Potentially Heritable Biomarkers of Neurodegeneration in a Marmoset Model of Alzheimer's Disease

Alzheimer's disease (AD) is the most common global cause of dementia, with no real cure available. Despite extensive genetic findings from large-scale genetic associations and similar studies, our understanding of AD is largely hindered by its long, asymptomatic progression with limited access to human brain tissue. Animal models like the marmoset allow for longitudinal analysis of disease by enabling the assaying of disease-specific phenotypes that mimic human pathophysiology. Here, we have analyzed the genetic associations with disease biomarkers in a cohort of wild type and PSEN1 C410Y mutant marmosets of varying age. Whole genome sequencing was carried out for a cohort of largely wild-type and a few PSEN1 mutant carriers (N = 100). Disease associated plasma biomarkers were measured to assess for the progression of neurodegeneration. The correlation structure underlying collected biomarkers and related phenotypes was calculated, separating for sex. Composite phenotypes were computed by extracting the principal component explaining the most variance for biomarkers of interest, and genetic associations assessed via tools implementing a linear mixed model for composite and individual phenotypes while adjusting for kinship. Females showed greater correlations compared to males between biomarkers specific to neurodegeneration, like total tau (tTau) and neurofilament light protein (NfL), in addition to the levels of the marker of astrocytic activation GFAP with the beta-amyloid peptides containing 40 and 42 amino acids. A statistically significant positive correlation of NfL with age was observed only in males. Many SNPs were found to be associated with the biomarkers under study in our genome-wide scans, and their identity and functional impacts are currently being investigated. Correlations between AD-relevant biomarkers in marmosets exceeded those observed in humans, which were not explained by age. This suggests a strong potential genetic contribution. Leveraging possible heritable associations with disease markers discovered in the marmosets to explain the progression of neurodegeneration could directly provide insights into human AD biology from a genetic point of view.