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1.  Why are spousal caregivers more prevalent than nonspousal caregivers as study partners in AD dementia clinical trials? 
Most Alzheimer’s disease (AD) caregivers are not spouses and yet most AD dementia trials enroll spousal study partners. This study examines the association between caregiver relationship to the patient and willingness to enroll in an AD clinical trial and how caregiver burden and research attitudes modify willingness.
Interviews with 103 AD caregivers who met criteria for ability to serve as a study partner.
54% of caregivers were spouses or domestic partners and the remaining were adult children. Willingness to enroll a patient in a clinical trial was associated with being a spouse (OR = 2.53, p = 0.01), increasing age (OR = 1.39, p = 0.01), and increasing scores on the Research Attitudes Questionnaire (OR = 1.39, p < 0.001). No measures of caregiver burden or patient health were significant predictors of willingness. In multivariate models both research attitudes (OR = 1.37, p < 0.001) and being a spouse, as opposed to an adult child, (OR = 2.06, p = 0.048) were independently associated with willingness to participate.
Spousal caregivers had both a higher willingness to participate and a more positive attitude toward research. Caregiver burden had no association with willingness to participate. The strongest predictor of willingness was research attitudes.
PMCID: PMC4223007  PMID: 24805971
Alzheimer’s disease; clinical trial recruitment; caregiver; research attitudes; research ethics
2.  Choosing Alzheimer’s disease prevention clinical trial populations 
Neurobiology of aging  2013;35(3):10.1016/j.neurobiolaging.2013.09.001.
To assist investigators in making design choices, we modeled Alzheimer’s disease (AD) prevention clinical trials. We used longitudinal Clinical Dementia Rating Scale Sum of the Boxes data, retention rates, and the proportions of trial eligible cognitively normal participants age 65 and older in the National Alzheimer’s Coordinating Center Uniform Data Set to model trial sample sizes, the numbers needed to enroll to account for dropout, and the numbers needed to screen to successfully complete enrollment. We examined how enrichment strategies impacted each component of the model. Relative to trials enrolling 65 year olds, trials enriching for older (minimum 70 or 75) age required reduced sample sizes, numbers needed to enroll, and numbers needed to screen. Enriching for subjective memory complaints reduced sample sizes and numbers needed to enroll more than age enrichment, but increased the number needed to screen. We conclude that AD prevention trials can enroll elderly participants with minimal impact on trial retention and that enriching for older individuals with memory complaints may afford efficient trial designs.
PMCID: PMC3864603  PMID: 24119546
Alzheimer’s disease; prevention; clinical trials
3.  Should we disclose amyloid imaging results to cognitively normal individuals? 
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.
PMCID: PMC4184474  PMID: 25285157
ethics; disclosure; amyloid PET; Alzheimer's disease
4.  A survey of attitudes toward clinical trials and genetic disclosure in autosomal dominant Alzheimer’s disease 
Because of its genetic underpinnings and consistent age of onset within families, autosomal dominant Alzheimer’s disease (ADAD) provides a unique opportunity to conduct clinical trials of investigational agents as preventative or symptom-delaying treatments. The design of such trials may be complicated by low rates of genetic testing and disclosure among persons at risk of inheriting disease-causing mutations.
To better understand the attitudes toward genetic testing and clinical trials of persons at risk for ADAD, we surveyed participants in the Dominantly Inherited Alzheimer’s Network (DIAN), a multisite longitudinal study of clinical and biomarker outcomes in ADAD that does not require learning genetic status to participate.
Eighty participants completed a brief anonymous survey by mail or on-line; 40 % reported knowing if they carried a gene mutation, 15 % did not know but expressed a desire to learn their genetic status, and 45 % did not know and did not desire to know their genetic status. Among participants who knew or wished to know their genetic status, 86 % were interested in participating in a clinical trial. Seventy-two percent of participants who did not wish to learn their genetic status reported that they would change their mind, if learning that they carried a mutation gave them the opportunity to participate in a clinical trial. Nearly all participants responded that they would be interested if an open-label extension were offered.
These results suggest that the availability of clinical trials to prevent ADAD can affect persons’ desire to undergo genetic testing and that consideration can be given to performing studies in which such testing is required.
PMCID: PMC4511231  PMID: 26203303
5.  Comparing recruitment, retention, and safety reporting among geographic regions in multinational Alzheimer’s disease clinical trials 
Most Alzheimer’s disease (AD) clinical trials enroll participants multinationally. Yet, few data exist to guide investigators and sponsors regarding the types of patients enrolled in these studies and whether participant characteristics vary by region.
We used data derived from four multinational phase III trials in mild to moderate AD to examine whether regional differences exist with regard to participant demographics, safety reporting, and baseline scores on the Mini Mental State Examination (MMSE), the 11-item Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-cog11), the Clinical Dementia Rating scale Sum of Boxes (CDR-SB), the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL), and the Neuropsychiatric Inventory (NPI). We assigned 31 participating nations to 7 geographic regions: North America, South America/Mexico, Western Europe/Israel, Eastern Europe/Russia, Australia/South Africa, Asia, and Japan.
North America, Western Europe/Israel, and Australia/South Africa enrolled similar proportions of men, apolipoprotein E ε4 carriers, and participants with spouse study partners, whereas Asia, Eastern Europe/Russia, and South America/Mexico had lower proportions for these variables. North America and South America/Mexico enrolled older subjects, whereas Asia and South America/Mexico enrolled less-educated participants than the remaining regions. Approved AD therapy use differed among regions (range: 73% to 92%) and was highest in North America, Western Europe/Israel, and Japan. Dual therapy was most frequent in North America (48%). On the MMSE, North America, Western Europe/Israel, Japan, and Australia/South Africa had higher (better) scores, and Asia, South America/Mexico, and Eastern Europe/Russia had lower scores. Eastern Europe/Russia had more impaired ADAS-cog11 scores than all other regions. Eastern Europe/Russia and South America/Mexico had more impaired scores for the ADCS-ADL and the CDR-SB. Mean scores for the CDR-SB in Asia were milder than all regions except Japan. NPI scores were lower in Asia and Japan than in all other regions. Participants in North America and Western Europe/Israel reported more adverse events than those in Eastern Europe/Russia and Japan.
These findings suggest that trial populations differ across geographic regions on most baseline characteristics and that multinational enrollment is associated with sample heterogeneity. The data provide initial guidance with regard to the regional differences that contribute to this heterogeneity and are important to consider when planning global trials.
PMCID: PMC4481112  PMID: 26120368
6.  Alzheimer’s disease progression by geographical region in a clinical trial setting 
To facilitate enrollment and meet local registration requirements, sponsors have increasingly implemented multi-national Alzheimer’s disease (AD) studies. Geographic regions vary on many dimensions that may affect disease progression or its measurement. To aid researchers designing and implementing Phase 3 AD trials, we assessed disease progression across geographic regions using placebo data from four large, multi-national clinical trials of investigational compounds developed to target AD pathophysiology.
Four similarly-designed 76 to 80 week, randomized, double-blind placebo-controlled trials with nearly identical entry criteria enrolled patients aged ≥55 years with mild or moderate NINCDS/ADRDA probable AD. Descriptive analyses were performed for observed mean score and observed mean change in score from baseline at each scheduled visit. Data included in the analyses were pooled from the intent-to-treat placebo-assigned overall (mild and moderate) AD dementia populations from all four studies. Disease progression was assessed as change from baseline for each of 5 scales - the AD Assessment Scale-cognitive subscale (ADAS-cog11), the AD Cooperative Study- Activities of Daily Living Scale (ADCS-ADL), Mini-Mental State Examination (MMSE), the Clinical Dementia Rating scored by the sum of boxes method (CDR-SB), and the Neuropsychiatric Inventory (NPI).
Regions were heterogeneous at baseline. At baseline, disease severity as measured by ADAS-cog11, ADCS-ADL, and CDR-SB was numerically worse for Eastern Europe/Russia compared with other regions. Of all regional populations, Eastern Europe/Russia showed the greatest cognitive and functional decline from baseline; Japan, Asia and/or S. America/Mexico showed the least cognitive and functional decline.
These data suggest that in multi-national clinical trials, AD progression or its measurement may differ across geographic regions; this may be in part due to heterogeneity across populations at baseline. The observed differences in AD progression between outcome measures across geographic regions may generalize to 'real-world' clinic populations, where heterogeneity is the norm.
Trial registrations NCT00594568 – IDENTITY. Registered 11 January 2008. NCT00762411 – IDENTITY2. Registered 26 September 2008 NCT00905372 – EXPEDITION. Registered 18 May 2009 NCT00904683 – EXPEDITION2. Registered 18 May 2009
PMCID: PMC4481070  PMID: 26120369
7.  Development of a process to disclose amyloid imaging results to cognitively normal older adult research participants 
The objective of this study was to develop a process to maximize the safety and effectiveness of disclosing Positron Emission Tomography (PET) amyloid imaging results to cognitively normal older adults participating in Alzheimer’s disease secondary prevention studies such as the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) Study.
Using a modified Delphi Method to develop consensus on best practices, we gathered and analyzed data over three rounds from experts in two relevant fields: informed consent for genetic testing or human amyloid imaging.
Experts reached consensus on (1) text for a brochure that describes amyloid imaging to a person who is considering whether to undergo such imaging in the context of a clinical trial, and (2) a process for amyloid PET result disclosure within such trials. Recommendations included: During consent, potential participants should complete an educational session, where they receive verbal and written information covering what is known and unknown about amyloid imaging, including possible results and their meaning, implications of results for risk of future cognitive decline, and information about Alzheimer’s and risk factors. Participants should be screened for anxiety and depression to determine suitability to receive amyloid imaging information. The person conducting the sessions should check comprehension and be skilled in communication and recognizing distress. Imaging should occur on a separate day from consent, and disclosure on a separate day from imaging. Disclosure should occur in person, with time for questions. At disclosure, investigators should assess mood and willingness to receive results, and provide a written results report. Telephone follow-up within a few days should assess the impact of disclosure, and periodic scheduled assessments of depression and anxiety, with additional monitoring and follow-up for participants showing distress, should be performed.
We developed a document for use with potential study participants to describe the process of amyloid imaging and the implications of amyloid imaging results; and a disclosure process with attention to ongoing monitoring of both mood and safety to receive this information. This document and process will be used in the A4 Study and can be adapted for other research settings.
PMCID: PMC4428104  PMID: 25969699
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.
PMCID: PMC3945167  PMID: 24322484
Alzheimer’s Disease; Recruitment; Registries; Clinical Trials; Community-Based Participatory Research; Research Participation
9.  The Impact of the Availability of Prevention Studies on the Desire to Undergo Predictive Testing in Persons at-risk for Autosomal Dominant Alzheimer’s Disease 
Contemporary clinical trials  2013;36(1):10.1016/j.cct.2013.07.006.
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.
PMCID: PMC3858206  PMID: 23876673
FAD; pre-symptomatic; genetic; testing; trials; prevention
10.  Novel targets for Alzheimer's disease treatment 
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.
PMCID: PMC4140224  PMID: 20420492
Alzheimer's disease; dementia; treatment; beta amyloid; tau; therapeutics; beta secretase; gamma secretase; immunotherapy
11.  Risk disclosure and preclinical Alzheimer’s disease clinical trial enrollment 
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.
PMCID: PMC3572336  PMID: 23141383
12.  Effect of study partner on the conduct of Alzheimer disease clinical trials 
Neurology  2013;80(3):282-288.
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.
PMCID: PMC3589183  PMID: 23255824
13.  Estimating sample sizes for pre-dementia Alzheimer’s trials based on the Alzheimer’s Disease Neuroimaging Initiative 
Neurobiology of aging  2012;34(1):62-72.
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.
PMCID: PMC3412892  PMID: 22503160
Alzheimer’s disease; clinical trials; mild cognitive impairment; preclinical; predementia; sample size; enrichment
14.  Does study partner type impact the rate of Alzheimer’s disease progression? 
Journal of Alzheimer's disease : JAD  2014;38(3):10.3233/JAD-131052.
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.
PMCID: PMC3842422  PMID: 23985417
Alzheimer’s disease; disease progression; caregivers; clinical trial; spouses; adult children
15.  Are patients whose study partners are spouses more likely to be eligible for Alzheimer’s disease clinical trials? 
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.
PMCID: PMC3477789  PMID: 22759982
Alzheimer’s disease; dementia; clinical trials; caregiver; study partner; recruitment
16.  Multilocus genetic profiling to empower drug trials and predict brain atrophy☆ 
NeuroImage : Clinical  2013;2:827-835.
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.
PMCID: PMC3777716  PMID: 24179834
Alzheimer's disease; Neuroimaging; Brain atrophy; Genetics; Genetic risk score; Clinical trial enrichment
18.  Addressing the challenges to successful recruitment and retention in Alzheimer's disease clinical trials 
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.
PMCID: PMC3031880  PMID: 21172069

Results 1-18 (18)