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Showing papers in "Alzheimers & Dementia in 2014"


Journal ArticleDOI
TL;DR: Research criteria for SCD in pre‐mild cognitive impairment (MCI) are presented and a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings.
Abstract: There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.

1,626 citations


Journal ArticleDOI
TL;DR: To compare the risk of developing Alzheimer's disease (AD) dementia in late mild cognitive impairment (LMCI), early MCI (EMCI), and subjective memory impairment (SMI) with normal test performance, three different approaches are considered.
Abstract: Objective To compare the risk of developing Alzheimer's disease (AD) dementia in late mild cognitive impairment (LMCI), early MCI (EMCI), and subjective memory impairment (SMI) with normal test performance. Methods The baseline sample (n = 2892) of the prospective cohort study in nondemented individuals (German Study on Aging, Cognition and Dementia in Primary Care Patients) was divided into LMCI, EMCI, SMI, and control subjects by delayed recall performance. These groups were subdivided by the presence of self-reported concerns associated with experienced memory impairment. AD dementia risk was assessed over 6 years. Results Across all groups, risk of AD dementia was greatest in LMCI. In those with self-reported concerns regarding their memory impairment, SMI and EMCI were associated with a similarly increased risk of AD dementia. In those subgroups without concerns, SMI was not associated with increased risk of AD dementia, but EMCI remained an at-risk condition. Conclusions SMI and EMCI with self-reported concerns were associated with the same risk of AD dementia, suggesting that pre-LMCI risk conditions should be extended to SMI with concerns.

407 citations


Journal ArticleDOI
TL;DR: The goal of this study was to estimate the changes in the prevalence of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) among elderly Chinese individuals and to analyze differences between urban and rural areas.
Abstract: Objective The Chinese population has been aging rapidly and the country's economy has experienced exponential growth during the past three decades. The goal of this study was to estimate the changes in the prevalence of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) among elderly Chinese individuals and to analyze differences between urban and rural areas. Methods For the years 2008 to 2009, we performed a population-based cross-sectional survey with a multistage cluster sampling design. Residents aged 65 years and older were drawn from 30 urban (n = 6096) and 45 rural (n = 4180) communities across China. Participants were assessed with a series of clinical examinations and neuropsychological measures. Dementia, AD, and VaD were diagnosed according to established criteria via standard diagnostic procedures. Results The prevalence of dementia, AD, and VaD among individuals aged 65 years and older were 5.14% (95% CI, 4.71–5.57), 3.21% (95% CI, 2.87–3.55), and 1.50% (95% CI, 1.26–1.74), respectively. The prevalence of dementia was significantly higher in rural areas than in urban ones (6.05% vs. 4.40%, P P P = .166). The difference in AD was not evident when the sample was stratified by educational level. Moreover, the risk factors for AD and VaD differed for urban and rural populations. Conclusions A notably higher prevalence of dementia and AD was found in rural areas than in urban ones, and education might be an important reason for the urban–rural differences.

316 citations


Journal ArticleDOI
TL;DR: Early changes of chronic traumatic encephalopathy are found in four young veterans of the Iraq and Afghanistan conflict who were exposed to explosive blast and in another young veteran who was repetitively concussed.
Abstract: Mild traumatic brain injury (mTBI) includes concussion, subconcussion, and most exposures to explosive blast from improvised explosive devices. mTBI is the most common traumatic brain injury affecting military personnel; however, it is the most difficult to diagnose and the least well understood. It is also recognized that some mTBIs have persistent, and sometimes progressive, long-term debilitating effects. Increasing evidence suggests that a single traumatic brain injury can produce long-term gray and white matter atrophy, precipitate or accelerate age-related neurodegeneration, and increase the risk of developing Alzheimer's disease, Parkinson's disease, and motor neuron disease. In addition, repetitive mTBIs can provoke the development of a tauopathy, chronic traumatic encephalopathy. We found early changes of chronic traumatic encephalopathy in four young veterans of the Iraq and Afghanistan conflict who were exposed to explosive blast and in another young veteran who was repetitively concussed. Four of the five veterans with early-stage chronic traumatic encephalopathy were also diagnosed with posttraumatic stress disorder. Advanced chronic traumatic encephalopathy has been found in veterans who experienced repetitive neurotrauma while in service and in others who were accomplished athletes. Clinically, chronic traumatic encephalopathy is associated with behavioral changes, executive dysfunction, memory loss, and cognitive impairments that begin insidiously and progress slowly over decades. Pathologically, chronic traumatic encephalopathy produces atrophy of the frontal and temporal lobes, thalamus, and hypothalamus; septal abnormalities; and abnormal deposits of hyperphosphorylated tau as neurofibrillary tangles and disordered neurites throughout the brain. The incidence and prevalence of chronic traumatic encephalopathy and the genetic risk factors critical to its development are currently unknown. Chronic traumatic encephalopathy has clinical and pathological features that overlap with postconcussion syndrome and posttraumatic stress disorder, suggesting that the three disorders might share some biological underpinnings.

305 citations


Journal ArticleDOI
TL;DR: The concept that peripheral and central nervous system inflammation link the pathogenesis of AD and metabolic diseases is discussed and the contribution of brain inflammation to defective insulin signaling and neuronal dysfunction is explored.
Abstract: A link between Alzheimer's disease (AD) and metabolic disorders has been established, with patients with type 2 diabetes at increased risk of developing AD and vice versa. The incidence of metabolic disorders, including insulin resistance and type 2 diabetes is increasing at alarming rates worldwide, primarily as a result of poor lifestyle habits. In parallel, as the world population ages, the prevalence of AD, the most common form of dementia in the elderly, also increases. In addition to their epidemiologic and clinical association, mounting recent evidence indicates shared mechanisms of pathogenesis between metabolic disorders and AD. We discuss the concept that peripheral and central nervous system inflammation link the pathogenesis of AD and metabolic diseases. We also explore the contribution of brain inflammation to defective insulin signaling and neuronal dysfunction. Last, we review recent evidence indicating that targeting neuroinflammation may provide novel therapeutic avenues for AD.

294 citations


Journal ArticleDOI
TL;DR: Cigarette smoking has been linked with both increased and decreased risk for Alzheimer's disease (AD), which is relevant for the US military because the prevalence of smoking in the military is approximately 11% higher than in civilians.
Abstract: Background Cigarette smoking has been linked with both increased and decreased risk for Alzheimer's disease (AD). This is relevant for the US military because the prevalence of smoking in the military is approximately 11% higher than in civilians. Methods A systematic review of published studies on the association between smoking and increased risk for AD and preclinical and human literature on the relationships between smoking, nicotine exposure, and AD-related neuropathology was conducted. Original data from comparisons of smoking and never-smoking cognitively normal elders on in vivo amyloid imaging are also presented. Results Overall, literature indicates that former/active smoking is related to a significantly increased risk for AD. Cigarette smoke/smoking is associated with AD neuropathology in preclinical models and humans. Smoking-related cerebral oxidative stress is a potential mechanism promoting AD pathology and increased risk for AD. Conclusions A reduction in the incidence of smoking will likely reduce the future prevalence of AD.

284 citations


Journal ArticleDOI
TL;DR: Recent evidence is reviewed that sheds light on how brain insulin dysfunction is initiated at a molecular level and why abnormal insulin signaling culminates in synaptic failure and memory decline and provides pathophysiological background for identification of novel molecular targets and for development of alternative therapeutic approaches in AD.
Abstract: Compelling preclinical and clinical evidence supports a pathophysiological connection between Alzheimer's disease (AD) and diabetes. Altered metabolism, inflammation, and insulin resistance are key pathological features of both diseases. For many years, it was generally considered that the brain was insensitive to insulin, but it is now accepted that this hormone has central neuromodulatory functions, including roles in learning and memory, that are impaired in AD. However, until recently, the molecular mechanisms accounting for brain insulin resistance in AD have remained elusive. Here, we review recent evidence that sheds light on how brain insulin dysfunction is initiated at a molecular level and why abnormal insulin signaling culminates in synaptic failure and memory decline. We also discuss the cellular basis underlying the beneficial effects of stimulation of brain insulin signaling on cognition. Discoveries summarized here provide pathophysiological background for identification of novel molecular targets and for development of alternative therapeutic approaches in AD.

278 citations


Journal ArticleDOI
TL;DR: The points addressed include: the major challenges in the development of blood‐based biomarkers of AD, including patient heterogeneity, inclusion of the “right” control population, and the blood–brain barrier; the need for standardization of preanalytical variables and analytical methodologies used by the field.
Abstract: Treatment of Alzheimer's disease (AD) is significantly hampered by the lack of easily accessible biomarkers that can detect disease presence and predict disease risk reliably. Fluid biomarkers of AD currently provide indications of disease stage; however, they are not robust predictors of disease progression or treatment response, and most are measured in cerebrospinal fluid, which limits their applicability. With these aspects in mind, the aim of this article is to underscore the concerted efforts of the Blood-Based Biomarker Interest Group, an international working group of experts in the field. The points addressed include: (1) the major challenges in the development of blood-based biomarkers of AD, including patient heterogeneity, inclusion of the "right" control population, and the blood–brain barrier; (2) the need for a clear definition of the purpose of the individual markers (e.g., prognostic, diagnostic, or monitoring therapeutic efficacy); (3) a critical evaluation of the ongoing biomarker approaches; and (4) highlighting the need for standardization of preanalytical variables and analytical methodologies used by the field.

276 citations


Journal ArticleDOI
TL;DR: In this paper, the most useful definition of the "cerebrospinal fluid Alzheimer profile," based on amyloid-s 1-42 (Aβ 42 ), total tau, and phosphorylated tau (p-tau), for diagnosis and prognosis of Alzheimer's disease (AD) was identified.
Abstract: Background We aimed to identify the most useful definition of the "cerebrospinal fluid Alzheimer profile," based on amyloid-s 1-42 (Aβ 42 ), total tau, and phosphorylated tau (p-tau), for diagnosis and prognosis of Alzheimer's disease (AD). Methods We constructed eight Alzheimer profiles with previously published combinations, including regression formulas and simple ratios. We compared their diagnostic accuracy and ability to predict dementia due to AD in 1385 patients from the Amsterdam Dementia Cohort. Results were validated in an independent cohort (n = 1442). Results Combinations outperformed individual biomarkers. Based on the sensitivity of the best performing regression formulas, cutoffs were chosen at 0.52 for the tau/Aβ 42 ratio and 0.08 for the p-tau/Aβ 42 ratio. Ratios performed similar to formulas (sensitivity, 91%–93%; specificity, 81%–84%). The same combinations best predicted cognitive decline in mild cognitive impairment patients. Validation confirmed these results, especially regarding the tau/Aβ 42 ratio. Conclusions A tau/Aβ 42 ratio of >0.52 constitutes a robust cerebrospinal fluid Alzheimer profile. We recommend using this ratio to combine biomarkers.

262 citations


Journal ArticleDOI
TL;DR: Whether quantitatively measured retinal microvascular parameters are associated with AD is determined by assessing the retina's noninvasive window to assess the microcirculation.
Abstract: Background Although cerebral small-vessel disease has been implicated in the development of Alzheimer's disease (AD), the cerebral microcirculation is difficult to visualize directly in vivo. Because the retina provides a noninvasive window to assess the microcirculation, we determined whether quantitatively measured retinal microvascular parameters are associated with AD. Methods We conducted a case-control study (case:control matching ≈ 1:2). Retinal photographs were analyzed using a computer program, and a spectrum of quantitative retinal microvascular parameters (caliber, fractal dimension, tortuosity, and bifurcation) were measured. Logistic regression models were used to compute the odds ratio (OR) and 95% confidence interval for AD adjusting for age, gender, ethnicity, smoking, hypertension, diabetes, hypercholesterolemia, and history of myocardial infarction. Results We included 136 demented patients with AD and 290 age-gender-race-matched controls. Persons with narrower venular caliber (OR per standard deviation [SD] decrease, 2.01 [1.27–3.19]), decreased arteriolar and venular fractal dimension (OR per SD decrease 1.35 [1.08–1.68], 1.47 [1.17–1.84], respectively) and increased arteriolar and venular tortuosity (OR per SD increase, 1.84 [1.40–2.31], 1.94 [1.48–2.53], respectively) were more likely to have AD. These associations still persisted when only AD cases without a history of cerebrovascular disease were included. Conclusions Patients with AD have altered microvascular network in the retina (narrower retinal venules and a sparser and more tortuous retinal vessels) compared with matched nondemented controls. These changes in retinal microvasculature may reflect similar pathophysiological processes in cerebral microvasculature in the brains of patients with AD.

247 citations


Journal ArticleDOI
TL;DR: The first systematic review and meta‐analysis that compares plasma levels of micronutrients and fatty acids in AD patients to those in cognitively intact elderly controls is provided.
Abstract: Background Alzheimer disease (AD) patients are at risk of nutritional insufficiencies because of physiological and psychological factors. Nutritional compounds are postulated to play a role in the pathophysiological processes that are affected in AD. We here provide the first systematic review and meta-analysis that compares plasma levels of micronutrients and fatty acids in AD patients to those in cognitively intact elderly controls. A secondary objective was to explore the presence of different plasma nutrient levels between AD and control populations that did not differ in measures of protein/energy nourishment. Methods We screened literature published after 1990 in the Cochrane Central Register of Controlled Trials, Medline, and Embase electronic databases using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for AD patients, controls, micronutrient, vitamins, and fatty acids, resulting in 3397 publications, of which 80 met all inclusion criteria. Status of protein/energy malnutrition was assessed by body mass index, mini nutritional assessment score, or plasma albumin. Meta-analysis, with correction for differences in mean age between AD patients and controls, was performed when more than five publications were retrieved for a specific nutrient. Results We identified five or more studies for folate, vitamin A, vitamin B12, vitamin C, vitamin D, vitamin E, copper, iron, and zinc but fewer than five studies for vitamins B1 and B6, long-chain omega-3 fatty acids, calcium, magnesium, manganese, and selenium (the results of the individual publications are discussed). Meta-analysis showed significantly lower plasma levels of folate and vitamin A, vitamin B12, vitamin C, and vitamin E ( P P = .050) and vitamin D ( P = .075) were found in AD patients. No significant differences were observed for plasma levels of copper and iron. A meta-analysis that was limited to studies reporting no differences in protein/energy malnourishment between AD and control populations yielded similar significantly lower plasma levels of folate and vitamin B12, vitamin C, and vitamin E in AD. Conclusions The lower plasma nutrient levels indicate that patients with AD have impaired systemic availability of several nutrients. This difference appears to be unrelated to the classic malnourishment that is well known to be common in AD, suggesting that compromised micronutrient status may precede protein and energy malnutrition. Contributing factors might be AD-related alterations in feeding behavior and intake, nutrient absorption, alterations in metabolism, and increased utilization of nutrients for AD pathology-related processes. Given the potential role of nutrients in the pathophysiological processes of AD, the utility of nutrition may currently be underappreciated and offer potential in AD management.

Journal ArticleDOI
TL;DR: Brain pathology of Alzheimer's diseases and the genetics of autosomal dominant familial AD have been the “lamp posts” under which the AD field has been looking for therapeutic targets, but none of the compounds tested to date have produced clinically meaningful results.
Abstract: Brain pathology of Alzheimer's diseases (AD) and the genetics of autosomal dominant familial AD have been the "lamp posts" under which the AD field has been looking for therapeutic targets. Although this approach still remains valid, none of the compounds tested to date have produced clinically meaningful results. This calls for developing complementary therapeutic approaches and AD targets. The allele e4 of apolipoprotein E4 ( APOE e4), is the most prevalent genetic risk factor for sporadic AD, and is expressed in more than half of the AD patients. However, in spite of its genetic prominence, the allele APOE e4 and its corresponding protein product apoE4 have been understudied. We presently briefly discuss the reasons underlying this situation and review newly developed AD therapeutic approaches that target apoE4 and which pave the way for future studies.

Journal ArticleDOI
TL;DR: Whether broad factors and specific facets of personality are associated with increased risk of incident Alzheimer's disease in a long‐run longitudinal study and a meta‐analysis of published studies is examined.
Abstract: Background We examine whether broad factors and specific facets of personality are associated with increased risk of incident Alzheimer's disease (AD) in a long-run longitudinal study and a meta-analysis of published studies. Methods Participants (n = 1671) were monitored for up to 22 years from a baseline personality assessment. The meta-analysis pooled results from up to five prospective studies (n = 5054). Results Individuals with scores in the top quartile of neuroticism (hazard ratio=3.1; 95% confidence interval=1.6–6.0) or the lowest quartile of conscientiousness (hazard ratio = 3.3; 95% confidence interval=1.4–7.4) had a threefold increased risk of incident AD. Among the components of these traits, self-discipline and depression had the strongest associations with incident AD. The meta-analysis confirmed the associations of neuroticism ( P = 2 × 10 −9 ) and conscientiousness ( P = 2 × 10 −6 ), along with weaker effects for openness and agreeableness ( P Conclusions The current study and meta-analysis indicate that personality traits are associated with increased risk of AD, with effect sizes similar to those of well-established clinical and lifestyle risk factors.

Journal ArticleDOI
TL;DR: The study aimed to validate previously discovered plasma biomarkers associated with AD, using a design based on imaging measures as surrogate for disease severity and assess their prognostic value in predicting conversion to dementia.
Abstract: Background The study aimed to validate previously discovered plasma biomarkers associated with AD, using a design based on imaging measures as surrogate for disease severity and assess their prognostic value in predicting conversion to dementia. Methods Three multicenter cohorts of cognitively healthy elderly, mild cognitive impairment (MCI), and AD participants with standardized clinical assessments and structural neuroimaging measures were used. Twenty-six candidate proteins were quantified in 1148 subjects using multiplex (xMAP) assays. Results Sixteen proteins correlated with disease severity and cognitive decline. Strongest associations were in the MCI group with a panel of 10 proteins predicting progression to AD (accuracy 87%, sensitivity 85%, and specificity 88%). Conclusions We have identified 10 plasma proteins strongly associated with disease severity and disease progression. Such markers may be useful for patient selection for clinical trials and assessment of patients with predisease subjective memory complaints.

Journal ArticleDOI
TL;DR: AD, which occurs in elderly, already vulnerable brains, with multiple age‐related changes, is precipitated by impaired microvascular function, resulting primarily from decreased Notch‐related angiogenesis, and with impaired microvasculature, a lack of vascular endothelial‐derived trophic factors and decreased cerebral blood flow cause the atrophy of neural structures.
Abstract: The "amyloid hypothesis" has dominated Alzheimer research for more than 20 years, and proposes that amyloid is the toxic cause of neural/synaptic damage and dementia. If correct, decreasing the formation or removing amyloid should be therapeutic. Despite discrepancies in the proposed mechanism, and failed clinical trials, amyloid continues to be considered the cause of a degenerative cascade. Alternative hypotheses must explain three features: ( i ) why amyloid toxicity is not the etiology of Alzheimer's disease (AD), ( ii ) what alternative mechanisms cause the degeneration and dementia of AD, and ( iii ) why increased amyloid accumulates in the brain in AD. We propose that AD, which occurs in elderly, already vulnerable brains, with multiple age-related changes, is precipitated by impaired microvascular function, resulting primarily from decreased Notch-related angiogenesis. With impaired microvasculature, a lack of vascular endothelial-derived trophic factors and decreased cerebral blood flow cause the atrophy of neural structures. Therapeutic strategies should focus on supporting normal angiogenesis.

Journal ArticleDOI
TL;DR: The objective of this study was to obtain external validation of the only available midlife dementia risk score cardiovascular risk factors, aging and dementia study (CAIDE) constituting age, education, hypertension, obesity, and hyperlipidemia in a larger, more diverse population.
Abstract: Objective The objective of this study was to obtain external validation of the only available midlife dementia risk score cardiovascular risk factors , aging and dementia study (CAIDE) constituting age, education, hypertension, obesity, and hyperlipidemia in a larger, more diverse population. Our second aim was to improve the CAIDE risk score by additional midlife risk factors. Methods This retrospective cohort study was conducted in an integrated health care delivery system. A total of 9480 Kaiser Permanente members who participated in a health survey study (age range, 40–55 years) from 1964 to 1973 were included in this study. Dementia diagnoses from primary care and medical specialist visits were collected from January 1, 1994 to January 16, 2006, using International Classification of Diseases 9 codes 290.0, 290.1 for “possible dementia,” and 331.0 and 290.4 for “specialist confirmed dementia.” Risk model prediction and validation were examined with the C statistic, net reclassification improvement, and integrated discrimination improvement. Dementia risk per sum score was calculated with Kaplan-Meier estimates. Results A total of 2767 participants (25%) were diagnosed with any type of dementia, of which 1011 diagnoses (10.7%) were specialist-confirmed diagnoses. Average time between midlife examination and end of follow-up was 36.1 years. The CAIDE risk score replicated well with a C statistic of 0.75, quite similar to the original CAIDE C statistic of 0.78. The CAIDE score also predicted well within different race strata. Other midlife risk factors (central obesity, depressed mood, diabetes mellitus, head trauma, lung function, and smoking) did not improve predictability. The risk score allowed stratification of participants into those with 40-year low (9%) and high (29%) dementia risk. Conclusions A combination of modifiable vascular risk factors in midlife is highly predictive of the likelihood of dementia decades later. Possible dementia prevention strategies should point to a life course perspective on maintaining vascular health.

Journal ArticleDOI
TL;DR: Nerve growth factor is an endogenous neurotrophic‐factor protein with the potential to restore function and to protect degenerating cholinergic neurons in Alzheimer's disease, but safe and effective delivery has proved unsuccessful.
Abstract: Background Nerve growth factor (NGF) is an endogenous neurotrophic-factor protein with the potential to restore function and to protect degenerating cholinergic neurons in Alzheimer's disease (AD), but safe and effective delivery has proved unsuccessful. Methods Gene transfer, combined with stereotactic surgery, offers a potential means to solve the long-standing delivery obstacles. An open-label clinical trial evaluated the safety and tolerability, and initial efficacy of three ascending doses of the genetically engineered gene-therapy vector adeno-associated virus serotype 2 delivering NGF (AAV2-NGF [CERE-110]). Ten subjects with AD received bilateral AAV2-NGF stereotactically into the nucleus basalis of Meynert. Results AAV2-NGF was safe and well-tolerated for 2 years. Positron emission tomographic imaging and neuropsychological testing showed no evidence of accelerated decline. Brain autopsy tissue confirmed long-term, targeted, gene-mediated NGF expression and bioactivity. Conclusions This trial provides important evidence that bilateral stereotactic administration of AAV2-NGF to the nucleus basalis of Meynert is feasible, well-tolerated, and able to produce long-term, biologically active NGF expression, supporting the initiation of an ongoing multicenter, double-blind, sham-surgery-controlled trial.

Journal ArticleDOI
TL;DR: Cerebrospinal fluid biomarkers β‐amyloid 1‐42 (Aβ1‐42) have proven diagnostic accuracy for mild cognitive impairment and Alzheimer's disease (AD).
Abstract: Background Cerebrospinal fluid (CSF) biomarkers β-amyloid 1-42 (Aβ 1-42 ), also expressed as Aβ 1-42 :Aβ 1-40 ratio, T-tau, and P-tau 181P , have proven diagnostic accuracy for mild cognitive impairment and Alzheimer's disease (AD). How to use, interpret, and disclose biomarker results drives the need for standardization. Methods Previous Alzheimer's Biomarkers Standardization Initiative meetings discussed preanalytical issues affecting Aβ 1-42 and tau in CSF. This second round of consensus meetings focused on issues related to clinical use of AD CSF biomarkers. Results Consensus was reached that lumbar puncture for AD CSF biomarker analysis be considered as a routine clinical test in patients with early-onset dementia, at the prodromal stage or with atypical AD. Moreover, consensus was reached on which biomarkers to use, how results should be interpreted, and potential confounding factors. Conclusions Changes in Aβ 1-42 , T-tau, and P-tau 181P allow diagnosis of AD in its prodromal stage. Conversely, having all three biomarkers in the normal range rules out AD. Intermediate conditions require further patient follow-up.

Journal ArticleDOI
TL;DR: The strongest associations of protein levels with AD outcomes were prostate-specific antigen complexed to α1-antichymotrypsin (AD diagnosis), pancreatic prohormone (ad diagnosis, left entorhinal cortex atrophy, and left hippocampus atrophy), clusterin (rate of cognitive decline), and fetuin B (left entorHinal atrophy).
Abstract: Blood proteins and their complexes have become the focus of a great deal of interest in the context of their potential as biomarkers of Alzheimer's disease (AD). We used a SOMAscan assay for quantifying 1001 proteins in blood samples from 331 AD, 211 controls, and 149 mild cognitive impaired (MCI) subjects. The strongest associations of protein levels with AD outcomes were prostate-specific antigen complexed to α1-antichymotrypsin (AD diagnosis), pancreatic prohormone (AD diagnosis, left entorhinal cortex atrophy, and left hippocampus atrophy), clusterin (rate of cognitive decline), and fetuin B (left entorhinal atrophy). Multivariate analysis found that a subset of 13 proteins predicted AD with an accuracy of area under the curve of 0.70. Our replication of previous findings provides further evidence that levels of these proteins in plasma are truly associated with AD. The newly identified proteins could be potential biomarkers and are worthy of further investigation.

Journal ArticleDOI
TL;DR: This work describes a biobanking system that is a platform for discovery research at the Center for Neurodegenerative Disease Research at the University of Pennsylvania and describes a flexible and user‐friendly database system that facilitates the sharing of information of all the teams in the network.
Abstract: Neurodegenerative diseases (NDs) are defined by the accumulation of abnormal protein deposits in the central nervous system (CNS), and only neuropathological examination enables a definitive diagnosis. Brain banks and their associated scientific programs have shaped the actual knowledge of NDs, identifying and characterizing the CNS deposits that define new diseases, formulating staging schemes, and establishing correlations between neuropathological changes and clinical features. However, brain banks have evolved to accommodate the banking of biofluids as well as DNA and RNA samples. Moreover, the value of biobanks is greatly enhanced if they link all the multidimensional clinical and laboratory information of each case, which is accomplished, optimally, using systematic and standardized operating procedures, and in the framework of multidisciplinary teams with the support of a flexible and user-friendly database system that facilitates the sharing of information of all the teams in the network. We describe a biobanking system that is a platform for discovery research at the Center for Neurodegenerative Disease Research at the University of Pennsylvania.

Journal ArticleDOI
TL;DR: This work proposes a general semiparametric model and iterative estimation procedure to estimate simultaneously the pathological timing and long‐term growth curves of Alzheimer's Disease Neuroimaging Initiative elders, and fine‐tuned using cognitive trajectories derived from the long-term “Personnes Agées Quid” study.
Abstract: Motivation Diseases that progress slowly are often studied by observing cohorts at different stages of disease for short periods of time. The Alzheimer's Disease Neuroimaging Initiative (ADNI) follows elders with various degrees of cognitive impairment, from normal to impaired. The study includes a rich panel of novel cognitive tests, biomarkers, and brain images collected every 6 months for as long as 6 years. The relative timing of the observations with respect to disease pathology is unknown. We propose a general semiparametric model and iterative estimation procedure to estimate simultaneously the pathological timing and long-term growth curves. The resulting estimates of long-term progression are fine-tuned using cognitive trajectories derived from the long-term "Personnes Agees Quid" study. Results We demonstrate with simulations that the method can recover long-term disease trends from short-term observations. The method also estimates temporal ordering of individuals with respect to disease pathology, providing subject-specific prognostic estimates of the time until onset of symptoms. When the method is applied to ADNI data, the estimated growth curves are in general agreement with prevailing theories of the Alzheimer's disease cascade. Other data sets with common outcome measures can be combined using the proposed algorithm. Availability Software to fit the model and reproduce results with the statistical software R is available as the grace package. ADNI data can be downloaded from the Laboratory of NeuroImaging.

Journal ArticleDOI
TL;DR: The first genome‐wide association study to examine rate of cognitive decline in a sample of AD patients with longitudinal measures of cognition is described.
Abstract: Background Substantial interindividual variability exists in the disease trajectories of Alzheimer's disease (AD) patients Some decline rapidly whereas others decline slowly, and there are no known explanations for this variability We describe the first genome-wide association study to examine rate of cognitive decline in a sample of AD patients with longitudinal measures of cognition Methods The discovery sample was 303 AD cases recruited in the Alzheimer's Disease Neuroimaging Initiative and the replication sample was 323 AD cases from the Religious Orders Study and Rush Memory and Aging Project In the discovery sample, Alzheimer's Disease Assessment Scale–cognitive subscale responses were tested for association with genome-wide single-nucleotide polymorphism (SNP) data using linear regression We tested the 65 most significant SNPs from the discovery sample for association in the replication sample Results We identified SNPs in the spondin 1 gene ( SPON1 ), the minor alleles of which were significantly associated with a slower rate of decline (rs11023139, P = 70 × 10 −11 ) in the discovery sample A SPON1 SNP 55 kb upstream was associated with decline in the replication sample (rs11606345, P = 002) Conclusion SPON1 has not been previously associated with AD risk, but is plausibly related because the gene product binds to the amyloid precursor protein and inhibits its cleavage by β-secretase These data suggest that SPON1 may be associated with the differential rate of cognitive decline in AD

Journal ArticleDOI
TL;DR: The hypothesis that reduced plasma 25‐hydroxyvitamin D (25[OH]D) is associated with increased risk of Alzheimer's disease (AD) and vascular dementia in the general population is tested.
Abstract: Background Vitamin D deficiency has been implicated as a risk factor for dementia in several cross-sectional studies. We tested the hypothesis that reduced plasma 25-hydroxyvitamin D (25[OH]D) is associated with increased risk of Alzheimer's disease (AD) and vascular dementia in the general population. Methods We measured baseline plasma 25(OH)D in 10,186 white individuals from the Danish general population. Results During 30 years of follow-up, 418 participants developed AD and 92 developed vascular dementia. Multivariable adjusted hazard ratios for AD were 1.25 (95% confidence interval [CI], 0.95–1.64) for 25(OH)D less than 25 nmol/L vs. greater than or equal to 50 nmol/L, and 1.29 (95% CI, 1.01–1.66) for less than the 25th seasonally adjusted 25(OH)D percentile vs. more than the 50th seasonally adjusted 25(OH)D percentile. Multivariable adjusted hazard ratios for vascular dementia were 1.22 (95% CI, 0.77–1.91) for 25(OH)D less than 50 nmol/L vs. greater than or equal to 50 nmol/L, and 1.22 (95% CI, 0.79–1.87) for less than or equal to the 50th vs. more than the 50th seasonally adjusted 25(OH)D percentile. Last, multivariable adjusted hazard ratios for the combined end point were 1.28 (95% CI, 1.00–1.64) for 25(OH)D less than 25 nmol/L vs. greater than or equal to 50 nmol/L, and 1.27 (95% CI, 1.01–1.60) for less than the 25th vs. more than the 50th seasonally adjusted 25(OH)D. Conclusions We observed an association of reduced plasma 25(OH)D with increased risk of the combined end point of AD and vascular dementia in this prospective cohort study of the general population.

Journal ArticleDOI
TL;DR: This manuscript summarizes the meeting of top scientists from around the world to discuss the state of blood based biomarker development, including potential next steps to move this area of research forward.
Abstract: Alzheimer's disease is the public health crisis of the 21st century. There is a clear need for a widely available, inexpensive and reliable method to diagnosis Alzheimer's disease in the earliest stages, track disease progression, and accelerate clinical development of new therapeutics. One avenue of research being explored is blood based biomarkers. In April 2012, the Alzheimer's Association and the Alzheimer's Drug Discovery Foundation convened top scientists from around the world to discuss the state of blood based biomarker development. This manuscript summarizes the meeting and the resultant discussion, including potential next steps to move this area of research forward.

Journal ArticleDOI
TL;DR: The association of type 2 diabetes with mild cognitive impairment ( MCI) and MCI subtype (aMCI and naMCI) overall and by sex is examined and the risk of nonamnestic MCI (naMCi) through vascular disease mechanisms is increased.
Abstract: Background Type 2 diabetes may increase the risk of amnestic mild cognitive impairment (aMCI) through Alzheimer's disease (AD)-related and vascular pathology and may also increase the risk of nonamnestic MCI (naMCI) through vascular disease mechanisms. We examined the association of type 2 diabetes with mild cognitive impairment (MCI) and MCI subtype (aMCI and naMCI) overall and by sex. Methods Participants were Olmsted County, Minnesota residents (70 years and older) enrolled in a prospective, population-based study. At baseline and every 15 months thereafter, participants were evaluated using the Clinical Dementia Rating scale, a neurological evaluation, and neuropsychological testing for a diagnosis of normal cognition, MCI, and dementia by a consensus panel. Type 2 diabetes was ascertained from the medical records of participants at baseline. Results Over a median 4.0 years of follow-up, 348 of 1450 subjects developed MCI. Type 2 diabetes was associated (hazard ratio [95% confidence interval]) with MCI (1.39 [1.08–1.79]), aMCI (1.58 [1.17–2.15]; multiple domain: 1.58 [1.01–2.47]; single domain: 1.49 [1.09–2.05]), and the hazard ratio for naMCI was elevated (1.37 [0.84–2.24]). Diabetes was strongly associated with multiple-domain aMCI in men (2.42 [1.31–4.48]) and an elevated risk of multiple domain naMCI in men (2.11 [0.70–6.33]), and with single domain naMCI in women (2.32 [1.04–5.20]). Conclusions Diabetes was associated with an increased risk of MCI in elderly persons. The association of diabetes with MCI may vary with subtype, number of domains, and sex. Prevention and control of diabetes may reduce the risk of MCI and Alzheimer's disease.

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TL;DR: Individuals with subjective memory impairment (SMI) report worsening of memory without impairment in cognitive tests, and they may be at higher risk of cognitive decline compared with individuals without SMI.
Abstract: Background Individuals with subjective memory impairment (SMI) report worsening of memory without impairment in cognitive tests. Despite normal cognitive performance, they may be at higher risk of cognitive decline compared with individuals without SMI. Methods We used a discriminative function (a support vector machine) trained on an independent data set of 226 healthy control subjects and 191 patients with probable Alzheimer's disease (AD) dementia to characterize the baseline gray matter patterns of 24 individuals with SMI and 53 control subjects. We tested for associations of these gray matter patterns with SMI presence, cognitive performance at baseline, and cognitive decline at follow-up. Results Individuals with SMI showed greater similarity to an AD gray matter pattern compared with control subjects without SMI. In addition, episodic memory decline was associated with an AD gray matter pattern in the SMI group. Conclusions Our results indicate a link between the gray matter atrophy pattern of patients with AD and the presence of SMI. Furthermore, multivariate pattern recognition approaches seem to be a sensitive method for identifying subtle brain changes that correspond to future memory decline in SMI.

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TL;DR: More well‐controlled, carefully executed longitudinal studies are needed to confirm the apparent association between stress and dementia, clarify causal relationships, develop reliable antemortem markers, and delineate distinct patterns of risk in subsets of individuals.
Abstract: The physiological consequences of acute and chronic stress on a range of organ systems have been well documented after the pioneering work of Hans Selye more than 70 years ago. More recently, an association between exposure to stressful life events and the development of later-life cognitive dysfunction has been proposed. Several plausible neurohormonal pathways and genetic mechanisms exist to support such an association. However, many logistical and methodological barriers must be overcome before a defined causal linkage can be firmly established. Here the authors review recent studies of the long-term cognitive consequences of exposures to cumulative ordinary life stressors as well as extraordinary traumatic events leading to posttraumatic stress disorder. Suggestive effects have been demonstrated for the role of life stress in general, and posttraumatic stress disorder in particular, on a range of negative cognitive outcomes, including worse than normal changes with aging, Alzheimer's disease, and vascular dementia. However, given the magnitude of the issue, well-controlled studies are relatively few in number, and the effects they have revealed are modest in size. Moreover, the effects have typically only been demonstrated on a selective subset of measures and outcomes. Potentially confounding factors abound and complicate causal relationships despite efforts to contain them. More well-controlled, carefully executed longitudinal studies are needed to confirm the apparent association between stress and dementia, clarify causal relationships, develop reliable antemortem markers, and delineate distinct patterns of risk in subsets of individuals.

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TL;DR: The annual number of deaths in the United States among older adults with AD from 2010 to 2050 is estimated and shows that the burden of AD in the population is understated.
Abstract: Background Alzheimer's disease (AD) profoundly affects the end-of-life experience. Yet, counts of deaths attributable to AD understate this burden of AD in the population. Therefore, we estimated the annual number of deaths in the United States among older adults with AD from 2010 to 2050. Methods We calculated probabilities of AD incidence and mortality from a longitudinal population-based study of 10,802 participants. From this population, 1913 previously disease-free individuals, selected via stratified random sampling, underwent 2577 detailed clinical evaluations. Over the course of follow-up, 990 participants died. We computed age-, sex-, race-, and education-specific AD incidences and education-adjusted AD mortality proportions specific to age, sex, and race group. We then combined these probabilities with US-wide census, education, and mortality data. Results In 2010, approximately 600,000 deaths occurred among individuals aged 65 years or older with AD, comprising 32% of all older adult deaths. By 2050, this number is projected to be 1.6 million, 43% of all older adult deaths. Conclusion Individuals with AD comprise a substantial number of older adult deaths in the United States, a number expected to rise considerably in coming decades.

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TL;DR: Current preclinical AD biomarkers are examined and how to generalize their use going forward is suggested, in the hope of defining a therapeutic window in which the neural substrate remains responsive to treatment.
Abstract: The increasing number of afflicted individuals with late-onset Alzheimer's disease (AD) poses significant emotional and financial burden on the world's population. Therapeutics designed to treat symptoms or alter the disease course have failed to make an impact, despite substantial investments by governments, pharmaceutical industry, and private donors. These failures in treatment efficacy have led many to believe that symptomatic disease, including both mild cognitive impairment (MCI) and AD, may be refractory to therapeutic intervention. The recent focus on biomarkers for defining the preclinical state of MCI/AD is in the hope of defining a therapeutic window in which the neural substrate remains responsive to treatment. The ability of biomarkers to adequately define the at-risk state may ultimately allow novel or repurposed therapeutic agents to finally achieve the disease-modifying status for AD. In this review, we examine current preclinical AD biomarkers and suggest how to generalize their use going forward.

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TL;DR: Epidemiologic studies on mild cognitive impairment (MCI) are limited in China and the need for further studies to establish a causative factor for MCI is still unclear.
Abstract: Background Epidemiologic studies on mild cognitive impairment (MCI) are limited in China. Methods Using a multistage cluster sampling design, a total of 10,276 community residents (6096 urban, 4180 rural) aged 65 years or older were evaluated and diagnosed with normal cognition, MCI, or dementia. MCI was further categorized by imaging into MCI caused by prodromal Alzheimer's disease (MCI-A), MCI resulting from cerebrovascular disease (MCI-CVD), MCI with vascular risk factors (MCI-VRF), and MCI caused by other diseases (MCI-O). Results The prevalences of overall MCI, MCI-A, MCI-CVD, MCI-VRF, and MCI-O were 20.8% (95% confidence interval [CI] = 20.0–21.6%), 6.1% (95% CI = 5.7–6.6%), 3.8% (95% CI = 3.4–4.2%), 4.9% (95% CI = 4.5–5.4%), and 5.9% (95% CI = 5.5–6.4%) respectively. The rural population had a higher prevalence of overall MCI (23.4% vs 16.8%, P Conclusions The prevalence of MCI in elderly Chinese is higher in rural than in urban areas. Vascular-related MCI (MCI-CVD and MCI-VRF) was most common.