Demonstration of brain accumulation of fibrillar amyloid beta protein via positron emission tomography (PET) with amyloid specific ligands may support the diagnosis of Alzheimer's disease (AD). There is increasing recognition of the potential use of amyloid imaging to detect in vivo the pathology of AD in individuals with no ostensible cognitive impairment. Research use of amyloid PET in cognitively normal patients will be key to pursuit of therapies able to delay cognitive impairment and dementia due to AD. We review the pros and cons of disclosing amyloid imaging results to cognitively normal individuals in clinical and research settings and provide draft recommendations.
ethics; disclosure; amyloid PET; Alzheimer's disease
Alzheimer’s disease (AD) research faces challenges to successful enrollment, especially to clinical trials and biomarker studies. Failure to recruit the planned number of participants in a timely fashion threatens the internal validity and success of clinical research, raising concerns about external validity and generalizability of results, and possibly leading to disparities in disease treatment. Methods to improve recruitment exist, but require varying levels of staff effort and financial resources and evidence of effectiveness is often lacking or inconsistent. In this review, we summarize some of the available methods to improve AD research recruitment, the available literature to support or refute these strategies, and some of the experiences at the authors’ AD Research Centers. We discuss the use of community-based participatory research principles and participant registries as a means to enhance research enrollment and increase diversity of research samples.
Alzheimer’s Disease; Recruitment; Registries; Clinical Trials; Community-Based Participatory Research; Research Participation
Persons at-risk for autosomal dominant neurodegenerative diseases provide the opportunity to efficiently test preventive interventions. Only a minority of such persons, however, choose to undergo revealing genetic testing, presenting a challenge to enrollment. Thirty-four preclinical Latinos (n = 26) and non-Latinos at-risk for familial Alzheimer’s disease (FAD) unaware of their genetic status were administered a questionnaire exploring their interest in undergoing revealing genetic testing at baseline and in the context of eligibility for four prevention trials of increasing invasiveness. Forty-four percent of subjects expressed a baseline interest in undergoing revealing testing which increased to 85% in order to be eligible for a study of an oral drug "felt to be very safe.” If there were a 50% chance of receiving placebo, this number dropped to 62% (p = 0.02). For those not interested in a study involving a 50% chance of receiving placebo, a range of 5% to 40% chance of receiving placebo was given as acceptable. For more invasive studies, living in the U.S. (as opposed to Mexico) positively influenced the likelihood of participating. Our data suggests that clinical trial designs in which persons must confront their genetic status prior to enrollment are feasible. Study designs to minimize the likelihood of being placed on placebo or provide the eventual administration of the drug through open-label extensions should be considered.
FAD; pre-symptomatic; genetic; testing; trials; prevention
Alzheimer's disease (AD) is a progressive neurodegenerative disease for which no cure exists. There is substantial need for new therapies that offer improved symptomatic benefit and disease-slowing capabilities. In recent decades there has been substantial progress in understanding the molecular and cellular changes associated with AD pathology. This has resulted in identification of a large number of new drug targets. These targets include but are not limited to therapies that aim to prevent production of or remove the beta amyloid (Aβ) protein that accumulates in neuritic plaques; prevent the hyperphosphorylation and aggregation into paired helical filaments of the microtubule-associated protein tau; and aim to keep neurons alive and functioning normally in the face of these pathologic challenges. We provide a review of these targets for drug development.
Alzheimer's disease; dementia; treatment; beta amyloid; tau; therapeutics; beta secretase; gamma secretase; immunotherapy
To identify facilitators and barriers to recruitment to clinical trials in preclinical Alzheimer’s disease (AD), fifty cognitively normal participants were interviewed after being randomized to one of two hypothetical AD risk scenarios: 1) the general age-related risk for AD, or 2) being at 50% increased risk for AD. Participants provided uncued barriers and facilitators to the hypothetical decision of whether they would enroll. Thirteen themes of facilitators and five themes of barriers were identified. The most common barrier was fear related to taking study drug. Those randomized to being at increased risk for AD more frequently cited lowering personal risk as a facilitator (p=0.01) and less frequently cited time as a barrier to enrollment (p=0.02). These results suggest potential challenges to recruitment to preclinical AD clinical trials and that disclosing risk information may enhance enrollment.
Alzheimer disease (AD) dementia clinical trials require 2 participants: a patient and a study partner. We assessed the prevalence of study partner types and how these types associate with patient-related outcome measures.
Retrospective analyses of 6 Alzheimer’s Disease Cooperative Study (ADCS) randomized clinical trials were conducted. Study partners were categorized as spouse, adult child, or other. Prevalence of study partner type and associations between study partner type and trial outcomes including study completion and placebo decline on the Mini-Mental State Examination, the Alzheimer’s Disease Assessment Scale–cognitive subscale, the Clinical Dementia Rating scale Sum of the Boxes score, and the ADCS–Activities of Daily Living were examined.
More participants (67%) enrolled with spouses than adult children (26%) or other study partners (7%). Participants with spouse partners had a lower dropout rate (25%) than those with adult child (32%) or other study partners (34%); only the difference vs others was statistically significant. Participants with adult child and other partners randomized to placebo performed worse at baseline than those with spouse partners on the ADCS–Activities of Daily Living (p = 0.04), but were not different at 18 months. There were no differences at baseline for the Mini-Mental State Examination, Clinical Dementia Rating scale Sum of the Boxes score, or Alzheimer’s Disease Assessment Scale–cognitive subscale. In multivariate models of the rates of change over time among placebo participants, no differences among study partner groups reached statistical significance.
Patients with nonspouse caregivers less frequently participate in AD dementia trials. Increased enrollment of AD patients with nonspouse caregivers may require additional recruitment and retention strategies.
This study modeled predementia Alzheimer’s disease (AD) clinical trials. Longitudinal data from cognitively normal (CN) and mild cognitive impairment (MCI) participants in the AD Neuroimaging Initiative were used to calculate sample size requirements for trials using outcome measures including: the Clinical Dementia Rating scale sum of boxes (CDR-sb), Mini Mental Status Examination (MMSE), AD assessment scale-cognitive subscale with and without delayed recall, and the Rey Auditory Verbal Learning task (RAVLT). We examined the impact on sample sizes of enrichment for genetic and biomarker criteria, including cerebrospinal fluid protein and neuroimaging analyses. We observed little cognitive decline in the CN population at 36 months, regardless of the enrichment strategy. Nonetheless, in CN subjects, using RAVLT total as an outcome at 36 months required the fewest subjects across enrichment strategies, with apolipoprotein E genotype ε4 carrier status requiring the fewest (n=499 per arm to demonstrate a 25% reduction in disease progression). In MCI, enrichment reduced the required sample sizes for trials, relative to estimates based on all subjects. For MCI, the CDR-sb consistently required the smallest sample sizes. We conclude that predementia clinical trial conduct in AD is enhanced by the use of biomarker inclusion criteria.
Alzheimer’s disease; clinical trials; mild cognitive impairment; preclinical; predementia; sample size; enrichment
Most patients with Alzheimer’s disease (AD) do not have a spouse. Despite this, the majority of AD research participants enroll with a spouse study partner. It remains unclear if differences between AD patients who do and do not have a spouse may bias study results. In this study, we examined whether AD patients with different study partner types (spouse vs adult child) demonstrate different rates of disease progression over two years on three outcome measures commonly used in AD research, including clinical trials. We used data from the National Alzheimer’s Coordinating Center Uniform Data Set to examine disease progression in participants age 55–90 with probable AD dementia. We examined disease progression as measured by the Clinical Dementia Rating Scale-Sum of the Boxes score, the Mini Mental Status Examination, and the Functional Assessment Questionnaire. Analyses were performed on data for all available eligible participants from the NACC UDS and after performing a propensity-matching model to better account for inherent differences between the populations of interest. Propensity matching was successful only when models did not include age and gender. For both propensity-matched analyses and those of all available data, we did not observe any differences between the study partner populations for any outcome measure. These results suggest that, if investigators can improve in recruiting AD patients with adult child caregivers to research, the implications to study results may be minimal.
Alzheimer’s disease; disease progression; caregivers; clinical trial; spouses; adult children
Alzheimer’s disease (AD) clinical trials enroll two participants: a patient and a study partner. The primary caregiver most often fills the role of study partner and most trial study partners are spousal caregivers.
AD trial inclusion criteria were applied to baseline data from 5674 probable AD dementia research participants in the National Alzheimer’s Coordinating Center Uniform Data Set. Eligibility was compared among patients with spousal, adult child, and other types of study partners.
Patients with spousal study partners were more frequently eligible than patients with adult child study partners. Compared to patients with spousal study partners, patients with adult child study partners were more frequently ineligible because of age, residence in skilled nursing facility, excluded low scores on the MMSE, excluded high score on Hachinski ischemia scale, and failure to fulfill a minimum number of weekly visits with the study partner.
In this sample, patients with adult child study partners were less likely to qualify for AD clinical trials than were patients with spousal study partners. This may contribute to the lower representation of patients with adult child caregivers in these studies.
Alzheimer’s disease; dementia; clinical trials; caregiver; study partner; recruitment
Designers of clinical trials for Alzheimer's disease (AD) and mild cognitive impairment (MCI) are actively considering structural and functional neuroimaging, cerebrospinal fluid and genetic biomarkers to reduce the sample sizes needed to detect therapeutic effects. Genetic pre-selection, however, has been limited to Apolipoprotein E (ApoE). Recently discovered polymorphisms in the CLU, CR1 and PICALM genes are also moderate risk factors for AD; each affects lifetime AD risk by ~ 10–20%. Here, we tested the hypothesis that pre-selecting subjects based on these variants along with ApoE genotype would further boost clinical trial power, relative to considering ApoE alone, using an MRI-derived 2-year atrophy rate as our outcome measure. We ranked subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) based on their cumulative risk from these four genes. We obtained sample size estimates in cohorts enriched in subjects with greater aggregate genetic risk. Enriching for additional genetic biomarkers reduced the required sample sizes by up to 50%, for MCI trials. Thus, AD drug trial enrichment with multiple genotypes may have potential implications for the timeliness, cost, and power of trials.
•ApoE genotype status helps enrich MCI trials, using a structural MRI outcome measure.•CLU, PICALM and CR1 risk genes boost potential MCI trial power beyond ApoE alone.•CLU, PICALM and CR1 show significant, aggregate effects on TBM maps of brain atrophy.
Alzheimer's disease; Neuroimaging; Brain atrophy; Genetics; Genetic risk score; Clinical trial enrichment
Among the key challenges in Alzheimer's disease drug development is the timely completion of clinical trials. Unfortunately, clinical trials often suffer from slow or insufficient enrollment. Successful clinical trial recruitment describes a balance between expeditiously achieving full enrollment and ensuring an appropriate study sample. Investigators face a number of challenges to the successful negotiation of this balance. The failure to address these challenges means that drug development may take more time and money and that trial results may not adequately represent drug efficacy or may not be applicable beyond the study. We review the challenges to recruitment and retention in Alzheimer's disease clinical trials and present a framework to address them.