The A4 Study: Stopping AD Before Symptoms Begin?

Sperling, Reisa A.; Rentz, Dorene M.; Johnson, Keith A.; Karlawish, Jason; Donohue, Michael C.; Salmon, David P.; Aisen, Paul S.

doi:10.1126/scitranslmed.3007941

Cited by 636 publications

(615 citation statements)

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“…Among more recently developed AD-specific drugs, only one is currently being tested in sporadic AD prevention. The A4 Study plans to test the efficacy of solanezumab (a humanized monoclonal anti-Ab antibody) in 1000 clinically normal older individuals identified as at-risk for progression to AD dementia due to brain amyloid accumulation on positron emission tomography (PET) imaging [33]. Furthermore, some prevention trials are testing antiamyloid therapies in autosomal-dominant AD [34,35].…”

Section: Ad-specific Drugsmentioning

confidence: 99%

“…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%

“…Several prevention trials have begun to use biomarkers as outcome measures [33,34,[78][79][80], but predominantly as secondary rather than primary outcome measures because no AD biomarker has yet been validated as a surrogate endpoint [81,82].…”

Section: Endpointsmentioning

confidence: 99%

“…Preventive interventions can, therefore, now be tested in pre-dementia stages of AD, which is now widely regarded as 'secondary' or 'tertiary' prevention, depending on whether or not cognitive impairment is also present [19]. The ongoing A4 trial is an example of such a trial [33]. Genetic inclusion criteria may also be used to target individuals at increased risk of AD.…”

Section: Target Populationmentioning

confidence: 99%

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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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Section: Ad-specific Drugsmentioning

confidence: 99%

Section: Endpointsmentioning

confidence: 99%

Section: Endpointsmentioning

confidence: 99%

Section: Target Populationmentioning

confidence: 99%

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

2015

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“…In the US most of the preventive trials are based on biomarkers and targeted drug approach (1)(2)(3)(4), in the EU most of the large European funded trials focuses on multidomain intervention (5,6). These different approaches will have probably to joint together in the future.…”

mentioning

confidence: 99%

Preventive trials for Alzheimer's diseases: The multi-domain and the targeted therapies approaches will have to be associated

Lin¹,

Dong

Vellas

2016

The Journal of nutrition, health and aging

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Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment

Resnick

Matsumoto

Stephens‐Shields

et al. 2017

JAMA

186

111

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IMPORTANCEMost cognitive functions decline with age. Prior studies suggest that testosterone treatment may improve these functions.OBJECTIVE To determine if testosterone treatment compared with placebo is associated with improved verbal memory and other cognitive functions in older men with low testosterone and age-associated memory impairment (AAMI). DESIGN, SETTING, AND PARTICIPANTSThe Testosterone Trials (TTrials) were 7 trials to assess the efficacy of testosterone treatment in older men with low testosterone levels. The Cognitive Function Trial evaluated cognitive function in all TTrials participants. In 12 US academic medical centers, 788 men who were 65 years or older with a serum testosterone level less than 275 ng/mL and impaired sexual function, physical function, or vitality were allocated to testosterone treatment (n = 394) or placebo (n = 394). A subgroup of 493 men met criteria for AAMI based on baseline subjective memory complaints and objective memory performance. Enrollment in the TTrials began June 24, 2010; the final participant completed treatment and assessment in June 2014.INTERVENTIONS Testosterone gel (adjusted to maintain the testosterone level within the normal range for young men) or placebo gel for 1 year. MAIN OUTCOMES AND MEASURESThe primary outcome was the mean change from baseline to 6 months and 12 months for delayed paragraph recall (score range, 0 to 50) among men with AAMI. Secondary outcomes were mean changes in visual memory (Benton Visual Retention Test; score range, 0 to −26), executive function (Trail-Making Test B minus A; range, −290 to 290), and spatial ability (Card Rotation Test; score range, −80 to 80) among men with AAMI. Tests were administered at baseline, 6 months, and 12 months. RESULTS Among the 493 men with AAMI (mean age, 72.3 years [SD, 5.8]; mean baseline testosterone, 234 ng/dL [SD, 65.1]), 247 were assigned to receive testosterone and 246 to receive placebo. Of these groups, 247 men in the testosterone group and 245 men in the placebo completed the memory study. There was no significant mean change from baseline to 6 and 12 months in delayed paragraph recall score among men with AAMI in the testosterone and placebo groups (adjusted estimated difference, −0.07 [95% CI, −0.92 to 0.79]; P = .88). Mean scores for delayed paragraph recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12 months in the testosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12 months in the placebo group. Testosterone was also not associated with significant differences in visual memory (−0.28 [95% CI, −0.76 to 0.19]; P = .24), executive function (−5.51 [95% CI, −12.91 to 1.88]; P = .14), or spatial ability (−0.12 [95% CI, −1.89 to 1.65]; P = .89).CONCLUSIONS AND RELEVANCE Among older men with low testosterone and age-associated memory impairment, treatment with testosterone for 1 year compared with placebo was not associated with improved memory or other cognitive functions.

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The A4 Study: Stopping AD Before Symptoms Begin?

Abstract: A secondary prevention trial in older people with amyloid accumulation at high risk for Alzheimer’s disease dementia should provide insights into whether anti-amyloid therapy can delay cognitive decline.

Cited by 636 publications

References 10 publications

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

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

Preventive trials for Alzheimer's diseases: The multi-domain and the targeted therapies approaches will have to be associated

Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment

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