These findings provide new insights into the neural mechanisms underlying the influence of the CD33 genotype on cognitive performance and highlight the importance of precise therapeutic strategies for high-risk AD populations.
A single nucleotide polymorphism (SNP) in exon 2 of the CD33 gene is associated with reduced susceptibility to late-onset Alzheimer's disease (AD) and causal for elevated mRNA lacking exon 2.
Moreover, genome-wide association studies have linked variants in several immune genes, such as TREM2 and CD33, the expression of which in the brain is restricted to microglia, with cognitive dysfunctions in LOAD.
The cluster of differentiation 33 (CD33) has been proved as a susceptibility locus associated with late-onset Alzheimer's disease (LOAD) based on recent genetic studies.
Thus, the present work aimed to assess the involvement of CD33 (rs3865444), ABCA7 (rs3764650), CR1 (rs6656401), and MS4A6A (rs610932) with LOAD in a sample from southeastern Brazil.
The association of variants in CLU, CR1, PICALM, BIN1, ABCA7, and CD33 genes with late-onset Alzheimer's disease (LOAD) was evaluated and confirmed through genome-wide association study.
Finally, we found rs6656401-rs3865444 (CR1-CD33) pairs were significantly associated with decreasing LOAD risk, while rs28834970-rs6656401 (PTK2B-CR1), and rs28834970-rs6656401 (PTK2B-CD33) were associated with increasing LOAD risk.
Reported odds ratios and population attributable fractions (PAF) for late-onset Alzheimer's disease (LOAD) risk loci (BIN1, ABCA7, CR1, MS4A4E, CD2AP, PICALM, MS4A6A, CD33, and CLU) come from clinically ascertained samples.
Leading examples, such as the CD33 polymorphism associated with late-onset Alzheimer's disease, are well supported by genetic replication and mechanistic studies, while some others (such as SIGLEC8 polymorphism associated with bronchial asthma and SIGLEC14 polymorphism associated with exacerbation of chronic obstructive pulmonary disease) may benefit reinforcement by independent genetic replication or mechanistic studies.
In addition to apolipoprotein E (APOE), recent large genome-wide association studies (GWASs) have identified nine other genes/loci (CR1, BIN1, CLU, PICALM, MS4A4/MS4A6E, CD2AP, CD33, EPHA1 and ABCA7) for late-onset Alzheimer's disease (LOAD).