SPARCL1 ACCELERATES SYMPTOM ONSET IN ALZHEIMER’S DISEASE AND INFLUENCES BRAIN STRUCTURE AND FUNCTION DURING AGING

Abstract

Recent evidence indicates that the expression of SPARCL1, an astrocyte-secreted synaptogenic protein, is dysregulated in Alzheimer's disease (AD). However, the precise relationship between altered SPARCL1 expression and AD pathogenesis remains unclear. Here, we examined associations between single nucleotide polymorphisms (SNPs) in the SPARCL1 gene and several AD-related endophenotypes, including rates of brain atrophy, trajectories of cognitive performance, and longitudinal changes in resting-state regional cerebral blood flow (rCBF), in the Baltimore Longitudinal Study of Aging (BLSA). We first identified SPARCL1 SNPs associated with altered gene expression of SPARCL1 in the brain (GTEx: http://www.gtexportal.org/home/). We selected two variants, rs9998212 and rs7695558, that are associated with reduced gene expression in the hippocampus and frontal cortex, respectively (Broad Institute SNP Annotation and Proxy Search: http://archive.broadinstitute.org/mpg/snap/ldsearchpw.php). In the BLSA neuroimaging substudy (BLSA-NI), we compared longitudinal changes in brain volumes (MRI; n=120 participants; 56–85 years old; number of scans= 826) and rCBF (measured by 15O - water PET; n=81 participants; 56–85 years old; number of scans= 664) in cognitively normal participants between carriers and non-carriers of the SPARCL1 minor alleles. We then analyzed longitudinal changes in cognitive performance of 591 participants who remained cognitively normal (mean age at first assessment: 61 years; range: 45–93 years) and 129 subjects who eventually developed MCI or AD (mean age at first assessment: 73 years; range: 59–89 years), comparing minor allele carriers versus non-carriers. Both SPARCL1 SNPs were associated with longitudinal changes in rCBF in several brain regions, including those vulnerable to AD pathology (e.g., inferior temporal cortex and precuneus). Furthermore, SPARCL1 SNP rs9998212 was associated with widespread and significantly faster rates of brain atrophy in cognitively normal individuals. Lastly, in participants who developed incident MCI or AD, SPARCL1 SNP rs7695558 was associated with faster memory decline prior to disease onset. These findings suggest that SPARCL1 may influence the early stages of AD pathogenesis through widespread effects on brain structure and function. These biological actions may be mediated through its role in synaptic repair during neuronal injury in AD.