Alterations in the Plasma Levels of Specific Choline Phospholipids in Alzheimer's Disease Mimic Accelerated Aging.

Alzheimer's disease (AD) is the most common neurodegenerative disease and of continuously rising prevalence. The identification of easy-to-measure biomarkers capable to assist in the prediction and early diagnosis of AD is currently a main research goal. Lipid metabolites in peripheral blood of human patients have recently gained major attention in this respect. Here, we analyzed plasma of 174 participants (not demented at baseline; mean age: 75.70±0.44 years) of the Vienna Transdanube Aging (VITA) study, a longitudinal, population-based birth cohort study, at baseline and after 90 months or at diagnosis of probable AD. We determined the levels of specific choline phospholipids, some of which have been suggested as potential biomarkers for the prediction of AD. Our results show that during normal aging the levels of lysophosphatidylcholine, choline plasmalogen, and lyso-platelet activating factor increase significantly. Notably, we observed similar but more pronounced changes in the group that developed probable AD. Thus, our results imply that, in terms of choline-containing plasma phospholipids, the conversion to AD mimics an accelerated aging process. We conclude that age, even in the comparatively short time frame between 75 and 82.5 years, is a crucial factor in the quest for plasma lipid biomarkers for AD that must be carefully considered in future studies and trials.

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.

MRI features of Binswanger's disease predict prognosis and associated pathology.

OBJECTIVE: To identify the prevalence of MRI features of Binswanger's disease (BD), specifically MRI with diffuse white matter lesions and scattered multiple lacunes (BD-MRI), and to describe neurological features and pathological outcomes of a community-based cohort study. METHODS: Of 697 participants (all 75 years old), 503 completed neurological examinations at baseline and were followed-up every 30 months thereafter with MRIs, the mini-mental state examination (MMSE) and the Unified Parkinson Disease Rating Scale-Motor Section (UPDRSM). Data from participants with BD-MRI were compared with those from participants with predominant white matter lesions (WML-MRI), scattered multiple lacunes (ML-MRI), or normal MRIs. RESULTS: Fourteen BD-MRI patients (2.8%) were detected at baseline. The mean MMSE scores in the BD-MRI, WML-MRI, ML-MRI, and normal MRIs groups were 26.4, 28.2, 28.4, and 28.5, respectively, and the mean UPDRSM scores were 9.1, 1.3, 3.1, and 1.7, respectively. At the 30-month follow-up, mortality rates in the normal MRIs, WML-MRI and ML-MRI were 4%, 9.1%, and 22.2%, respectively, and follow-up MRIs were available for 80%, 82%, and 61% of the participants, respectively. In the BD-MRI, however, five patients were deceased, and only five follow-up individual MRIs were available (33.3%). Autopsies were performed on six of eight BD-MRI brains, and these brains fulfilled the pathological criteria for BD independent of Alzheimer disease pathology. All these six individuals also showed systemic atherosclerosis and renal arterio-arteriolosclerosis. INTERPRETATION: The BD-MRI participants had poor prognoses and showed pure BD pathology with advanced systemic vascular disease. BD-MRI appears to be a predictor of vascular neurocognitive impairment.

Disproportionate subarachnoid space hydrocephalus-outcome and perivascular space.

OBJECTIVE: We sought to identify the prevalence of MRI features of disproportionately enlarged subarachnoid space hydrocephalus in possible idiopathic normal pressure hydrocephalus (DESH-iNPH) and to describe the clinico-radiological features and outcomes of a community-based investigation (The Vienna Trans-Danube Aging study). METHODS: Of the 697 inhabitants (all 75 years old), 503 completed extensive neurological examinations at baseline and were followed up every 30 months thereafter with MRIs, mini-mental state examination (MMSE), and the Unified Parkinson Disease Rating Scale-Motor Section (UPDRSM). The DESH-iNPH participant data were compared with the data from participants with Evans index ratios >0.3 (ex vacuo hydrocephalus), cerebral small-vessel diseases, and normal MRIs. The widening of perivascular space was also evaluated by MRI in these groups. RESULTS: Eight participants with DESH-iNPH (1.6%) and 76 with ex vacuo hydrocephalus (16.1%) at baseline were identified. The mean MMSE in DESH-iNPH, ex vacuo hydrocephalus, and normal MRIs was 26.4, 27.9, and 28.3, respectively, and the mean UPDRSM was 9.75, 2.96, and 1.87, respectively. After a 90-month follow-up, the mortality rates for DESH-iNPH, ex vacuo hydrocephalus, and normal MRIs were 25.0%, 21.3%, and 10.9%, respectively. The perivascular-space widening scores were significantly smaller in the DESH-iNPH cases, particularly at the centrum semiovale, compared to cerebral small-vessel disease and ex vacuo hydrocephalus cases. INTERPRETATION: The prevalence of DESH-iNPH was 1.6% for participants aged 75 years and revealed significantly lower MMSE and higher UPDRSM scores compared to the ex vacuo hydrocephalus and controls. Moreover, it is suggested that perivascular-space narrowing is a morphological and pathophysiological marker of DESH-iNPH.

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.

Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series.

Neurodegenerative diseases are characterised by neuronal loss and cerebral deposition of proteins with altered physicochemical properties. The major proteins are amyloid-ß (Aß), tau, α-synuclein, and TDP-43. Although neuropathological studies on elderly individuals have emphasised the importance of mixed pathologies, there have been few observations on the full spectrum of proteinopathies in the ageing brain. During a community-based study we performed comprehensive mapping of neurodegeneration-related proteins and vascular pathology in the brains of 233 individuals (age at death 77-87; 73 examined clinically in detail). While all brains (from individuals with and without dementia) showed some degree of neurofibrillary degeneration, Aß deposits were observed only in 160 (68.7 %). Further pathologies included α-synucleinopathies (24.9 %), non-Alzheimer tauopathies (23.2 %; including novel forms), TDP-43 proteinopathy (13.3 %), vascular lesions (48.9 %), and others (15.1 %; inflammation, metabolic encephalopathy, and tumours). TDP-43 proteinopathy correlated with hippocampal sclerosis (p < 0.001) and Alzheimer-related pathology (CERAD score and Braak and Braak stages, p = 0.001). The presence of one specific variable (cerebral amyloid angiopathy, Aß parenchymal deposits, TDP-43 proteinopathy, α-synucleinopathy, vascular lesions, non-Alzheimer type tauopathy) did not increase the probability of the co-occurrence of others (p = 0.24). The number of observed pathologies correlated with AD-neuropathologic change (p < 0.0001). In addition to AD-neuropathologic change, tauopathies associated well with dementia, while TDP-43 pathology and α-synucleinopathy showed strong effects but lost significance when evaluated together with AD-neuropathologic change. Non-AD neurodegenerative pathologies and their combinations have been underestimated, but are frequent in reality as demonstrated here. This should be considered in diagnostic evaluation of biomarkers, and for better clinical stratification of patients.

Blood alterations preceding clinical manifestation of glioblastoma.

BACKGROUND: There is little knowledge on blood alterations of glioblastoma. We had the opportunity to investigate markers from plasma taken 66, 36, and 6 months before glioblastoma in a patient in the VITA study. METHODS: We determined S100B, secretagogin, neuropeptide-Y, micro-RNA-21, let-7, micro-RNA-128, and micro-RNA-342-3p in our patient and 10 controls from VITA. RESULTS: We found a four-fold increase of micro-RNA-21 in the plasma of glioblastoma patient, whereas controls showed a significant decrease. There was no difference in other protein or micro-RNA levels between the patient and controls. CONCLUSION: Plasma micro-RNA-21 may be associated with glioblastoma development in individual cases.

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.

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.

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.

Peroxisomal alterations in Alzheimer's disease.

In Alzheimer's disease (AD), lipid alterations are present early during disease progression. As some of these alterations point towards a peroxisomal dysfunction, we investigated peroxisomes in human postmortem brains obtained from the cohort-based, longitudinal Vienna-Transdanube Aging (VITA) study. Based on the neuropathological Braak staging for AD on one hemisphere, the patients were grouped into three cohorts of increasing severity (stages I-II, III-IV, and V-VI, respectively). Lipid analyses of cortical regions from the other hemisphere revealed accumulation of C22:0 and very long-chain fatty acids (VLCFA, C24:0 and C26:0), all substrates for peroxisomal ß-oxidation, in cases with stages V-VI pathology compared with those modestly affected (stages I-II). Conversely, the level of plasmalogens, which need intact peroxisomes for their biosynthesis, was decreased in severely affected tissues, in agreement with a peroxisomal dysfunction. In addition, the peroxisomal volume density was increased in the soma of neurons in gyrus frontalis at advanced AD stages. Confocal laser microscopy demonstrated a loss of peroxisomes in neuronal processes with abnormally phosphorylated tau protein, implicating impaired trafficking as the cause of altered peroxisomal distribution. Besides the original Braak staging, the study design allowed a direct correlation between the biochemical findings and the amount of neurofibrillary tangles (NFT) and neuritic plaques, quantified in adjacent tissue sections. Interestingly, the decrease in plasmalogens and the increase in VLCFA and peroxisomal volume density in neuronal somata all showed a stronger association with NFT than with neuritic plaques. These results indicate substantial peroxisome-related alterations in AD, which may contribute to the progression of AD pathology.

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.

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.