Abstract
Background: The occurrence of Behavioral and Psychological Symptoms of Dementia (BPSD) in Alzheimer’s Disease (AD) patients hampers the clinical management and exacerbates the burden for caregivers. The definition of the clinical distribution of BPSD symptoms, and the extent to which symptoms are genetically determined, are still open to debate. Moreover, genetic factors that underline BPSD symptoms still need to be identified. Purpose. To characterize our Italian AD cohort according to specific BPSD symptoms as well as to endophenotypes. To evaluate the associations between the considered BPSD traits and COMT, MTHFR, and APOE genetic variants. Methods. AD patients (n = 362) underwent neuropsychological examination and genotyping. BPSD were assessed with the Neuropsychiatric Inventory scale. Results. APOE and MTHFR variants were significantly associated with specific single BPSD symptoms. Furthermore, “Psychosis” and “Hyperactivity” resulted in the most severe endophenotypes, with APOE and MTHFR implicated as both single risk factors and “genexgene” interactions. Conclusions. We strongly suggest the combined use of both BPSD single symptoms/endophenotypes and the “genexgene” interactions as valid strategies for expanding the knowledge about the BPSD aetiopathogenetic mechanisms.
Highlights
The core clinical criteria for Alzheimer’s Disease (AD), the most common neurodegenerative dementing illness, focus on the presence of memory disturbance or other cognitive symptoms that interfere with the ability to function at work or in usual daily activities [1]. cognitive symptoms are the actual hallmark of disease, patients often show a broad range of “non-cognitive” disturbances, more commonly known with the term “Behavioral and Psychological Symptoms of Dementia (BPSD)”
In order to verify the possible degradation, all samples were analyzed on a 0.8% agarose gel electrophoresis and a long Polymerase Chain Reaction (PCR) protocol was developed for exploring genetic variability in Methylene tetrahydrofolate reductase (MTHFR), COMT, and Apolipoprotein E (APOE)
Socio-demographic and clinical features of our Italian AD cohort, as well as the alleles, genotypes, and carriers frequencies of the all polymorphisms in APOE, MTHFR, and COMT genes are shown in Tables 1 and 2
Summary
The core clinical criteria for Alzheimer’s Disease (AD), the most common neurodegenerative dementing illness, focus on the presence of memory disturbance or other cognitive symptoms that interfere with the ability to function at work or in usual daily activities [1]. The Apolipoprotein E (APOE) gene, the main recognized genetic risk factor for late-onset AD (LOAD) (allele ε4) [16], seems to give more consistent results, with the well-known alleles ε4 and ε2 associated with specific BPSD symptoms (for review [10]). The Methylene tetrahydrofolate reductase (MTHFR) gene, whose genetic defects lead to hyperhomocysteinemia, could be a good and new candidate in the aetiopathogenetic mechanisms of BPSD. Within this gene, the two most commonly studied SNPs are the C677T (rs1801133) and the A1298C (rs1801131). In this study we analyzed an Italian cohort of AD patients in order to: 1. define the clinical distribution of BPSD symptoms through the characterization of single BPSD symptoms as well as of endophenotype clusters; 2. confirm and clarify the aetiopathogenetic effect of APOE and COMT variants in relation to both single symptoms and behavioral endophenotypes, selecting functional polymorphisms such as rs429358 (Cys130Arg) and rs7412 (Arg176Cys) and Val108/158Met, respectively [15,16]; 3. evaluate for the first time the putative involvement of MTHFR in single BPSD symptoms and likewise behavioral endophenotypes, selecting functional polymorphisms such as C677T (rs1801133) and the A1298C (rs1801131) [23,24,29,30]; 4. highlight for individual symptoms and endophenotypes a “single gene” involvement and/or a “genexgene” interaction of APOE, COMT, and MTHFR
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