Alzheimer's & Dementia: The Journal of the Alzheimer's Association

Requiring an amyloid-β1-42 biomarker for prodromal Alzheimer's disease or mild cognitive impairment does not lead to more efficient clinical trials

2010-09-01

Abstract: Background: Low cerebrospinal fluid (CSF) amyloid-β1-42 concentration and high total-tau/Aβ1-42 ratio have been recommended to support the diagnosis of prodromal Alzheimer's disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and also to select patients for clinical trials (Shaw et al, Ann Neurol 2009;65:403–13; Dubois et al, Lancet Neurol 2007;6:734–46).Methods: We tested this recommendation with clinical trials simulations using patients from the Alzheimer Disease Neuroimaging Initiative who fulfilled the following entry criteria: (1) aMCI, (2) aMCI with CSF Aβ1-42 ≤192 mg/mL, (3) and aMCI with total-tau/Aβ1-42 >0.39. For each criterion, we randomly resampled the database obtaining samples for 1000 trials for each trial scenario, planning for 1 or 2 year trials with samples from 50 to 400 patients per treatment or placebo group, with up to 40% dropouts, outcomes after using the AD assessment scale-cognitive subscale and clinical dementia rating scale with effect sizes ranging from 0.15 to 0.75, and calculated statistical power.Findings: Approximately 70% to 74% of aMCI patients with CSF measures met biomarker criteria. The addition of the low Aβ1-42 or high tau/Aβ1-42 requirement resulted in minimal or no increase in the power of the trials compared with enrolling aMCI without requiring the biomarker criteria. Slightly larger mean differences between the placebo and treatment groups fulfilling biomarker criteria were offset by increased outcome variability within the groups.Interpretations: Although patients with aMCI or patients with prodromal AD meeting CSF biomarkers criteria were slightly more cognitively impaired and showed greater decline than patients with aMCI diagnosed without considering the biomarkers, the requirement of biomarker-positive patients would most likely not result in more efficient clinical trials, and trials would take longer because fewer patients would be available. A CSF Aβ1-42 marker, however, could be useful as an explanatory variable or covariate when warranted by the action of a drug.

Plasma ceramides are altered in mild cognitive impairment and predict cognitive decline and hippocampal volume loss

2010-09-01

Abstract: Background: A blood-based biomarker of Alzheimer's disease (AD) would be superior to cerebrospinal fluid (CSF) and neuroimaging measures in terms of cost, invasiveness, and feasibility for repeated measures. We previously reported that blood ceramides varied in relation to timing of memory impairment in a population-based study. The present objective was to examine whether plasma ceramides varied by AD severity in a well-characterized clinic sample and were associated with cognitive decline and hippocampal volume loss over 1 year.Methods: Participants included 25 normal controls (NC), 17 amnestic Mild Cognitive Impairment (MCI), and 21 early probable AD. A thorough neuropsychological battery and neuroimaging with hippocampal volume determination were conducted at baseline and 1 year later. Plasma ceramides were assayed at baseline using high performance liquid chromatography coupled electrospray ionization tandem mass spectrometry.Results: Although all saturated ceramides were lower in MCI compared with AD at baseline, ceramides C22:0 and C24:0 were significantly lower in the MCI group compared with both NC and AD groups (P < .01). Ceramide levels did not differ (P > .05) in AD versus NC. There were no cross-sectional associations between ceramides C22:0 and C24:0 and either cognitive performance or hippocampal volume among any group. However, among the MCI group, higher baseline ceramide C22:0 and C24:0 levels were predictive of cognitive decline and hippocampal volume loss 1 year later.Conclusion: Results suggest that very long-chain plasma ceramides C22:0 and C24:0 are altered in MCI and predict memory loss and right hippocampal volume loss among subjects with MCI. These plasma ceramides may be early indicators of AD progression.

Drug treatment of Alzheimer's disease patients leads to expression changes in peripheral blood cells

Margaret A. Calciano, Weiyin Zhou, Peter J. Snyder, Richard Einstein — 2010-02-26

Abstract: Background: Increasing cholinergic activity has been the primary mechanism for treating dementia due to Alzheimer's disease. However, the effectiveness of cholinesterase inhibitors (ChEIs) is still widely debated. The identification of specific biomarkers capable of identifying patients more likely to respond to these treatments could potentially provide specific evidence to clearly address this controversy through patient stratification. The goal of this study was to determine the feasibility of discovering biomarkers specific for the treatment of Alzheimer's disease.Methods: Peripheral blood was collected from a cohort of patients treated with different ChEIs. Total RNA was isolated and profiled on the human Genome-Wide SpliceArray (GWSA) to test the feasibility of discriminating the different treatment subgroups of subjects based on the expression patterns generated from the Genome-Wide SpliceArray.Results: Specific expression differences were identified for the various treatment groups that lead to a clear separation between patients treated with ChEIs versus naïve patients when Principal Component Analysis was performed on probe sets selected for differential expression. In addition, specific probe sets were identified to be dependent on the inhibitor used among the treated patients.Conclusions: Distinct separation between non-treated, galantamine, donepezil, and rivastigmine-treated patients was clearly identified based on small sets of expression probes. The ability to identify drug-specific treatment expression differences strengthens the potential for using peripheral gene signatures for the identification of individuals responding to drug treatment.

White matter is altered with parental family history of Alzheimer's disease

2010-08-16

Abstract: Background: Brain alterations in structure and function have been identified in people with risk factors for sporadic type Alzheimer's disease (AD), suggesting that alterations can be detected decades before AD diagnosis. Although the effect of apolipoprotein E (APOE) ɛ4 on the brain is well-studied, less is known about the effect of family history of AD. We examined the main effects of family history and APOE ɛ4 on brain integrity, in addition to assessing possible additive effects of these two risk factors.Methods: Diffusion tensor imaging was performed in 136 middle-aged asymptomatic participants stratified on family history and APOE ɛ4. Mean diffusivity and fractional anisotropy (FA) were entered in factorial analyses to test the effect of AD risk on microstructural brain integrity. We performed a post hoc analysis of the three principal diffusivities (λ1, λ2, λ3) to provide potential additional insight on underlying tissue differences.Results: Parental family history of AD was associated with lower FA in regions of the brain known to be affected by AD, including cingulum, corpus callosum, tapetum, uncinate fasciculus, hippocampus, and adjacent white matter. Contrary to previous reports, there was no main effect of APOE ɛ4; however, there was an additive effect of family history and APOE ɛ4 in which family history–positive participants who were also APOE ɛ4 carriers had the lowest FA compared with the other groups.Conclusions: The data indicate that unknown risk factors contained in family history are associated with changes in microstructural brain integrity in areas of the brain known to be affected by AD. Importantly, the results provide further evidence that AD pathology might be detected before cognitive changes, perhaps decades before disease onset.

Cerebral atrophy, apolipoprotein E ɛ4, and rate of decline in everyday function among patients with amnestic mild cognitive impairment

2010-09-01

Abstract: Background: Patients with amnestic mild cognitive impairment (MCI) demonstrate decline in everyday function. In this study, we investigated whether whole brain atrophy and apolipoprotein E (APOE) genotype are associated with the rate of functional decline in MCI.Methods: Participants were 164 healthy controls, 258 MCI patients, and 103 patients with mild Alzheimer's disease (AD), enrolled in the Alzheimer's Disease Neuroimaging Initiative. They underwent brain MRI scans, APOE genotyping, and completed up to six biannual Functional Activities Questionnaire (FAQ) assessments. Random effects regressions were used to examine trajectories of decline in FAQ across diagnostic groups, and to test the effects of ventricle-to-brain ratio (VBR) and APOE genotype on FAQ decline among MCI patients.Results: Rate of decline in FAQ among MCI patients was intermediate between that of controls and mild AD patients. Patients with MCI who converted to mild AD declined faster than those who remained stable. Among MCI patients, increased VBR and possession of any APOE ɛ4 allele were associated with faster rate of decline in FAQ. In addition, there was a significant VBR by APOE ɛ4 interaction such that patients who were APOE ɛ4 positive and had increased atrophy experienced the fastest decline in FAQ.Conclusions: Functional decline occurs in MCI, particularly among patients who progress to mild AD. Brain atrophy and APOE ɛ4 positivity are associated with such declines, and patients who have elevated brain atrophy and are APOE ɛ4 positive are at greatest risk of functional degradation. These findings highlight the value of genetic and volumetric MRI information as predictors of functional decline, and thus disease progression, in MCI.

Influence of apolipoprotein E ɛ4 on rates of cognitive and functional decline in mild cognitive impairment

2010-09-01

Abstract: Background: Apolipoprotein E ɛ4 (APOE ɛ4) allele carrier status has been well established as a risk factor for developing Alzheimer's disease. However, the specific influence of APOE ɛ4 allele status on cognitive and functional rates of decline in mild cognitive impairment (MCI) is poorly understood. We examine the prospective association of APOE ɛ4 allele status on measures of cognitive and functional decline in subjects with amnestic MCI (aMCI).Methods: A total of 516 aMCI participants aged 55–90 years who received placebo or vitamin E from the Alzheimer's Disease Cooperative Study's MCI treatment trial were evaluated. During the 36-month study period, neurocognitive and functional measures were collected. These measures were assessed over time for change and association with APOE ɛ4 status. Generalized Estimating Equations were performed to model each outcome measure over the study period.Results: APOE ɛ4 status had a significant impact on cognitive and functional decline on multiple measures; those who were APOE ɛ4 positive had significantly more rapid decline in performance on all cognitive and functional measures except Number Cancellation and Maze tracing (P < .05). The greatest decline was seen in global measures of cognition and function including the Clinical Diagnostic Rating scale, followed by the Mini-Mental State Examination, Global Deterioration scale, and the Alzheimer's Disease Assessment Scale-Cognitive Subscale.Conclusions: These findings demonstrate that APOE ɛ4 genotype is predictive of increased general rates of decline with global measures of cognition and function most affected. With accelerated declines in common clinical trial primary efficacy measures, APOE ɛ4 status needs to be accounted for in treatment trials of MCI.

Alzheimer's disease, a multifactorial disorder seeking multitherapies

Khalid Iqbal, Inge Grundke-Iqbal — 2010-09-01

Abstract: Alzheimer's disease (AD) is multifactorial and apparently involves several different etiopathogenic mechanisms. There are at least five subgroups of AD based on cerebrospinal fluid levels of Aβ1–42, a marker of beta-amyloid (Aβ) plaques, and tau and ubiquitin, two markers of neurofibrillary tangles. These different AD subgroups may respond differently to a given disease-modifying drug, and hence, different therapeutic drugs for different disease subgroups might be required. Stratification of AD patients by disease subgroups in clinical trials is critical to the successful development of potent disease-modifying drugs. Levels of disease markers in the cerebrospinal fluid are promising, both in identifying various subgroups of AD and in monitoring the response to therapeutic drugs.

Web-based application to project the burden of Alzheimer's disease

2010-08-06

Abstract: Background: Health care planning and research would benefit from tools that enable researchers to project the future burden of Alzheimer's disease (AD) and evaluate the effect of potential interventions.Methods: We created a web-based application of the AD prevalence model developed by Brookmeyer et al (Am J Public Health 1998;88:1337–42; Alzheimers Dement 2007;3:186–91). The user defines the disease parameters and any interventions that may either reduce risk or slow disease progression. We expanded the parameters to include the cost and weights for disability-adjusted life years.Application: The secure, web-based application generates detailed AD projections for each calendar year to 2050, and allows users to create personal accounts for them to save, retrieve, and modify the input parameters. The flexibility of the application is illustrated with a forecast for the state of Maryland, USA.Conclusions: The application generates AD burden projections, costs, and disability-adjusted life years, along with changes associated with potential interventions.

Alzheimer's Association Update September 2010

2010-09-01

Nearly 4,000 researchers from 60 countries gathered in Honolulu, Hawaii, July 10–15 to learn the latest in Alzheimer research at the Alzheimer's Association International Conference on Alzheimer's Disease (AAICAD) 2010. The world's largest gathering of Alzheimer's disease (AD) researchers included a full day of presentations focused on imaging technologies related to early detection and diagnosis of AD. The Alzheimer's Imaging Consortium drew a record 800 attendees to this burgeoning area of research.

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2010-09-01

Editorial Board

2010-09-01

Medical and Scientific Advisory Council

2010-09-01

Alzheimer's & Dementia: The Journal of the Alzheimer's Association

Requiring an amyloid-β1-42 biomarker for prodromal Alzheimer's disease or mild cognitive impairment does not lead to more efficient clinical trials

Plasma ceramides are altered in mild cognitive impairment and predict cognitive decline and hippocampal volume loss

Drug treatment of Alzheimer's disease patients leads to expression changes in peripheral blood cells

White matter is altered with parental family history of Alzheimer's disease

Cerebral atrophy, apolipoprotein E ɛ4, and rate of decline in everyday function among patients with amnestic mild cognitive impairment

Influence of apolipoprotein E ɛ4 on rates of cognitive and functional decline in mild cognitive impairment

Alzheimer's disease, a multifactorial disorder seeking multitherapies

Web-based application to project the burden of Alzheimer's disease

Alzheimer's Association Update September 2010

Subscriber Information

Contents

Editorial Board

Medical and Scientific Advisory Council