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BACKGROUND: Over the past two decades, the APOE gene and its polymorphisms have been among the most studied risk factors of Alzheimer disease (AD) development; yet, there are discrepancies between various studies regarding their impact. For this reason, the evaluation of the APOE genotype has not been included in the current European Federation of Neurological Societies guidelines for AD diagnosis and management. This aim of this study was to add to this discussion by assessing the possible influence of multiple polymorphisms in the promoter region of the APOE gene and genotypes of its allele E on the risk for dementia. METHODS: We performed a comprehensive analysis of APOE gene polymorphisms, assessed the detected genotypes and correlated molecular findings with serum apolipoprotein E concentrations. The study comprised 110 patients with AD and 110 age-matched healthy individuals from the Polish population. RESULTS: Four polymorphisms of the APOE gene had minor allele frequency exceeding 5% and were included in the analysis: -491A/T (rs449647), -427T/C (rs769446), -219T/G (rs405509) in the promoter region and +113G/C (rs440446) in intron 1. A protective effect of the -219G allele on AD development was observed. Also, the -491T and -219G alleles were found to be underrepresented in the carriers of the APOE E4 variant. On the basis of the genotype and linkage disequilibrium studies, a relative score was attributed to given genotypes with respect to the estimated probability of their protective effects against AD, giving rise to the 'preventive score'. This 'preventive score', based on the total sums of the relative scores, expresses the protective effect deriving from the synergistic action of individual single-nucleotide polymorphisms. The 'preventive score' was identified as an independent predictive factor. CONCLUSIONS: We propose a novel, more complex approach to AD risk assessment based on the additive effect of multiple polymorphic loci within the APOE promoter region, which on their own may have too weak an impact to reach the level of significance. This has potentially practical implications, as it may help to improve the informative potential of APOE testing in a clinical setting. Subsequent studies of the proposed system in large, multi-ethnic cohorts are necessary for its validation and to assess its potential practical value for clinical applications.

Original publication




Journal article


Alzheimers Res Ther

Publication Date





APOE, APOE promoter polymorphisms, Alzheimer’s disease, Apolipoprotein E isoforms, Risk factor, Aged, Aged, 80 and over, Algorithms, Alzheimer Disease, Apolipoproteins E, Female, Gene Frequency, Haplotypes, Humans, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Risk Assessment