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INTRODUCTION: CD33 rs3865444 and hypertension (HTN) are related to cognitive impairment, individually. However, little is known about their combined effects on cognitive function in older adults. METHODS: This population-based study included 4368 dementia-free participants (age ≥65 years) in the Multimodal Interventions to Delay Dementia and Disability in Rural China (MIND-China), with data available in 1044 persons for gray matter volume and 85 persons for cerebral blood flow (CBF). We used general linear regression and mediation models to examine the associations of rs3865444 and HTN with cognition, brain atrophy, and CBF. RESULTS: Among rs3865444 CC carriers, HTN and late-life HTN were significantly associated with impaired cognition. Midlife and late-life HTN were correlated with brain atrophy. CD33 rs3865444 CC moderated the mediation effect of gray matter volume on the association between HTN and global cognition. HTN was correlated with low CBF in rs3865444 CC carriers. DISCUSSION: There are synergistic associations of CD33 rs3865444 and HTN with brain and cognitive aging in dementia-free older adults.

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BACKGROUND: We sought to examine the associations of the Lifestyle for Brain Health (LIBRA) index with cognitive function among rural Chinese older adults and to explore the potential role of cluster of differentiation 33 gene (CD33) in the associations. METHODS: This population-based cross-sectional study included 4914 dementia-free participants (age ≥60 years; 56.43 % women) in the 2018 baseline examination of MIND-China. The LIBRA index was generated from 11 factors. We used a neuropsychological test battery to assess episodic memory, verbal fluency, attention, executive function, and global cognition. The CD33(rs3865444) polymorphism was detected using multiple-polymerase chain reaction amplification. Data were analyzed using the general linear regression models. RESULTS: A higher LIBRA index was associated with multivariable-adjusted ß-coefficient (95 %CI) of -0.011(-0.020- -0.001) for global cognitive z-score, -0.020(-0.033- -0.006) for episodic memory, and -0.016(-0.029- -0.004) for verbal fluency. The CD33(rs3865444) was associated with a lower global cognitive z-score in the additive (CA vs. CC: ß-coefficient=0.042; 95 %CI=0.008-0.077), the dominant (CA+AA vs. CC: 0.040; 0.007-0.073), and the over-dominant (CA vs. CC+AA: 0.043; 0.009-0.077) models. Similar results were obtained for verbal fluency and attention. The CD33 gene showed statistical interactions with LIBRA index on cognitive function (Pinteraction<0.05) such that a higher LIBRA index was significantly associated with lower z-scores of global cognition and attention only among CD33 CC carriers (P < 0.05). CONCLUSIONS: This population-based study reveals for the first time that a higher LIBRA index is associated with worse cognitive performance in rural Chinese older adults and that CD33 gene could modify the association.

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BACKGROUND: Microglial activation is considered to assume a role in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). To date, the relationship between ALS and the rs3865444 polymorphism of the cluster of differentiation 33 (CD33) has not been explored. The current report aimed to investigate the potential connection between CD33 rs3865444 and ALS. METHODS: Patients diagnosed with sporadic ALS according to the revised El Escorial criteria, as well as age and sex matched community controls, were enrolled. Two evenly numbered, age and sex matched groups of 155 participants each were genotyped. RESULTS: No association was found between rs3865444 and ALS [log-additive odds ratio (OR) = 0.83 (0.57, 1.22), over-dominant OR = 0.86 (0.55, 1.36), recessive OR = 0.73 (0.25, 2.17), dominant OR = 0.82 (0.52, 1.29), co-dominant OR1 = 0.68 (0.23, 2.05) and co-dominant OR2 = 0.84 (0.53, 1.33)]. Moreover, no relationship was established between rs3865444 and the age of ALS onset based on both unadjusted and sex adjusted Cox-proportional hazards models. Finally, no association between rs3865444 and ALS was found in subgroup analyses based on the site of ALS onset (bulbar or spinal) and sex. CONCLUSIONS: The current analysis is the first to report that rs3865444 is not linked to ALS. Larger multi-racial studies are required to confirm these findings.

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Polymorphisms in genes encoding receptors that modulate the activity of microglia and macrophages are attractive candidates for participation in genetic susceptibility to multiple sclerosis (MS). The aims of the study were to (1) investigate the association between Alzheimer's disease-linked variant rs3865444:C>A in the CD33 gene and MS risk, (2) assess the effect of the strongest MS risk allele HLA-DRB1*15:01 on this association, and (3) analyze the correlation of rs3865444 with selected clinical phenotypes, i.e., age of onset and disease severity. CD33 rs3865444 was genotyped in a cohort of 579 patients and 1145 controls and its association with MS risk and clinical phenotypes was analyzed by logistic and linear regression analysis, respectively. Statistical evaluation revealed that rs3865444 reduces the risk of MS in the HLA-DRB1*15:01-positive subpopulation but not in the cohort negative for HLA-DRB1*15:01. A significant antagonistic epistasis between rs3865444 A and HLA-DRB1*15:01 alleles in the context of MS risk was detected by the interaction synergy factor analysis. Comparison of allele and genotype distribution between relapsing-remitting MS, secondary progressive MS, and control groups revealed that rs3865444 C to A substitution may also be associated with a decreased risk of transition of MS to its secondary progressive form, irrespective of the HLA-DRB1*15:01 carrier status. On the other hand, no correlation could be found between rs3865444 and the age of disease onset or MS severity score. Future studies are required to shed more light on the role of CD33 in MS pathogenesis.

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BACKGROUND: Alzheimer's (AD) and Parkinson's diseases (PD) share a few elements of their clinical, pathological and genetic backgrounds. The CD33 rs3865444 has emerged as a strong genetic locus associated with AD through genome-wide association study (GWAS). However, little is known for its role in PD. OBJECTIVE: To assess the role of CD33 rs3865444 on PD risk. METHODS: We genotyped 358 patients with PD and 358 healthy controls for theCD33 rs3865444. Odds ratios (ORs) with the respective 95% confidence intervals (CIs)], were calculated with the SNPStats software, assuming five genetic models (co-dominant, dominant, recessive, over-dominant and log-additive), with the G allele as the reference allele. RESULTS: The CD33 rs3865444 was associated with decreased PD risk in the dominant [GG vs GT + TT; OR (95% CI) = 0.61 (0.45-0.82), p = 0.001], the over-dominant [GG + TT vs GT; OR (95% CI) = 0.65 (0.48-0.89), p = 0.0061], log-additive [OR (95% CI) = 0.67 (0.52-0.86), p = 0.0014], and co-dominant [with overall p = 0.0043, and OR (95% CI) = 0.62 (0.45-0.84) for the TG genotype compared to the GG], modes of inheritance. CONCLUSIONS: The CD33 rs3865444 is associated with decreased PD risk, and larger studies investigating the role of CD33 rs3865444 on PD are needed.

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BACKGROUND: Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS). Myeloid lineage cells (microglia and macrophages) may participate in the pathogenic mechanisms leading to MS. CD33 is a transmembrane receptor, mainly expressed by myeloid lineage cells. CD33 rs3865444 is a promoter variant previously associated with Alzheimer's disease, whose role in MS remains obscure. OBJECTIVE: To assess the role of CD33 rs3865444 in MS risk. METHODS: We genotyped 1396 patients with MS and 400 healthy controls for the presence of the CD33 rs3865444 variant. Odds ratios (ORs) with the respective 95% confidence intervals (CIs), were calculated with the SNPStats software, assuming five genetic models (co-dominant, dominant, recessive, over-dominant, and log-additive), with the G allele as the reference allele. The value of 0.05 was set as the threshold for statistical significance. RESULTS: CD33 rs3865444 was associated with MS risk in the dominant (GG vs. GT + TT; OR (95% C.I.) = 0.79 (0.63-0.99), p = 0.041) and the over-dominant (GG + TT vs. GT; OR (95% C.I.) = 0.77 (0.61-0.97), p = 0.03) modes of inheritance. Given that the GG genotype was more frequent and the GT genotype was less frequent in MS patients compared to controls-while the observed frequency of the TT genotype did not differ between the two groups-the observed difference in MS risk may be stemming from either the GG (as a risk factor) or the GT (as a protective factor) genotype of CD33 rs3865444. CONCLUSIONS: Our preliminary results suggest a possible contribution of CD33 rs3865444 to MS. Therefore, larger multiethnic studies should be conducted, investigating the role of CD33 rs3865444 in MS.

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