of Alzheimer's disease (AD). Nevertheless, the genetic and biomarker profiles of SCD individuals remain mostly unexplored.

Methods: We evaluated apolipoprotein E (APOE) ε4's effect in the risk of presenting SCD, using the Fundacio ACE Healthy Brain Initiative (FACEHBI) SCD cohort and Spanish controls, and performed a meta-analysis addressing the same question. We assessed the relationship between APOE dosage and brain amyloid burden in the FACEHBI SCD and Alzheimer's Disease Neuroimaging Initiative cohorts.

Results: Analysis of the FACEHBI cohort and the meta-analysis demonstrated SCD individuals presented higher allelic frequencies of APOE ε4 with respect to controls. APOE dosage explained 9% (FACEHBI cohort) and 11% (FACEHBI and Alzheimer's Disease Neuroimaging Initiative cohorts) of the variance of cerebral amyloid levels.

Discussion: The FACEHBI sample presents APOE ε4 enrichment, suggesting that a pool of AD patients is nested in our sample. Cerebral amyloid levels are partially explained by the APOE allele dosage, suggesting that other genetic or epigenetic factors are involved in this AD endophenotype.
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http://dx.doi.org/10.1016/j.jalz.2017.10.005DOI Listing
May 2018

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.

Nat Genet 2017 09 17;49(9):1373-1384. Epub 2017 Jul 17.

Boston University School of Medicine, Boston, Massachusetts, USA.

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10, odds ratio (OR) = 0.68, minor allele frequency (MAF) = 0.0059, MAF = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10, OR = 1.43, MAF = 0.011, MAF = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10, OR = 1.67, MAF = 0.0143, MAF = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
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http://dx.doi.org/10.1038/ng.3916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669039PMC
September 2017

Impact of Recruitment Methods in Subjective Cognitive Decline.

J Alzheimers Dis 2017 ;57(2):625-632

Alzheimer Research Center and Memory Clinic of Fundació ACE, Institut Catalá de Neurociències Aplicades, Barcelona, Spain.

Background: Recruitment methods can determine sample characteristics in mild cognitive impairment and Alzheimer's disease dementia, but little is known about its influence in subjective cognitive decline (SCD).

Objective: To determine the influence of two types of recruitment methods in the characteristics of individuals with SCD.

Methods: We select and compare clinical and neuropsychological features, and frequency of APOE ɛ4 allele of 326 subjects with SCD from two cohorts: Open House Initiative (OHI) versus Memory Unit (MU). A logistic regression analysis (LRA), using gender and years of education as covariates, was used to examine the neuropsychological variables.

Results: The OHI sample were mostly women (75.9% versus 64.5%, p < 0.05), with higher educational level (12.15 [3.71] versus 10.70 [3.80] years, p = 0.001), and more family history of dementia (138 [62.7%] versus 44 [41.5%], p < 0.001) than the MU sample. Also, the OHI sample showed better overall neuropsychological performance than the MU sample, and after a LRA, this trend continued in automatic response inhibition capacity, abstract reasoning, and recognition memory. We did not find differences in age, depression history, and/or APOE ɛ4 allele frequency.

Conclusion: SCD subjects showed different demographic and neuropsychological characteristics depending on the recruitment method, which should be taken into account in the design of research studies with this target population.
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http://dx.doi.org/10.3233/JAD-160915DOI Listing
February 2018
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