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.

The reduced release of GH by GHRH in 8 subjects aged 65-69 years is augmented considerably by rivastigmine, a drug for Alzheimer's disease.

BACKGROUND: The growth hormone (GH) secretion declines by 14% with each decade of adult life. Several attempts have been made to reverse the manifestations of the senile GH deficiency, termed somatopause, but GH substitution treatment in old age has not yet developed an established regimen. Cholinesterase inhibitors like pyridostigmine are able to elicit GH secretion when administered alone and to enhance the GH response to growth hormone releasing hormone (GHRH), but its clinical use is limited due to the strong peripheral cholinergic side effects. OBJECTIVE: The aims of our experiments were to find out whether the GH response to GHRH can be augmented by rivastigmine, a new orally applicable and well-tolerated selective inhibitor of cerebral acetylchoinesterase. METHODS: Eight healthy volunteers (age range 65-69 years) were studied. After an overnight fast, GHRH tests were done: 1 microg/kg GHRH was injected as an intravenous bolus. Blood samples for an immunoradiometric GH assay were taken at the time of GHRH injection (time 0) and after 15, 30, 45, 60, and 120 min. First, the baseline experiment was done: it consisted of two subsequent GHRH tests which were carried out within an interval of 120 min. Four weeks later the rivastigmine experiment was done identically, but 60 min before performing the second GHRH test, rivastigmine (4.5 mg) was administered orally. The GH secretory responses were expressed as areas under the curve (AUC; median, interquartile range), Wilcoxon's signed-rank test was used for statistical comparisons. RESULTS: Baseline experiment: The GH AUC of the first GHRH test was 1040 (range 420-1250) ng/ml/h. The repeated GHRH stimulation after 120 min (second GHRH test) showed a 13-fold decrease to 80 (range 60-130) ng/ml/h. Rivastigmine experiment: The GH AUC of the first GHRH test was 950 (range 540-1430) ng/ml/h and, therefore, similar to that of the baseline experiment. 60 min after ingestion of the single oral dose of rivastigmine (4.5 mg), the following GHRH stimulation (second GHRH test) nearly doubled the GH AUC to 1580 (range 860-3330) ng/ml/h. Comparing the DeltaGH AUC values (DeltaGH AUC = GH AUC of the first GHRH test minus GH AUC of the second GHRH test), baseline experiment versus rivastigmine experiment, there was a 20-fold (p = 0.018) increase in GH AUC after rivastigmine pretreatment. CONCLUSIONS: Rivastigmine is a powerful drug to enhance GH release to repeated GHRH stimulation in healthy elderly human subjects. Future investigations are necessary to find out whether rivastigmine can restore the senile decline of the circadian GH secretion in the long term and, therefore, has new implications for patient treatment.