Evaluation of CD33 as a genetic risk factor for Alzheimer’s disease

Abstract

In 2011, genome wide association studies implicated a polymorphism near CD33 as a genetic risk factor for Alzheimer's disease. This finding sparked interest in this member of the sialic acidbinding immunoglobulin-type lectin family which is linked to innate immunity. Subsequent studies found that CD33 is expressed in microglia in the brain and then investigated the molecular mechanism underlying the CD33 genetic association with Alzheimer's disease. The allele that protects from Alzheimer's disease acts predominately to increase a CD33 isoform lacking exon 2 at the expense of the prototypic, full-length CD33 that contains exon 2. Since this exon encodes the sialic acid ligand binding domain, the finding that loss of exon 2 was associated with decreased Alzheimer's disease risk was interpreted as meaning that a decrease in functional CD33 and its associated immune suppression was protective from Alzheimer's disease. However, this interpretation may need to be reconsidered given current findings that a genetic deletion which abrogates CD33 is not associated with Alzheimer's disease risk. Therefore, integrating currently available findings leads us to propose a model wherein the CD33 isoform lacking the ligand binding domain represents a gain of function variant that reduces Alzheimer's disease risk.

Association of CD33 rs3865444:C˃A polymorphism with a reduced risk of late‐onset Alzheimer's disease in Slovaks is limited to subjects carrying the APOE ε4 allele

“…On the other hand, no influence of APOE ε4 status on association between CD33 rs3865444 and LOAD could be found in several other European (Naj et al, 2011), Canadian (Omoumi et al, 2014), Chinese (Deng et al, 2012), Korean (Chung et al, 2013) and Colombian (Moreno et al, 2017) studies, suggesting the existence of a heterogeneity in APOE × CD33 interactions across different populations. pro-inflammatory cytokine production (Crocker et al, 2007;Estus et al, 2019). Hence, CD33 plays an important role in AD pathogenesis by inhibiting Aβ42 uptake by microglial cells and promoting its deposition and plaque formation (Griciuc et al, 2013).…”

“…Hence, the decreased expression of a functional full-length CD33 in rs3865444 A allele carriers is likely to protect from AD via enhanced clearance of Aβ and reduced accumulation of neuritic amyloid pathology (Bradshaw et al, 2013;Griciuc et al, 2013;Raj et al, 2014). An alternative hypothesis for the protective effect of rs3865444 A allele has been recently proposed, suggesting that D2-CD33 represents a gain of function variant in which the loss of the IgV domain allows D2-CD33 to cluster in a novel conformation and constitutively act as an immunoreceptor tyrosine-based activation motif (ITAM) to activate microglial function and Aβ clearance (Estus et al, 2019).…”

Novel Alzheimer’s disease risk genes: exhaustive investigation is paramount

“…The review cluster in this issue of Acta Neuropathologica provides detailed discussions of three of these AD risk genes (SORL1, CD33 and ABCA7) for which significant advances have been made in identifying genetic variants that directly modulate Alzheimer's disease risk [3][4][5]. A fourth paper gives a bird's-eye view of the new genetic landscape of AD, and uses recent experimental evidence on AD genes to give a different interpretation of the GWAS data in the shape of a new model of AD pathogenesis [6].…”

“…While neither rare variants in SORL1 nor in ABCA7 can account for the GWAS association signals at these loci, common functional polymorphisms explaining the GWAS signals in ABCA7 as well as in CD33 have been identified, as reviewed [4,5]. In ABCA7, a common protein truncating variant caused by a large deletion explains the GWAS association signal in African Americans, and a pathogenic repeat expansion explains the GWAS association signal in Europeans (reviewed in Ref.…”

“…This observation has led to the formulation of a loss of function hypothesis for CD33 in AD risk. In their review, however, Estus and colleagues propose a new gain of function hypothesis based on recent experimental evidence [4]. While additional evidence will be required to reconcile all existing data in this new model, progress on CD33 exemplifies that in silico pathwaybased analyses that lack this level of detail are unlikely to accurately approximate the pathogenesis of AD.…”