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

BACKROUND : Hippocampal sclerosis of aging (HS-aging) is frequently present in individuals over 85 who die with dementia. Recent studies suggest that some loci associated with Alzheimer’s disease (AD) may be more related to HS-aging. We aimed to find AD-associated SNPs potentially related to HS-aging. METHODS : We used different regression models to assess 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 participants without dementia. We meta-analyzed 1,708 individuals to associate their AD-PRS (83 variants) with AD alongside HS-aging. We also performed co-regulatory network analyses and over-representation enrichment analyses in order to identify biological pathways enriched with co-regulatory networks of genes associated with HS-aging. RESULTS : HS-by-proxy measures of fimbria and hippocampal body and head show association with AD-PRS, SHARPIN , GRN and TNIP1 , also after replication. Our results also show an association of the LUBAC complex with our proxy phenotype. We replicated the stronger AD-PRS association with AD in the presence of HS-aging compared to AD alone. CONCLUSIONS : Results 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.