Genetic dissection of hippocampal sclerosis of ageing using magnetic resonance imaging surrogates

Clàudia Olivé; Itziar de Rojas; Linda Zhang; Óscar Sotolongo‐Grau; Inés Quintela; Pablo García‐González; Raquel Puerta; Fernando García‐Gutiérrez; Laura Montrreal; María Capdevila-Bayo; Andrea Miguel; Josep Blázquez-Folch; Miguel Calero; Alberto Rábano; Ana Belén Pastor; Teodoro del Ser; Miguel Medina; Ángel Carracedo; Alfredo Ramı́rez; Laura Molina‐Porcel; Lluís Tárraga; Amanda C. Cano; Sergi Valero; Marta Marquié; Pascual Sánchez‐Juan; Merçé Boada; Bryan Andrew Strange; María Victoria Fernández; Agustı́n Ruiz

doi:10.1101/2025.03.10.25323307

Genetic & Genomic MedicinemedRxivMar 10, 2025

Preprint

Genetic dissection of hippocampal sclerosis of ageing using magnetic resonance imaging surrogates

Clàudia Olivé iD, Itziar de Rojas iD, Linda Zhang iD, Óscar Sotolongo‐Grau iD, Inés Quintela iD, Pablo García‐González iD, Raquel Puerta iD, Fernando García‐Gutiérrez iD, Laura Montrreal iD, María Capdevila-Bayo, Andrea Miguel iD, Josep Blázquez-Folch iD, Miguel Calero iD, Alberto Rábano iD, Ana Belén Pastor iD, Teodoro del Ser iD, Miguel Medina iD, Ángel Carracedo iD, Alfredo Ramı́rez iD, Laura Molina‐Porcel iD, Lluís Tárraga iD, Amanda C. Cano iD, Sergi Valero iD, Marta Marquié iD, Pascual Sánchez‐Juan iD, , Agustı́n Ruiz iD

Abstract

INTRODUCTIONHippocampal sclerosis of aging (HS-aging) is frequently present in individuals over 85 who die with dementia. Recent studies suggest that some loci associated with Alzheimers disease (AD) may be more related to HS-aging. We aimed to find AD-associated SNPs potentially related to HS-aging. METHODSWe assessed the relation of the AD polygenic risk score (AD-PRS) with hippocampal subfield volumes assessed by magnetic resonance imaging (MRI) as HS-by-proxy in 1,130 non-demented participants. We analyzed 1,708 individuals to associate their AD-PRS (83 variants) with AD alongside HS-aging. RESULTSHS-by-proxy measures of fimbria and hippocampal body and head show association with AD-PRS, SHARPIN, GRN and TNIP1, also after replication. We replicated the stronger AD-PRS association with AD in the presence of HS-aging compared to AD alone. DISCUSSIONResults show association between some AD-SNPs and HS-proxy, enriched in immune-brain axis pathways, differentiating HS-aging from AD. This insight aids in understanding their interrelationships and identifying specific therapeutic targets.

PDF DOI