The potential and limits for clinical trials for early Alzheimer’s disease and some recommendations

Abstract

Recommendations for clinical trials methods for 'pre-dementia,' 'prodromal,' or early Alzheimer's disease are discussed. Early AD can be considered as subsets of both 'amnestic MCI' and 'probable AD.' In principle, it can be operationalized using recently proposed, new research criteria for AD that specifically does not require impairment in non-memory cognitive function and activities of daily living, and consequently does not require the presence of dementia. The criteria also require patients to show abnormal putative biomarkers but require validation. Trials in early AD should be done when models of drug action and response suggest that the drug in development likely would be effective in early AD and clinical effects could be expected in a relatively short time.Biomarkers should be used as stratification or explanatory variables that may help to explain clinical outcomes from early AD trials rather than as inclusion/exclusion criteria in order to avoid pseudospecificity.Trials should be multicentered, double-blinded, randomized, placebo-controlled, generally with dose-ranging of two doses if indicated. Duration of trials should be based on expected onsets and durations of effects, and generally should be less than one year. Crossover trials should be considered when appropriate.Primary outcomes should specifically assess memory and include repeated assessments. Potential secondary outcomes could include self-and observer-rated health-related quality of life and global impressions of change in lieu of activities of daily living. Onset of dementia should not be an endpoint because many patients would be on the cusp of dementia and dementia onset is influenced by numerous biological and environmental factors. Inferences that can be made from trials results will likely involve the effects of the test drug on memory and self-rated global function. Disease modification is not likely to be inferred except in trials over two years in duration in which a change in a biomarker can be used as an adjunctive assessment. Models and simulations using existing clinical trials databases would be helpful in planning early AD trials.

Repurposing antihypertensive drugs for the prevention of Alzheimer’s disease: a Mendelian Randomization study

“…In these trials, the proportion of dementia cases that derived from vascular mechanisms might be disproportionately high compared with other study populations. (34,35) This difference might explain the more favourable point estimate obtained in the meta-analysis. Since the publication of the meta-analysis, the first trial to consider an antihypertensive drug (calcium channel blocker Nilvadipine) as a direct intervention in Alzheimer's disease has been published -it found no benefit of the treatment.…”

Modifiable Predictors of Dementia in Mild Cognitive Impairment: A Systematic Review and Meta-Analysis

“…Biomarkers may also allow participants to be recruited when the pathological process is less advanced and treatments more effective. Incident dementia is often the primary outcome as dementia prevention is a clear goal, but Schneider has suggested it is a problematic endpoint because many participants would be on the cusp of dementia and dementia onset is influenced by numerous biological and environmental factors 101 .…”

Recruitment, retention and other methodological issues related to clinical trials for Alzheimer's disease

“…In the past few years, many drug trials have been conducted in the field of Alzheimer's disease (AD). While there has been much written (1)(2)(3)(4)(5)(6)(7)(8)(9) in this journal about methodological aspects of these trials --cognitive tests, global function and neuropsychiatric measures, biomarkers and imaging -strategies for recruitment and retention have been largely neglected. In fact, there has been virtually no research on these topics by either academia or industry over the past 20 years, despite the development of many trials.…”