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.

The relationship between cerebral white matter hyperintensities and lower urinary tract function in a population based, geriatric cohort.

INTRODUCTION: White matter hyperintensities (WHM) in cerebral MRI-scan have been suspected to be involved in the pathogenesis for geriatric LUTS. Aim of this study was to investigate this association in a geriatric cohort. MATERIALS AND METHODS: The VITA-study is a prospective, population-based study initiated 2000/2001. All inhabitants of a well-defined area in Vienna aged 75 years were recruited and underwent detailed regular visits including cerebral MRI-scans. Subcortical and periventricular WMHs were classified according to the Fazekas-classification. In 2010, all subjects alive were contacted to complete the Bristol LUTS questionnaire. RESULTS: Two hundred seventeen participants (75 men, 142 women), all 85 years old, entered this analysis. Urgency, frequency, and nocturia was present in 39 (50.7%), 53 (52%), and 55 (73.3%) men and 79 (55.6%), 81 (78.2%), and 68 (47.9%) women, respectively. OAB symptoms were seen in 55% of women and 50% of men. At baseline, WMH were present in 68.2% and this percentage increased to 85.7% at the most recent follow-up. Several symptoms were more prevalent in participants without WMH as compared to those with WMH, (urgency: 71% vs. 53%, P=0.06, nocturia: 77% vs. 53%, P=0.01: OAB-symptoms: 71% vs. 51%, P=0.05. Only frequency was more prevalent in participants with WMH (77% vs. 68%, P=0.27). In general, sub-categorization into periventricular and subcortical WMH confirmed these data. Furthermore the amount of WMH-burden did not correlate to LUT dysfunction. CONCLUSION: This study failed to demonstrate a clear association between several aspects of LUTS and WMH in a rather healthy, population-based 85-year-old cohort.

Are specific symptoms of depression predictive of Alzheimer's dementia?

OBJECTIVE: To investigate whether specific symptoms of major depression are associated with later development of possible or probable Alzheimer's dementia. METHOD: The analysis is part of the Vienna Transdanube Aging Study, a prospective, community-based cohort study of all 75-year-old inhabitants of 2 Viennese districts. Current depressive symptoms were captured with a DSM-IV-TR-based questionnaire. Diagnosis of possible or probable Alzheimer's dementia was performed according to criteria by the National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association. The baseline sample included 437 not-demented and not previously depressed individuals. At 60-month follow-up, 65 of the remaining 296 subjects had possible or probable Alzheimer's dementia. The primary outcome measure was the probability of diagnosis of Alzheimer's dementia related to baseline depressive symptoms. Baseline data were collected between May 2000 and December 2002; 60-month follow-up data were collected between June 2005 and February 2008. RESULTS: 10.8% of those who were diagnosed with possible or probable Alzheimer's dementia at 60-month follow-up had shown loss of interest versus 2.2% in the nondemented group. The analysis showed a significant association of loss of interest only with the later occurrence of possible or probable Alzheimer's dementia (adjusted P value <.05, OR = 5.27 [95% CI, 1.62-17.2], area under the receiver operating characteristic curve = 0.541). The specificity of this symptom in predicting Alzheimer's dementia was 97.8, and the sensitivity was 10.4. CONCLUSIONS: Of 9 symptoms of depression, only loss of interest was associated with the development of Alzheimer's dementia over a period of 5 years in a sample of 75-year-old not-demented, never-depressed subjects, suggesting that depressive symptoms in the elderly are mostly symptoms of genuine depression.

Lower urinary tract symptoms and urinary incontinence in a geriatric cohort - a population-based analysis.

OBJECTIVES: To assess prevalence and severity of lower urinary tract function in 85-year-old men and women. Little is known on the prevalence of lower urinary tract dysfunction in this geriatric age group, which is now the fastest growing sector of the population worldwide. PATIENTS AND METHODS: The Vienna Trans-Danube Aging study (VITA) is a longitudinal, population-based study initiated in 2000 that included men/women aged 75 years living in a well-defined area in Vienna. The main purpose of the VITA study was to identify risk factors for incident Alzheimer's disease. All study participants alive in 2010 were contacted by mail to complete a detailed questionnaire on various aspects of lower urinary tract symptoms (LUTS) and urinary incontinence (UI). RESULTS: The response rate was 68%, resulting in a total of 262 questionnaires available for analysis (men n= 96; women n= 166). All study participants were 85 years of age. Urinary incontinence defined as any involuntary loss during the past 4 weeks was reported by 24% of men and 35% of women (P= 0.04). Stress UI was more frequent in women (39%) than in men (14%, P < 0.01), the difference for urge UI (women 35%, men 25%) was on the border of statistical significance (P= 0.05). Only four individuals (1.5%) needed permanent catheterization. Urgency (women 56%, men 54%) and daytime frequency (women 70%, men 74%) were equally distributed (P > 0.05). Nocturia more often than twice was more prevalent in men (69%) than in women (49%) (P= 0.02). Overactive bladder, according to International Continence Society criteria, was present in 55% of women and 50% of men. No difference regarding quality of life impairment as the result of LUTS and UI was noticed between sexes. A few co-morbidities were identified to correlate with UI and storage symptoms. CONCLUSIONS: These data provide insights into the prevalence and severity of LUTS and UI in individuals in their eighties, to our knowledge the largest population-based study in this age group. Demographic changes in upcoming decades underline the importance of a thorough understanding of lower urinary tract dysfunction in a geriatric population.

The influence of depression on processing speed and executive function in nondemented subjects aged 75.

Neuropsychological deficits are commonly found to be part of depression in old age and might simultaneously represent early symptoms of dementia. We investigated the influence of depression on processing speed and executive function in subjects who did not develop dementia during the following 5 years to examine whether these neuropsychological dysfunctions are due to depression or are influenced by other causes (e.g., education, cerebral comorbidity). A total of 287 subjects aged 75 (mean: 75.76) were available for analyses. Processing speed was measured by the Trail Making Test-A, Executive Function by the Trail Making Test-B and Verbal Fluency. DSM-IV-criteria were used for diagnosing depression. Cerebral comorbidity (e.g., stroke, Parkinson's disease), sex, education, antidepressant, and/or benzodiazepine medication, and a history of depression were taken into account as covariates. Univariate analyses and multiple regression analyses were calculated. Higher education was strongly related to better performance in all three psychometric tests. Cerebral comorbidity significantly slowed TMT-A performance and reduced Verbal Fluency scores. In multiple regression analysis depression showed only a minor, slowing influence on TMT-A and TMT-B performance. Depression only had a minor influence on processing speed and executive function in this sample of nondemented subjects. By comparison, the influence of education and cerebral comorbidity was seen to be stronger.

Circulating retinol-binding protein 4 and metabolic syndrome in the elderly.

BACKGROUND: Retinol-binding protein (RBP) 4, a human adipokine that specifically binds to retinol, has been reported to provide a link between obesity and insulin resistance. Plasma RBP4 concentration may be under the influence of age and obesity, but only a few studies has investigated this link in elderly individuals. Consequently, we tested the correlation between RBP4 concentrations and type 2 diabetes/metabolic syndrome (MetS) components in a large population based cohort study (VITA) of elderly [1, 2]. Using a single birth cohort, this investigation could exclude the influence of age. METHODS: We evaluated the correlation of RBP4 with type 2 diabetes and MetS components including Body Mass Index (BMI), blood pressure, lipid parameters, fasting glucose insulin, homeostasis model assessment insulin resistance (HOMA-IR), and smoking in exclusively 75-76 year old participants (N = 232). RESULTS: In the present study, RBP4 concentrations were associated with type 2 diabetes and metabolic syndrome (MetS) components. Of all the individual components of metabolic syndrome that were associated with RBP4 concentrations, the correlations of RBP4 with serum triglycerides and a negative correlation with HDL were the strongest ones observed in our study cohort (p<0.0001). CONCLUSIONS: RBP4 plays a role in biological mechanisms that are responsible for insulin resistance and development of type 2 diabetes.

Prospective study on association between plasma amyloid beta-42 and atherosclerotic risk factors.

An association between plasma Amyloid beta peptides (Aß) with blood lipids was reported in cross-sectional studies. The present study examined the 5-year prospective association of atherosclerotic risk factors with plasma Aß42 in 440 elderly persons without both Alzheimer's disease (AD) or mild cognitive impairment (MCI) at baseline. Persons in the highest tertile of total cholesterol (TC) or LDL-C at baseline showed low plasma Aß42 at 5 years. Regression analysis confirmed TC and LDL-C as negative predictors of Aß42 (p = 0.001). An increase over 5 years of HDL-C was a negative predictor and the presence of an APOE ε4 allele was a positive predictor for decrease of Aß42 in converters to MCI. In converters to AD, increase of both TC and of HbA1c were positive predictors of Aß42 levels at 5 years. Analysis of covariance showed a positive association between Δ-TC, Δ-LDL-C, Δ-HbA1c, and levels of Aß42 at 5 years (p = 0.006; 0.013 and 0.027 resp.) in converters to AD independently on lipid-lowering treatment. The association of vascular risk factors TC, LDL-C, and HbA1c with higher Aß42 levels might, after confirmation in other cohorts, influence the development of lifestyle interventions concerning plasma Aß42 and AD.

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.

Plasma amyloid beta-42 independently predicts both late-onset depression and Alzheimer disease.

OBJECTIVES: Depression in the elderly might represent a prodromal phase of Alzheimer disease (AD). High levels of plasma amyloid beta-42 (Aß42) were found in prestages of AD and also in depressed patients in cross-sectional studies. This study examined the association of emerging late-onset depression (LOD) and AD with plasma Aß42 in a sample of never depressed and not demented persons at baseline. DESIGN: Prospective 5-year longitudinal study. PARTICIPANTS: A community dwelling of older adults (N = 331) from the Vienna Transdanube Aging study. MEASUREMENTS: Laboratory measurements, cognitive functioning, and depressive symptoms were assessed at baseline, 2.5, and 5 years follow-ups. RESULTS: After exclusion of converters to AD, regression analysis revealed that higher plasma Aß42 at baseline was a positive predictor for conversion to first episode of LOD. Independent of whether persons with mild cognitive impairment (MCI) at 2.5 years were included or excluded into regressions, higher plasma Aß42 at baseline was a significant predictor for the development of probable or possible AD at 5 years. Higher conversion to AD was also associated with male gender but not with either higher scores on the Geriatric Depression Scale (GDS), with stroke or cerebral infarction nor apolipoprotein E ε4 allele. No association was found for an interaction between plasma Aß42 levels and GDS. CONCLUSIONS: Higher plasma Aß42 at baseline predicted the development of first episode of LOD and conversion to probable or possible AD. Emerging depression as measured by scores on GDS at the 2.5-year follow-up, either alone or as an interaction factor with plasma Aß42, failed to predict the conversion to AD at 5 years.

Vascular risk factors and their association to serum androgen levels in a population-based cohort of 75-year-old men over 5 years: results of the VITA study.

PURPOSE: In contrast to the high prevalence of late onset hypogonadism, little is known regarding correlates for low androgen levels in aging men. METHODS: We investigated participants of the Vienna Transdanube Aging study and assessed the relationship between vascular risk factors and hormonal status over 5 years. RESULTS: A total of 247 men with a mean age of 75.8 years were analyzed. Despite a tendency for lower testosterone levels in men with vascular risk factors and vascular diseases, none of these associations reached statistical significance. Men with low DHEA-S levels had a lower risk of hypercholesterinemia (-55.2%; P = 0.01) yet an increased prevalence of diabetes (+95.7%; P = 0.02) and coronary heart disease (+47.6%; P = 0.05). Testosterone and DHEA-S remained stable over 5 years of follow-up. CONCLUSION: While reduced levels of total testosterone did not show an association to vascular disease, low DHEA-S was linked to hypercholesterinemia, diabetes, and coronary heart disease.

Prediction of Alzheimer dementia with short neuropsychological instruments.

The aim of this study was to evaluate the neuropsychological instruments in predicting Alzheimer dementia after 5 years in the context of a longitudinal population-based cohort study. A total of 585 nondemented 75-year-old individuals completed neuropsychological examination at the baseline investigation; 479 subjects were followed after 30 months and 404 after 60 months. Cognition, depression and memory complaints were evaluated with psychometric instruments. Known risk factors for Alzheimer dementia were included in the analyses. Univariate logistic regression analyses and stepwise multiple models were calculated. A combination of reduced verbal memory, reduced visual motor speed, subjective memory complaints and the APOE epsilon4 carriage was best in predicting incident probable Alzheimer dementia (R(2) = 0.42, ROC curve = 0.91). The model achieved a positive predictive value of 23.3%, a negative predictive value of 98.7%, a sensitivity of 82.8% and a specificity of 82.4%. Alzheimer dementia can be predicted by neuropsychological instruments measuring episodic memory and motor speed. A high percentage of 98.7% subjects at age 75 years could be predicted as remaining non-demented at age 80 years. The prediction of those unlikely to develop AD would be more important in the future to spare further expensive diagnostic testing and protective therapies in individuals at low risk.

Late-onset depression in elderly subjects from the Vienna Transdanube Aging (VITA) study.

OBJECTIVES: To assess whether prevalence of depression increases with age. To determine possible risk factors of late-onset depression. METHOD: The Vienna Transdanube Aging (VITA) study is a community-based cohort study investigating every inhabitant of the area on the left shore of the river Danube, in Vienna, Austria, born between May 1925 and June 1926. It includes a thorough neurologic, psychiatric, and neuropsychological battery. Occurrence of a current depressive episode was diagnosed according to a DSM-IV-based questionnaire, the Hamilton Rating Scale for Depression, and the Short Geriatric Depression Scale. A gerontopsychiatric life events scale was used for the assessment of life events. 1505 subjects were contacted and 606 participated. At baseline, 406 nondemented and never-depressed individuals were included in the study. Follow-up after 30 months was possible in 331 of the 406 participants. Baseline data were collected from May 2000 to December 2002, and 30-month follow-up data were collected from November 2002 to September 2005. RESULTS: Of the 331 participants who were not depressed at baseline, 31.4% had developed a subsyndromal, minor, or major depressive episode at the 30-month follow-up; 14.2% were diagnosed with mild cognitive impairment at follow-up, 42.5% of whom were also diagnosed with new-onset depression. In the multiple analyses, "troubles with relatives" was a significant variable (p = .018, OR = 0.5, 95% CI = 0.28 to 0.89, R(2) = 0.16). Summative scores on the Fuld Object Memory Evaluation showed a significant influence (p = .048, OR = 0.9, 95% CI = 0.88 to 0.99, R(2) = 0.01) on the occurrence of newly onset depression. None of the other investigated possible risk factors had a significant influence on the new occurrence of depression. CONCLUSION: Prevalence of late-onset depression increases with age. Having severe troubles with relatives and pre-existing cognitive impairments may enhance the probability of developing a late-onset depression.

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.

Risk factors for Alzheimer dementia in a community-based birth cohort at the age of 75 years.

BACKGROUND: Few prospective community-based cohort studies have so far concentrated specifically on the risk factors for Alzheimer dementia (AD) with onset after the age of 75 years. METHODS: We prospectively investigated a birth cohort of 585 nondemented inhabitants in the area on the East bank of the river Danube who were born between 1925 and 1926. They were investigated at the age of 75 years and followed up after 30 months. The follow-up was possible with 488 probands; 36 died, and 61 refused to participate. RESULTS: In multivariate analysis an elevated risk for late-onset AD could be found for (1) history of depressive episodes (OR = 2.09; 95% CI = 1.25-3.48); (2) the epsilon 4 allele of the APOE gene (OR = 1.86; 95% CI = 1.08-3.23); (3) lower serum level of folate (OR = 0.92; 95% CI = 0.87-0.98); (4) no chronic use of nonsteroidal anti-inflammatory drugs (OR = 0.40; 95% CI = 0.20-0.81), and (5) lower education (OR = 1.43; 95% CI = 1.03-2.00). CONCLUSIONS: Five risk factors for late-onset AD could be confirmed, which might be targets for preventive strategies.

Do subjective memory complaints predict senile Alzheimer dementia?

Many elderly complain about their memory and undergo dementia screening by the Mini-Mental State Examination (MMSE). While objective memory impairment always precedes Alzheimer dementia (AD) it is unclear whether subjective memory complaints are predicting AD. We tried to answer this question in a prospective cohort study. The 75-years old non-demented inhabitants of Vienna-Transdanube were investigated for conversion to AD after 30 months. The predictive value of subjective memory complaints was analysed in two groups: subjects with high MMSE-score (28-30) and subjects with low MMSE-score (23-27). Only in subjects with high MMSE univariate analyses showed an association between subjective memory complaints and incident AD. In both groups the verbal memory test was the main predictor of AD in multivariate analyses. We suggest to perform memory testing in subjects complaining about memory irrespective of their performance in a screening procedure like the MMSE.

Effects of medications on plasma amyloid beta (Abeta) 42: longitudinal data from the VITA cohort.

In the course of cognitive deterioration leading to Alzheimer's disease (AD) the increase of amyloid beta (Abeta42) in cerebrospinal fluid or plasma might be an initial event. We previously reported about the associations between concomitant medication and plasma Abeta42 levels in the non-demented population cohort of the Vienna transdanube aging study at baseline. In the present study, the longitudinal influence of insulin, gingko biloba, non-steroidal anti-inflammatory drugs (NSAIDs), oral anti-diabetics (sulfonylurea and biguanides), estrogens, fibrates, and statins on plasma Abeta42 are presented. Associated with medial temporal lobe atrophy (MTA), users of insulin showed significantly increased levels of Abeta42. Long-term users of gingko biloba, independent of their MTA, had significantly decreased plasma Abeta42 and the age-dependent increase of plasma Abeta42 was significantly smaller in long-term gingko biloba treated subjects. The use of fibrates also decreased plasma Abeta42 levels. In multiple testing considering interactions between medications, gender, APOE-epsilon4 presence and creatinine, insulin long-term users again showed significantly increased levels; fibrate and gingko biloba users showed a trend to rather decreased plasma Abeta42 levels compared to the non-users (p=0.05-0.08). Neither statins nor NSAIDs showed a significant effect on plasma Abeta42 in this model. Measuring the effect on cognition, no single medication studied was a significant predictor of conversion to AD or mild cognitive impairment (MCI). Whether the use of gingko biloba might prevent the conversion to MCI or AD needs to be proven in prospective, clinical trials.