The Preclinical Alzheimer Cognitive Composite

Donohue, Michael; Sperling, Reisa A.; Salmon, David P.; Rentz, Dorene M.; Raman, Rema; Thomas, Ronald G.; Weiner, Michael; Aisen, Paul S.

doi:10.1001/jamaneurol.2014.803

Cited by 583 publications

(654 citation statements)

References 44 publications

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“…Nonetheless, the strength and consistency of our results with that in sporadic Alzheimer's disease is important because they suggest that strategies designed to increase CNS BDNF levels may be a viable therapeutic alternative or addition to those which seek to reduce the neurotoxic effects of amyloid-b. Our results also suggest strongly that the BDNF Val66Met polymorphism should be considered as a potential moderator of clinical trial outcomes in current treatment and prevention trials in ADAD and sporadic Alzheimer's disease (Mills et al, 2013;Donohue et al, 2014).…”

Section: Discussionsupporting

confidence: 56%

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BDNFVal66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease

Lim

Hassenstab

Cruchaga

et al. 2016

Brain

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) for a scientific commentary on this article. The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-b-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer's disease. However, the effect of BDNF in autosomal dominant Alzheimer's disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-b in preclinical autosomal dominant Alzheimer's disease. We explored effects of apolipoprotein E (APOE) "4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation noncarriers and 143 preclinical autosomal dominant Alzheimer's disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val 66 homozygotes, 48 Met 66 carriers). Among preclinical mutation carriers, Met 66 carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val 66 homozygotes. Cortical amyloid-b and cerebrospinal fluid amyloidb 42 levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val 66 homozygotes and Met 66 carriers. There was an effect of APOE on amyloid-b levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer's disease, the deleterious effects of amyloid-b on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer's disease mutation carriers are greater in Met 66 carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-b in autosomal dominant Alzheimer's disease.

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Section: Discussionsupporting

confidence: 56%

“…Standardized scores were then averaged to form four cognitive domain-specific composite scores (Donohue et al, 2014).…”

Section: Neuropsychological Assessmentmentioning

confidence: 99%

BDNFVal66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease

Lim

Hassenstab

Cruchaga

et al. 2016

Brain

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“…For example, the Alzheimer's Disease Cooperative Studies-Preclinical Alzheimer's Cognitive Composite, the primary outcome measure in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's study, is a composite of episodic memory, list learning, digit symbol substitution, and the Mini Mental State Examination. 14 While it has shown promise in retrospective analyses of observational studies, it has not yet been fully validated.…”

Section: Mobile Cognitive Outcomesmentioning

confidence: 99%

Mobile and pervasive computing technologies and the future of Alzheimer’s clinical trials

2018

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The rapid growth of mobile phones, automated speech recognizing personal assistants, and internet access among the elderly provides new opportunities for incorporating such technologies into clinical research and personalized medical care. Alzheimer's disease is a good test case given the need for early detection, the high rate of clinical trial failures, the need to more efficiently recruit patients for trials, and the need for sensitive and ecologically valid trial outcomes.

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“…These measures target either specific cognitive domains, particularly memory, or global cognitive function measured by global tests, such as the Mini-Mental State Examination (MMSE), or batteries of multiple cognitive tests. Composite cognitive outcome measures, focusing in particular on memory and executive function, have recently begun to be developed, and constitute the primary outcome measure for several ongoing trials [33,[72][73][74]. Such measures aim to detect early cognitive changes and essentially serve as surrogate endpoints for AD incidence.…”

Section: Endpointsmentioning

confidence: 99%

“…However, to date there are only very limited data about trajectories of cognitive decline measured by these composite measures. Further validation is still required, especially in prospective studies, to determine the optimal weighting of the different components, responsiveness, the clinical relevance of cognitive changes on such measures, and whether or not a significant treatment effect would actually translate into a reduction in the number of cases of clinically apparent AD [72,75,76].…”

Section: Endpointsmentioning

confidence: 99%

Prevention Studies in Alzheimer’s Disease: Progress Towards the Development of New Therapeutics

2015

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Alzheimer's disease (AD) is the most common form of dementia and is a major cause of disability and dependency amongst older people. AD drugs approved so far are symptomatic treatments and are not thought to affect the underlying disease process. Trials conducted with agents aiming to slow or stop disease progression in patients with AD have all failed, perhaps because they were tested too late in the disease process. Therefore, there has been a move towards prevention of AD. This paper presents an overview of trials testing pharmacological interventions for sporadic AD prevention. Those tested to date were initially developed for the treatment of AD or for the treatment of other conditions, rather than being specifically developed for AD prevention. Associated issues, such as evidence of 'proof-of-concept,' doses and safety, are discussed. A major shift has taken place in the methodology of AD prevention trials since the results of the first trials were published in the 1990s. New directions that are currently being considered in ongoing or future prevention trials are discussed, in terms of endpoints, target populations, and study design. The use of AD-specific drugs to prevent AD in high-risk individuals is currently limited by a lack of validated predictive and surrogate markers. Population approaches, such as lifestyle changes, are an alternative strategy that could be of public health interest, but may provide only limited benefits for individuals. The best chance of preventing AD may come from a combination of individual and population prevention approaches. Key PointsFollowing the failure of treatment trials in symptomatic Alzheimer's disease (AD), there has been a move towards prevention of AD.To date, no specific pharmacological intervention has been developed for sporadic AD prevention and trial results have been disappointing.A major shift has taken place in the methodology of AD prevention trials and new directions are being considered in terms of endpoints, target populations, and study design.

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The Preclinical Alzheimer Cognitive Composite

Cited by 583 publications

References 44 publications

BDNFVal66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease

BDNFVal66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease

Mobile and pervasive computing technologies and the future of Alzheimer’s clinical trials

Prevention Studies in Alzheimer’s Disease: Progress Towards the Development of New Therapeutics

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