SYNAPTONEMAL COMPLEX PROTEIN 2 LIKE GENE PROTECTS AGAINST HIPPOCAMPAL ATROPHY AND MEMORY DECLINE

Abstract

Alzheimer's disease is characterized by progressive neurodegeneration and cognitive impairment, with early focal atrophy observed in the hippocampus. While hippocampal volume has been estimated to be 40–60% heritable, very little is known about the genetic drivers of hippocampal volume across the spectrum of normal aging and Alzheimer's disease. The current project sought to identify novel genetic drivers of hippocampal volume using a predicted gene expression model within the ADNI dataset. Participants with normal cognition (n=254, NC), mild cognitive impairment (n=430, MCI) and Alzheimer's disease (n=124, AD) were drawn from the Alzheimer's Disease Neuroimaging Initiative. Gene expression in the hippocampus was imputed using the PrediXcan method, which builds multi- single nucleotide polymorphism (SNP) predictors of gene expression from an expression quantitative trait loci database (GTExPortal.org) and applies those predictors using the genotypes within the sample of interest. We imputed all genes that were strong predicted in GTEx (R2>0.05, p<0.01) for a total of 2495 genes. Predicted gene expression was then related to total hippocampal volume using linear regression adjusting for age, sex, education, APOE, and intracranial volume (corrected α=2.0x10-5). Post-hoc analyses evaluated the association between identified hits and memory performance. Higher levels of predicted expression of the Synaptonemal Complex Protein 2 Like (SYCP2L) gene in the hippocampus was strongly associated with larger hippocampal volume at baseline (β=522, p=9.1x10-6) and showed a modest association with a slower rate of hippocampal atrophy (β=40, p=0.010). These associations were strongest among individuals with MCI. In post hoc analyses, SYCP2L was not associated with baseline memory performance (p=0.69), but was associated with a slower rate of longitudinal memory decline (β=0.10, p=0.005) particularly among individuals with NC and MCI (p-values<0.05). Genetically determined levels SYCP2L expression in the hippocampus are associated with large hippocampal volumes at baseline, slower rates of hippocampal atrophy, and slower rates of longitudinal cognitive decline. Results suggest that SYCP2L may serve a neuroprotective role in the hippocampus during aging and neurodegeneration, perhaps through alterations in DNA replication or chromosomal segregation through the synaptonemal complex.