Explorative results from multistep screening for potential genetic risk loci of Alzheimer's disease in the longitudinal VITA study cohort.

Alzheimer's disease (AD) is a neurodegenerative disorder that preferentially affects individuals of advanced age. Heritability estimates for AD range between 60 and 80%, but only few genetic risk factors have been identified so far. In the present explorative study, we aimed at characterizing the genetic contribution to late-onset AD in participants of the Vienna Transdanube Aging (VITA) longitudinal birth cohort study in a two-step approach. First, we performed a genome-wide screen of pooled DNA samples (n = 588) to identify allele frequency differences between AD patients and non-AD individuals using life-time diagnoses made at the age of 80 (t = 60 months). This analysis suggested a high proportion of brain-expressed genes required for cell adhesion, cell signaling and cell morphogenesis, and also scored in known AD risk genes. In a second step, we confirmed associations using individual genotypes of top-ranked markers examining AD diagnoses as well as the dimensional scores: FULD and MMSE determined up to the age of 82.5 (t = 90 months). Taken together, our study proposes genes ANKS1B, ENST00000414107, LOC100505811, SLC22A14, QRFPR, ZDHHC8P1, ADAMTS3 and PPFIA1 as possible new candidates involved in the etiology of late-onset AD, with further research being needed to clarify their exact roles.

Investigation of association of serotonin transporter and monoamine oxidase-A genes with Alzheimer's disease and depression in the VITA study cohort: a 90-month longitudinal study.

Alzheimer's disease (AD) and depression (DE) are common psychiatric disorders strongly intertwined with one another. Nevertheless, etiology and early diagnosis of the disorders are still elusive. Several genetic variations have been suggested to associate with AD and DE, particularly in genes involved in the serotonergic system such as the serotonin transporter (SERT/SLC6A4), responsible for the removal from the synaptic cleft, and the monoamine-oxidase-A (MAOA), responsible for the presynaptic degradation of serotonin. Here, we attempt to characterize this pleiotropic effect for the triallelic SERT gene-linked polymorphic region (5HTTLPR) and for the MAOA-uVNTR, in participants in the Vienna-Transdanube-Aging (VITA)-study. The VITA-study is a community-based longitudinal study following a birth cohort (75 years old at baseline examination, n = 606) from Vienna for a period of 90 months with a regular follow-up interval of 30 months. Our main finding, confirming previous reports, is that the 5HTTLPR S-allele is a risk allele for DE (OR = 1.55 CI 95% 1.03-2.32) and its carriers had a steeper increase in SGDS sum score. No association to AD was found. MAOA-uVNTR did not associate with either AD or DE. However, in AD MAOA-uVNTR S-allele carriers a steeper increase of HAMD and STAI1 sum scores (P < 0.05) was observed. Although the VITA-study cohort is rather small with low power to detect gene alterations, the uniqueness of this very thoroughly investigated and homogenous cohort strengthens the results through exceptional data collection. Still, reinvestigation in a larger cohort similar to this, as well as a meta-analysis, is important to confirm these results.

Disorder-specific effects of polymorphisms at opposing ends of the Insulin Degrading Enzyme gene.

BACKGROUND: Insulin-degrading enzyme (IDE) is the ubiquitously expressed enzyme responsible for insulin and amyloid beta (Aß) degradation. IDE gene is located on chromosome region 10q23-q25 and exhibits a well-replicated peak of linkage with Type 2 diabetes mellitus (T2DM). Several genetic association studies examined IDE gene as a susceptibility gene for Alzheimer's disease (AD), however with controversial results. METHODS: We examined associations of three IDE polymorphisms (IDE2, rs4646953; IDE7, rs2251101 and IDE9, rs1887922) with AD, Aß42 plasma level and T2DM risk in the longitudinal Vienna Transdanube Aging (VITA) study cohort. RESULTS: The upstream polymorphism IDE2 was found to influence AD risk and to trigger the Aß42 plasma level, whereas the downstream polymorphism IDE7 modified the T2DM risk; no associations were found for the intronic variant IDE9. CONCLUSIONS: Based on our SNP and haplotype results, we delineate the model that IDE promoter and 3' untranslated region/downstream variation may have different effects on IDE expression, presumably a relevant endophenotype with disorder-specific effects on AD and T2DM susceptibility.

Genetic variation in the choline O-acetyltransferase gene in depression and Alzheimer's disease: the VITA and Milano studies.

Linkage studies point to the long arm of chromosome 10 being a susceptibility region for Alzheimer's disease (AD). Additionally, the gene choline O-acetyltransferase (CHAT) located on chromosome 10 was discussed for conveying risk towards AD, but the results are ambiguous. We examined a possible association of nineteen single-nucleotide polymorphisms (SNPs) in the CHAT gene in a longitudinal cohort study, the Vienna Tansdanube Aging (VITA)-study, in which all subjects were 75 years old at baseline. For replication, we used a more heterogeneous case-control sample from Milano with early and late AD. Nominal allelic and genotypic associations with AD risk in the cross-sectional VITA sample were found for rs3810950 (p = 0.038 for genotype, OR = 1.66 95% CI 1.03-2.68, p = 0.052 allele-wise). When combining both VITA- and Milano study rs3810950 was significantly associated with AD (p(combined) = 0.01634; power = 82%). This association was highly significant for APOEε4 carriers (p = 0.009 for genotype, OR = 3.21 95% CI 1.43-7.19 p = 0.007 allele-wise). Furthermore, an association of rs1880676 with AD was specific to carriers of the APOEε4 risk allele (p = 0.008, genotype; OR = 3.47 95% CI 1.50-8.01 p = 0.005 allele-wise). For depressive symptoms, we found a nominally significant association of rs3810950 with minor and major depression (p = 0.023, genotype; p = 0.008, allele). Applying Benjamini and Hochberg correction these associations could not be confirmed and also not be replicated in the more heterogeneous Milano sample. While our data therefore do not seem to support a major role for CHAT genetic variation in geriatric depression and AD, there might be a minor contribution in geriatric patients with depression and late onset AD, in particular those carrying the APOEε4 genotype.

Association of a functional NOS1 promoter repeat with Alzheimer's disease in the VITA cohort.

NO synthase, type I (NOS-I) has been suggested to play a role in the etiology of Alzheimer's disease (AD). The gene encoding NOS-I harbors at least nine alternative first exons; in the promoter region of exon 1f, a polymorphic repeat (NOS1 ex1f-VNTR) has been described which influences gene expression and neuronal transcriptome. We have shown that short alleles of this repeat are associated with AD. Here, we sought to further explore this finding by investigating a longitudinal cohort sample from the Vienna-Transdanube-Aging (VITA) study consisting of 606 subjects enrolled at the age of 75 (of these, genotypes were available for 574 subjects) and followed up for 60 months. The ex1f-VNTR risk genotype was associated with AD in the total sample and at the second follow-up. Thus, either long alleles of NOS1 ex1f-VNTR are protective against disease or conversely, short alleles predispose to earlier onset of disease. As demonstrated, ex1f-VNTR interacted with the apolipoprotein E ε4 risk allele (OR in the presence of both risk alleles 3.63; 95% CI: 1.45-9.12). These findings provide further evidence for an association of NOS1 with AD.

Genetic risk factors and markers for Alzheimer's disease and/or depression in the VITA study.

OBJECTIVES: In ageing population, both Alzheimer's disease (AD) and depression are common. Significant depressive symptoms are often co-morbid with cognitive impairment and dementia. In this study, we attempted to find various factors and markers for both AD and depression in a longitudinal cohort, the Vienna-Transdanube-Aging (VITA)-study. METHODS: The VITA-Study consisted of 305 healthy subjects, 174 subjects with depression only, 55 subjects diagnosed with AD only and 72 subjects with depression as well as AD. Associations between AD and/or depression to gene polymorphisms APO E (epsilon4), choline acetyltransferase (ChAT) 4G to A, serotonin-transporter gene promoter-length, dopamine-D4-receptor, ciliary-neurotrophic-factor-null mutation and brain-derived neurotrophic factor (C270T) and to various known factors were analyzed. RESULTS: AD and depression were significant associated. Significant risk factors found for AD were low education, low folic acid and depressive-symptoms, while for depression were low education and higher nonsteroidal anti-inflammatory drugs (NSAID) consume. Moreover, the ChAT polymorphism associated significant to depression. Gender, education, and ChAT significantly associated with the combination AD and/or depression. CONCLUSION: Such studies must be conducted cautiously, as co-morbidities and gene-environmental-social influences may sway the results dramatically. We found in the VITA-study significant association between depression and AD and between ChAT polymorphism and depression.

Monoamine oxidase-B inhibition in Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia in late life. There is still no clear-cut consensus whether this disease involves genetic or environmental factors or both. There is a great need to find a way to delay the disease, as delaying the onset of the disease will bring a great relieve on social and medical resources. The monoamine oxidase-B (MAO-B) inhibitors were shown to be effective in treating Parkinson's disease and possibly AD, with concomitant extension of life span. This article gives a short review on MAO-B inhibitors and their mechanism for neuroprotective effects in AD.

Up-regulation of striatal adenosine A(2A) receptors in schizophrenia.

Adenosine A (2A) receptors have been implicated in the pathophysiology of schizophrenia by clinical, anatomical, biochemical and genetic studies. We hypothesized that a genetically determined low number of adenosine A (2A) receptors could be a vulnerability factor for the development of the disease. The density of adenosine A (2A) receptors was investigated in human postmortem striatum of patients with schizophrenia (n = 9) and matched controls ( n= 9) using [ H)CGS 21680 as a radioligand probe. The maximum number of binding sites (B) (max) was 70% higher in patients with schizophrenia than in matched controls (609.4 +/- 259.1 354.0 +/- 156.4 fmol/mg protein, p=0.04). No significant difference could be discerned for the affinity of caffeine for adenosine A receptors between patients and controls. The increase in receptor density correlated with the dose of antipsychotic medication in chlorpromazine equivalents (r =0.61, = 0.014). We failed to provide evidence for a genetically determined reduction of adenosine A 2(A) receptors in schizophrenia. Instead, consistent with findings from animal experiments, our observation supports a role of adenosine A (2A) receptors in the molecular effects of antipsychotic drugs.