To evaluate the impact of Single Nucleotide Polymorphisms (SNP) related to genes playing a role in vesicular transport on early onset Alzheimer’s disease (EOAD).

Multiple lines of evidence suggests that defects in vesicular transport and trafficking contribute to the pathology of many neurodegenerative diseases such as Alzheimer's Disease (AD). It is less clear if and how these contribute to age of onset of AD.

We queried the Alzheimer's Disease Genetics Consortium data within the latest Haplotype Reference Consortium data (HRC). We curated a list of 209 genes in the ClinGen database, related to vesicle-mediated transport as defined by their Gene Ontology annotations that identified 1,358 SNPs as pathogenic, of which 61 were present in the HRC-imputed dataset (4% of all requested variants). 10,540 (28.9%) HRC-imputed subjects had age at onset data documented and among them 4680 (44.4%) subjects also had SNP information. Using a logistic regression model adjusting for sex and APOEε4 status the odds of EOAD was assessed for combinations of curated SNPs.

Any additive combination of 3 vesicular transport related SNPs (3 hits) in the same subject was noted to significantly decrease EOAD odds, even after taking into account APOE ε4 status and sex. The significant β coefficients for Intercept (-1.83), APOE ε4 (0.57), Sex (-0.22), 3SNPs (-0.26) had p values <0.0001, 0.007, 0.03 and Odds ratios of 1.8, 0.8 and 0.77 respectively.    Looking closely into the identity of the SNPs contributing to above result, 12 of the 61 SNPs accounted for 99% of available vesicular transport SNPs in the cohort. Interestingly, among them rs78655421 (CFTR) on its own significantly increases EOAD odds (β 0.69, p=0.02 and OR 2.0) comparable to APOE ε 4

SNPs related to vesicular transport related genes impact odds of EOAD