The roles of CD33 and TREM2 in neurodegeneration associated with Alzheimer's disease (AD) and Frontotemporal dementia (FTD)

Frontotemporal dementia (FTD) and Alzheimer's disease (AD) are two multifactorial, heterogeneous and genetically complex neurodegenerative disorders. Despite massive research and drug development efforts, there are still no therapies that slow down or stop their progression. Several genes have been associated with both pathologies, suggesting that an as yet unknown common molecular pathway could exist. Mutations in genes related to neuroinflammation may be predisposing factors in these diseases. Coding and non-coding polymorphisms in genes expressed in microglia, including CD33 and TREM2, are risk factors and could be entry points for therapeutic intervention. Two SNPs in CD33 and one in TREM2 were described to be risk factors associated with Late Onset Alzheimer disease (LOAD). Specifically, CD33 SNPs rs3856444 and rs12459419 in minor alleles were found to confer strong protection while conferring elevated risk of LOAD in major alleles. These SNPs directly modulate the CD33 exon 2 splicing efficiency. In addition, the rare heterozygous missense variant rs75932628-T in TREM2 exon 2 was strongly associated with the ability of TREM2 to activate microglial cells. In order to assess the presence of these polymorphisms in an FTD cohort, we analyzed 216 Caucasians, mean age 60-85 years, diagnosed with LOAD, and 50 age-matched healthy controls. We used High Resolution Melting analysis (HRM) on genomic DNA from the whole blood of patients as a screen for mismatches. We sequenced the DNA from individuals with different melting curves using the Sanger method and used these results as a reference in our analysis. Our patients exhibited the coinheritance of SNPs rs12459419 and rs3865444, being heterozygous in 40%, homozygous for the major allele in 56.48% and homozygous for the minor allele in 3.7% of individuals. In addition, we identified a third SNP in CD33 exon 2, rs2455069, which belongs to a previously identified LD SNP block associated with an increased rate of cognitive decline. We found that all patients analyzed for SNP rs75932628 in the TREM2 gene are homozygous for the wild-type allele. However, some individuals are heterozygous for the nearby SNP rs143332484, which could be potentially associated with AD in our population. Further investigations are in progress to understand the mechanism of action of these two genes.