Linking genomic and proteomic signatures to brain amyloid burden

Alzheimer's disease (AD) is a complex disease with a strong genetic component, yet many genetic risk factors remain unknown. We combined genome-wide association studies (GWAS) on amyloid endophenotypes measured in cerebrospinal fluid (CSF) and positron emission tomography (PET) as surrogates of...

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Autores: Puerta, Raquel|||0000-0002-1191-5893, De Rojas, Itziar|||0000-0002-2148-381X, García-González, Pablo|||0000-0003-0125-5403, Olivé Roig, Clàudia|||0000-0002-9438-5639, Sotolongo Grau, Oscar|||0000-0002-9679-0670, García-Sánchez, Ainhoa, García-Gutiérrez, Fernando, Montrreal Navarro, Laura|||0000-0002-0010-645X, Tartari, Juan Pablo, Sanabria, Ángela|||0000-0002-7501-9895, Pytel, Vanesa, Lage, Carmen|||0000-0003-1703-121X, Quintela, Inés|||0000-0002-0239-7975, Aguilera, Nuria, Rodríguez-Rodríguez, Eloy|||0000-0001-7742-677X, Alarcón-Martín, Emilio|||0000-0002-0985-872X, Orellana del Río, Adelina|||0000-0002-0204-1944, Pastor, Pau|||0000-0002-7493-8777, Pérez-Tur, Jordi|||0000-0002-9111-1712, Piñol-Ripoll, Gerard, Lopez de Munain, Adolfo|||0000-0002-9509-4032, García-Alberca, Jose María|||0000-0003-2951-6644, Royo, Jose Luís, Bullido, María J.|||0000-0002-6477-1117, Alvarez, Victoria|||0000-0002-1916-2523, Real, Luis M.|||0000-0003-4932-7429, Gómez-Garre, Dulcenombre|||0000-0002-5056-6489, Franco-Macías, Emilio|||0000-0003-4186-1037, Mir, Pablo|||0000-0003-1656-302X, Medina, Miguel|||0000-0002-7016-5340, Sanchez-Valle, Raquel|||0000-0001-7750-896X, Dols Icardo, Oriol|||0000-0003-2656-8748, Sáez, María Eugenia|||0000-0001-9299-2534, Carracedo, Ángel|||0000-0003-1085-8986, Tárraga, Lluís|||0000-0002-8423-946X, Valero, Sergi|||0000-0002-6599-948X, Marquié, Marta|||0000-0002-0660-0950, Boada, Mercè|||0000-0003-2617-3009, Cano, Amanda|||0000-0001-9567-4283, Ruiz Laza, Agustín|||0000-0003-2633-2495, Corbatón-Anchuelo, Arturo, Martínez-Larrad, María Teresa, Alegret, Montse, Sánchez-Juan, Pascual|||0000-0002-6081-8037, Cavazos, Jose Enrique, Cabrera-Socorro, Alfredo
Tipo de recurso: artículo
Fecha de publicación:2025
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:dnet:uabarcelona_::07a49065356be0ef3fefe1390aeaa07f
Acceso en línea:https://ddd.uab.cat/record/328493
https://dx.doi.org/urn:doi:10.1007/s10142-025-01581-6
Access Level:acceso abierto
Palabra clave:Aβ42
CSF biomarkers
PET tomography
GWAS
Proteome
Descripción
Sumario:Alzheimer's disease (AD) is a complex disease with a strong genetic component, yet many genetic risk factors remain unknown. We combined genome-wide association studies (GWAS) on amyloid endophenotypes measured in cerebrospinal fluid (CSF) and positron emission tomography (PET) as surrogates of amyloid pathology, which may provide insights into the underlying biology of the disease. We performed a meta-GWAS of CSF Aβ42 and PET measures combining six independent cohorts (n = 2,076). Given the opposite beta direction of Aβ phenotypes in CSF and PET measures, only genetic signals showing opposite directions were considered for analysis (n = 376,599). We explored the amyloidosis signature in the CSF proteome using SOMAscan proteomics (ACE cohort, n = 1,008), connected it with GWAS loci modulating amyloidosis and performed an enrichment analysis of overlapping hits. Finally, we compared our results with a large meta-analysis using publicly available datasets in CSF (n = 13,409) and PET (n = 13,116). After filtering the meta-GWAS, we observed genome-wide significance in the rs429358-APOE locus and annotated nine suggestive hits. We replicated the APOE loci using the large CSF-PET meta-GWAS, identifying multiple AD-associated genes including the novel GADL1 locus. Additionally, we found 1,387 FDR-significant SOMAscan proteins associated with CSF Aβ42 levels. The overlap among GWAS loci and proteins associated with amyloid burden was minimal (n = 35). The enrichment analysis revealed mechanisms connecting amyloidosis with the plasma membrane's anchored component, synapse physiology and mental disorders that were replicated in the large CSF-PET meta-analysis. Combining CSF and PET amyloid GWAS with CSF proteome analyses may effectively elucidate causative molecular mechanisms behind amyloid mobilization and AD physiopathology.

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