Original article On the lack of a clear-cut association between alpha-2-macroglobulin deletion and the risk of Alzheimer disease in Poland

Abstract

A b s t r a c t Alzheimer disease (AD) is a complex, multi-factorial disease with the potential involvement of several genes. Alpha-2-macroglobulin (A2M) has been implicated in AD on the basis of its ability to mediate the clearance and degradation of β-amyloid peptide. Nevertheless, it is not clear whether there are racial differences in frequency of polymorphisms of A2M in AD. We examined a group of 50 unrelated patients from Poland (38 women and 12 men), who were diagnosed clinically as probably developing AD (according to the N1NCD3 -ADR PA criteria). The patients were examined by a neurologist and a psychologist and had a CT or MRI scan of the brain. Fifty individuals of matched age, withoutany signs of dementia, were studied as a control group. DNA was extracted by a routine method from a blood sample. Amplification and genotyping at A2M was performed as described by Blacker et al. (1997). The genotypic distribution in A2M exon 18 in patients with AD and genotype TT in A2M exon 24 was similar to that in the controls. Significant differences were noted only in early onset AD in males and for old onset disease in females. The deletions were found more frequently in AD; however, they were found in only a small proportion of studied patients. These findings indicate that A2M is not the only biological candidate gene for AD determination.

Alpha 2-Macroglobulin Polymorphisms and Susceptibility to Alzheimer’s Disease: A Comprehensive Meta-Analysis Based on 62 Studies

“…Significant heterogeneity at different levels between studies was found in all genetic contrasts in combined population or in several subgroups with the exception of male and early-onset AD groups (data not shown). After excluding studies with deviation from HWE [15,40,69,74,75], the heterogeneity decreased significantly or disappeared in combined population or subgroups. The final relationship between this polymorphism and AD remained unchanged (data not shown) in all genetic comparisons.…”

“…The sensitivity analyses were performed after removing the aforementioned specific studies, such as studies with NOS scores < 7 [18,46], studies being not in HWE [15,40,69,74,75], studies with zero in frequency for genotype distribution [59,63], studies with all samples from neuropathological diagnosis [46], or studies with samples from the mixed neuropathological and clinical diagnoses [28,34,50,53]. The final results were not altered in all comparisons except for female group, in which, the analysis demonstrated a significant association of II homozygote and V allele with AD risk after excluding studies with samples from mixed neuropathological and clinical diagnosis [50] (For II: OR, 95%CI: 0.43, 0.26-0.73, pFDR = 0.003 and for V: OR, 95%CI: 2.15, 1.38-3.35, pFDR = 0.0024) (Supplementary Figures 1 and 2).…”

Neuroprotective Function of Non-Proteolytic Amyloid-β Chaperones in Alzheimer’s Disease

“…α2M decreases with age and its clearance mechanisms for Aβ get impaired [57]. A2M gene polymorphisms are associated with sporadic AD in some populations and α2M is also present in amyloid plaques [58]. ApoE isoforms E2, E3 and E4 can delay amyloid aggregation through differential activity as extracellular chaperones [59].…”