Alzheimer Preventive Trial Research Articles

Spatial extent as a sensitive amyloid-PET metric in preclinical Alzheimer's disease.

Spatial extent-based measures of how far amyloid beta (Aβ) has spread throughout the neocortex may be more sensitive than traditional Aβ-positron emission tomography (PET) measures of Aβ level for detecting early Aβ deposits in preclinical Alzheimer's disease (AD) and improve understanding of Aβ's association with tau proliferation and cognitive decline. Pittsburgh Compound-B (PIB)-PET scans from 261 cognitively unimpaired older adults from the Harvard Aging Brain Study were used to measure Aβ level (LVL; neocortical PIB DVR) and spatial extent (EXT), calculated as the proportion of the neocortex that is PIB+. EXT enabled earlier detection of Aβ deposits longitudinally confirmed to reach a traditional LVL-based threshold for Aβ+ within 5 years. EXT improved prediction of cognitive decline (Preclinical Alzheimer Cognitive Composite) and tau proliferation (flortaucipir-PET) over LVL. These findings indicate EXT may be more sensitive to Aβ's role in preclinical AD than level and improve targeting of individuals for AD prevention trials. Aβ spatial extent (EXT) was measured as the percentage of the neocortex with elevated Pittsburgh Compound-B. Aβ EXT improved detection of Aβ below traditional PET thresholds. Early regional Aβ deposits were spatially heterogeneous. Cognition and tau were more closely tied to Aβ EXT than Aβ level. Neocortical tau onset aligned with reaching widespread neocortical Aβ.

Characterizing Clinical Progression in Cognitively Unimpaired Older Individuals with Brain Amyloid: Results from the A4 Study

BackgroundClinical Dementia Rating (CDR) global (CDR-G) and sum of box scores (CDR-SB) are commonly used as primary outcome variables to measure progression or treatment effects in symptomatic Alzheimer disease (AD) clinical trials.ObjectivesWe sought to determine whether the CDR is sensitive to change in pre-symptomatic AD and whether there are specific CDR boxes that are dynamic during the multi-year Anti-Amyloid in Asymptomatic Alzheimer’s Disease (A4) secondary prevention study.DesignAll participants entered the study with a CDR-G of 0. Box scores were examined individually and as composites of cognition (memory, orientation and judgment/problem solving) and function (community affairs and home/hobbies). A progression in box score was tabulated only when the change occurred at two consecutive visits.SettingThe A4 study took place at 67 sites in Australia, Canada, Japan and the United States.Participants1,147 individuals, ages 65–85, were randomized to either placebo (n= 583) or solanezumab (n= 564). All participants received a baseline flobetapir PET scan, an annual CDR, and cognitive testing every 6 months with the Primary Alzheimer Cognitive Composite (PACC) over the course of 240 weeks.MeasurementsGeneralized estimating equations and generalized least square models were used to explore the modeled mean progression rate in the CDR-G, CDR-SB, individual CDR boxes, and CDR composite scores in the combined solanezumab and placebo groups. Models were refitted to explore the probability of CDR progression in centiloid tertiles of amyloid at baseline (< 46.1 CL, 46.1 to 77.2 CL, > 77.2 CL). All models included effects for age, education, APOEε4 carrier status, baseline amyloid with flobetapir PET, treatment, and time-by-treatment.ResultsThere were no statistical differences between the placebo or solanezumab groups in CDR-G, CDR-SB, specific CDR boxes or CDR composite scores over the course of the trial. Changes in judgment/problem solving were present at baseline and persisted over time, but progression on the CDR memory box and the CDR cognitive composite quickly predominated. Community affairs and home/hobbies showed little progression. Personal care remained stable. The probability of cognitive and functional progression in CDR boxes began either at the intermediate or advanced amyloid level (46.1 to 77.2 CL, > 77.2 CL), while amyloid at the lowest level (< 46.1 CL) showed relatively little CDR progression.ConclusionsThe findings suggest that the CDR memory box and the CDR cognitive composite progressed over 240 weeks and were associated with intermediate and advanced stages of amyloid at baseline. Functional changes in community affairs and home/hobbies were relatively stable. These finding suggest that specific CDR box score changes may help refine our measurement of expected treatment effects in future AD prevention trials.

Novel measures of cognition and function for the AD spectrum in the Novel Measures for Alzheimer's Disease Prevention Trials (NoMAD) project: Psychometric properties, convergent validation, and contrasts with established measures.

This study derived composite scores for two novel cognitive measures, the No Practice Effect (NPE) battery and the Miami Computerized Functional Skills Assessment and Training system for use in early-stage Alzheimer's disease (AD) clinical trials. Their psychometric properties and associations with AD risk markers were compared to those of well-established measures. For 291 older adults with healthy cognition or early mild cognitive impairment, Exploratory factor analyses were used to identify the factor structure of the NPE. Factor and total scores were examined for their psychometric properties and associations with AD risk biomarkers. Composite scores from the novel cognitive and functional measures demonstrated better psychometric properties (distribution and test-retest reliability) and stronger associations with AD-related demographic, genetic, and brain risk markers than well-established measures, DISCUSSION: These novel measures have potential for use as primary cognitive and functional outcomes in early-stage AD clinical trials. Well-established cognitive tests may not accurately detect subtle cognitive changes. No Practice Effect (NPE) and Computerized Functional Skills Assessment and Training are novel measures designed to have improved psychometric properties. NPE had Executive Function, Cognitive Control/Speed, and Episodic Memory domains. Novel measures had better psychometric properties compared to established measures. Significant associations with Alzheimer's disease biomarkers were found with novel measures.

Cognitive and Functional Change Over Time in Cognitively Healthy Individuals According to Alzheimer Disease Biomarker-Defined Subgroups.

It is unclear to what extent cognitive outcome measures are sensitive to capture decline in Alzheimer disease (AD) prevention trials. We aimed to analyze the sensitivity to changes over time of a range of neuropsychological tests in several cognitively unimpaired, biomarker-defined patient groups. Cognitively unimpaired individuals from the Amsterdam Dementia Cohort and the SCIENCe project with available AD biomarkers, obtained from CSF, PET scans, and plasma at baseline, were followed over time (4.5 ± 3.1 years, range 0.6-18.9 years). Based on common inclusion criteria for clinical trials, we defined groups (amyloid, phosphorylated tau [p-tau], APOE ε4). Linear mixed models, adjusted for age, sex, and education, were used to estimate change over time in neuropsychological tests, a functional outcome, and 2 cognitive composite measures. Standardized regression coefficients of time in years (βtime) were reported as outcome of interest. We analyzed change over time with full follow-up, as well as with follow-up limited to 1.5 and 3 years. We included 387 individuals (aged 61.7 ± 8.6 years; 44% female) in the following (partly overlapping) biomarker groups: APOE ε4 carriers (n = 212), amyloid-positive individuals (n = 109), amyloid-positive APOE ε4 carriers (n = 66), CSF p-tau-positive individuals (n = 127), plasma p-tau-positive individuals (n = 71), and amyloid and CSF p-tau-positive individuals (n = 50), or in a control group (normal biomarkers; n = 65). An executive functioning task showed most decline in all biomarker groups (βtime range -0.30 to -0.71), followed by delayed word list recognition (βtime range -0.18 to -0.50). Functional decline (βtime range -0.17 to -0.63) was observed in all, except the CSF and plasma tau-positive groups. Both composites showed comparable amounts of change (βtime range -0.12 to -0.62) in all groups, except plasma p-tau-positive individuals. When limiting original follow-up duration, many effects disappeared or even flipped direction. In conclusion, functional, composite, and neuropsychological outcome measures across all cognitive domains detect changes over time in various biomarker-defined groups, with changes being most evident among individuals with more AD pathology. AD prevention trials should use sufficiently long follow-up duration and/or more sensitive outcome measures to optimally capture subtle cognitive changes over time.

Effects of the active amyloid beta immunotherapy CAD106 on PET measurements of amyloid plaque deposition in cognitively unimpaired APOE ε4 homozygotes.

Alzheimer's Prevention Initiative Generation Study 1 evaluated amyloid beta (Aβ) active immunotherapy (vaccine) CAD106 and BACE-1 inhibitor umibecestat in cognitively unimpaired 60- to 75-year-old participants at genetic risk for Alzheimer's disease (AD). The study was reduced in size and terminated early. Results from the CAD106 cohort are presented. Sixty-five apolipoprotein E ε4 homozygotes with/without amyloid deposition received intramuscular CAD106 450μg (n=42) or placebo (n=23) at baseline; Weeks 1, 7, 13; and quarterly; 51 of them had follow-up Aβ positron emission tomography (PET) scans at 18 to 24 months. CAD106 induced measurable serum Aβ immunoglobulin G titers in 41/42 participants, slower rates of Aβ plaque accumulation (mean [standard deviation] annualized change from baseline in amyloid PET Centiloid: -0.91[5.65] for CAD106 versus 8.36 [6.68] for placebo; P<0.001), and three amyloid-related imaging abnormality cases (one symptomatic). Despite early termination, these findings support the potential value of conducting larger prevention trials of Aβ active immunotherapies in individuals at risk for AD. This was the first amyloid-lowering prevention trial in persons at genetic risk of late-onset Alzheimer's disease (AD). Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial. CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes. CAD106 was generally safe and well tolerated, with only three amyloid-related imaging abnormality cases (one symptomatic). Such an approach deserves further evaluation in larger AD prevention trials.

Meta-Analysis of Animal Fluency Performance in Amnestic Mild Cognitive Impairment and Cognitively Unimpaired Older Adults.

Animal fluency is a commonly used neuropsychological measure that is used in the diagnosis of amnestic mild cognitive impairment (aMCI) and Alzheimer disease. Although most individuals with aMCI have clinically normal scores on this test, several studies have shown that aMCI individuals' performance is significantly lower than that of cognitively unimpaired (CU) individuals. The aim of this meta-analysis was to characterize the effect size of animal fluency performance differences between aMCI and CU individuals. Literature search with search terms used were: "animal fluency and mild cognitive impairment," "semantic fluency and mild cognitive impairment," "category fluency and mild cognitive impairment." Both the standardized mean difference and the raw mean difference were derived from random effects analyses. Demographically adjusted z-scores for animal fluency performance for the aMCI groups were obtained to determine normative performance. Nineteen studies were included in the analysis. The standardized mean difference for animal fluency performance between CU and aMCI was 0.89 (95% confidence interval: [0.73; 1.04], P <0.001), I2 =70.3% [52.7%; 81.4%], which reflects a large effect size with moderate heterogeneity. The raw mean difference was -4.08 [-4.75; -3.38], P <0.001. The mean animal fluency z-score for aMCI groups was in the Low Average range (z=-0.77). This study found a substantial difference in animal fluency performance between aMCI and CU individuals. The aMCI groups' normative performance did not fall into the impaired range, indicating that there are important subclinical differences in animal fluency performance that may inform the design of cognitive end points for Alzheimer's disease prevention trials.

Associations of the Harvard Automated Phone Task and Alzheimer's Disease Pathology in Cognitively Normal Older Adults: Preliminary Findings.

Detecting clinically meaningful changes in instrumental activities of daily living (IADL) at the earliest stages of Alzheimer's disease (AD) is critical. The objective of this exploratory study was to examine the cross-sectional relationship between a performance-based IADL test, the Harvard Automated Phone Task (APT), and cerebral tau and amyloid burden in cognitively normal (CN) older adults. Seventy-seven CN participants underwent flortaucipir tau and Pittsburgh Compound B amyloid PET. IADL were assessed using the three Harvard APT tasks: prescription refill (APT-Script), health insurance company call (APT-PCP), and bank transaction (APT-Bank). Linear regression models were used to determine associations between each APT task and entorhinal cortex, inferior temporal, or precuneus tau with or without an interaction with amyloid. Significant associations were found between APT-Bank task rate and interaction between amyloid and entorhinal cortex tau, and APT-PCP task and interactions between amyloid and inferior temporal and precuneus tau. No significant associations were found between the APT tasks and tau or amyloid alone. Our preliminary findings suggest an association between a simulated real-life IADL test and interactions of amyloid and several regions of early tau accumulation in CN older adults. However, some analyses were underpowered due to the small number of participants with elevated amyloid, and findings should be interpreted with caution. Future studies will further explore these associations cross-sectionally and longitudinally in order to determine whether the Harvard APT can serve as a reliable IADL outcome measure for preclinical AD prevention trials and ultimately in the clinic setting.

Predicting Conversion to Alzheimer Disease using Module‐Based Polygenic Risk Scores Informed by Brain Proteome Profiles

AbstractBackgroundNeuropathologically confirmed Alzheimer disease (AD) patients are heterogeneous in their cognitive functions, brain atrophy patterns, and neuropathological traits. Genetic risk profiles informed by brain proteome signatures may predict the conversion of clinically normal individuals to AD.MethodWe discovered co‐expressed proteome networks using 201 AD brains from the prefrontal cortex area in the Religious Orders Study and Memory and Aging Project (ROSMAP) and validated the findings using 328 AD brains in the Emory study. Of the preserved modules, we selected modules with significant association (P&lt;0.01) between neuropathologically and clinically confirmed AD (symptomatic) and neuropathologically confirmed AD but clinically unimpaired brains. We generated polygenic risk scores of the symptom‐associated modules (mbPRSs) using existing genome‐wide summary statistics for AD (Kunkle, 2019) in 309 AD, 483 mild cognitive impairment (MCI), and 301 cognitively normal (CN) subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We investigated relationships between the derived mbPRSs and previously clustered brain atrophy patterns in the ADNI (Yang, 2021). We defined at‐risk CN and MCI subjects in the ADNI for each module if mbPRSs of the subject &gt; the third quantile. Age‐adjusted Cox proportional hazard models were applied for conversion status to AD with at‐risk subjects of the symptom‐associated modules comparing with all CN and MCI subjects as a reference group.ResultWe detected 12 preserved modules that showed significant associations for symptomatic AD (P‐value&lt;0.05). The mbPRSs of the yellow and the lightcyan modules were significantly associated with brain atrophy cluster 3 (P‐value: yellow‐mbPRS = 5.5e‐03; lightcyan‐mbPRS = 7.1e‐05). At the same time, Of the mbPRSs for the 12 symptom‐associated modules, the at‐risk subjects defined by the lightcyan‐mbPRS were also predicted to be earlier conversion from CN or MCI to AD (Hazard ratio = 1.63, P‐value = 3.8e‐02). Lightcyan‐mbPRS shows a good prediction of conversion to AD and also the association with MRI endophenotypes.ConclusionThis study demonstrates for the first time that PRSs informed by symptom‐associated protein networks may identify at‐risk CN and MCI subjects who will develop clinical symptoms and enable targeted prevention and treatment trials for AD for these at‐risk subjects in preclinical stages of AD.

Cross-sectional and prospective associations between homocysteine and a frailty index: A post-hoc analysis of the multidomain Alzheimer's prevention trial (MAPT)

BackgroundHomocysteine (Hcy) has been associated with several health problems, including reduced physical capacity. No study appears to have looked at the role of Hcy values longitudinally on physical capacity deterioration in older adults. The objective is to examine cross-sectional and prospective associations between Hcy values and frailty in the elderly and investigate Hcy potential association with the onset of frailty. Methods769 community-dwelling older adults from the MAPT study were recruited for this study. Total Hcy was measured at baseline. Frailty was evaluated at 5 different collection timepoints: baseline, 6-month, 1-, 2-, and 3-year using a frailty index (FI) composed of 19 items. Linear regressions adjusted for all the confounders (age, gender, educational level, MAPT group allocation and Omega-3) were performed to examine the cross-sectional associations of homocysteine values with the FI. A cox model was used to test the association of Hcy with the onset of frailty. Results:Mean Hcy values (15.9 ± 5.6 μmol\\L) were obtained from 769 community-dwelling adults (75.7 ± 4.6 years old). After adjustments, a significant (β = 0.002, (00002–0.003)) and positive association between baseline Hcy values and FI was found (ß = 0.002). Additionally, higher values of Hcy were associated with a worsening of FI after 3 years (ß = 0.002, p = 0.003). A significant association between baseline Hcy values and the likelihood of developing frailty was discovered by incident event analysis (HR: 1.04 (1.01–1.06), p = 0.004). ConclusionHigh levels of Hcy are associated with the fragility process in community-dwelling older adults.

Planning for Prevention of Parkinson Disease: Now Is the Time.

Parkinson disease (PD) is a chronic progressive neurodegenerative disease with increasing worldwide prevalence. Despite many trials of neuroprotective therapies in manifest PD, no disease-modifying therapy has been established. Over the past several decades, a series of breakthroughs have identified discrete populations at substantially increased risk of developing PD. Based on this knowledge, now is the time to design and implement PD prevention trials. This endeavor builds on experience gained from early prevention trials in Alzheimer disease and Huntington disease. This article first reviews prevention trial precedents in these other neurodegenerative diseases before focusing on the critical design elements for PD prevention trials, including whom to enroll for these trials, what therapeutics to test, and how to measure outcomes in prevention trials. Our perspective reflects progress and remaining challenges that motivated a 2021 conference, "Planning for Prevention of Parkinson: A Trial Design Symposium and Workshop."

Novel approaches to measuring neurocognitive functions in Alzheimer's disease clinical trials.

We comprehensively examined recent advancements in developing novel cognitive measures that could significantly enhance detection of outcome changes in Alzheimer's disease clinical trials. Previously established measures were largely limited in their ability to detect subtle cognitive declines in preclinical stages of Alzheimer's disease, particularly due to weak psychometric properties (including practice effects and ceiling effects) and requirement of in-person visits that impacted ascertainment. We present novel cognitive measures that were designed to exhibit reduced practice effects and stronger correlations with Alzheimer's disease biomarkers. In addition, we summarized some recent efforts in developing remote testing measures protocols that are aimed to overcome the limitations and inconvenience of in-person testing, and digital phenotyping, which analyses subtle forms of digital behaviour indicative of cognitive phenotypes. We discuss each measure's prognostic accuracy and potential utility in Alzheimer's disease research while also commenting on their limitations. We also describe our study, the Development of Novel Measures for Alzheimer's Disease Prevention Trials (NoMAD), that employed a parallel group design in which novel measures and established measures are compared in a clinical trials armature. Overall, we believe that these recent developments offer promising improvements in accurately detecting clinical and preclinical cognitive changes in the Alzheimer's disease spectrum; however, further validation of their psychometric properties and diagnostic accuracies is warranted before reliably implementing these novel measures in Alzheimer's disease clinical trials.

Prospective Associations of Plasma Growth Differentiation Factor 15 With Physical Performance and Cognitive Functions in Older Adults.

Growth differentiation factor 15 (GDF15) has been associated with several age-related disorders, but its associations with functional abilities in community-dwelling older adults are not well studied. The study was a secondary analysis of 1 096 community-dwelling older adults (aged 69-94 years) recruited from the Multidomain Alzheimer's Preventive Trial. Plasma GDF15 was measured 1 year after participants' enrollment. Annual data of physical performance (grip strength and Short Physical Performance Battery [SPPB]) and global cognitive functions (Mini-Mental State Examination [MMSE] and a composite cognitive score) were measured for 4 years. Adjusted mixed-effects linear models were performed for cross-sectional and longitudinal association analyses. A higher GDF15 was cross-sectionally associated with a weaker grip strength (β = -1.1E-03, 95% CI [-2.0E-03, -1.5E-04]), a lower SPPB score (β = -3.1E-04, 95% CI [-5.4E-04, -9.0E-05]), and worse cognitive functions (β = -2.4E-04, 95% CI [-3.3E-04, -1.6E-04] for composite cognitive score; β = -4.0E-04, 95% CI [-6.4E-04, -1.6E-04] for MMSE). Participants with higher GDF15 demonstrated greater longitudinal declines in SPPB (β = -1.0E-04, 95% CI [-1.7E-04, -2.0E-05]) and composite cognitive score (β = -2.0E-05, 95% CI [-4.0E-05, -3.6E-06]). The optimal initial GDF15 cutoff values for identifying participants with minimal clinically significant decline after 1 year were 2 189 pg/mL for SPPB (AUC: 0.580) and 2 330 pg/mL for composite cognitive score (AUC: 0.587). Plasma GDF15 is cross-sectionally and longitudinally associated with lower-limb physical performance and global cognitive function in older adults. Circulating GDF15 alone has a limited capacity of discriminating older adults who will develop clinically significant functional declines. NCT00672685.

Using historical data to facilitate clinical prevention trials in Alzheimer disease? An analysis of longitudinal MCI (mild cognitive impairment) data sets

BackgroundThe Placebo Group Simulation Approach (PGSA) aims at partially replacing randomized placebo-controlled trials (RPCTs), making use of data from historical control groups in order to decrease the needed number of study participants exposed to lengthy placebo treatment. PGSA algorithms to create virtual control groups were originally derived from mild cognitive impairment (MCI) data of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. To produce more generalizable algorithms, we aimed to compile five different MCI databases in a heuristic manner to create a “standard control algorithm” for use in future clinical trials.MethodsWe compared data from two North American cohort studies (n=395 and 4328, respectively), one company-sponsored international clinical drug trial (n=831) and two convenience patient samples, one from Germany (n=726), and one from Switzerland (n=1558).ResultsDespite differences between the five MCI samples regarding inclusion and exclusion criteria, their baseline demographic and cognitive performance data varied less than expected. However, the five samples differed markedly with regard to their subsequent cognitive performance and clinical development: (1) MCI patients from the drug trial did not deteriorate on verbal fluency over 3 years, whereas patients in the other samples did; (2) relatively few patients from the drug trial progressed from MCI to dementia (about 10% after 4 years), in contrast to the other four samples with progression rates over 30%.ConclusionConventional MCI criteria were insufficient to allow for the creation of well-defined and internationally comparable samples of MCI patients. More recently published criteria for MCI or “MCI due to AD” are unlikely to remedy this situation. The Alzheimer scientific community needs to agree on a standard set of neuropsychological tests including appropriate selection criteria to make MCI a scientifically more useful concept. Patient data from different sources would then be comparable, and the scientific merits of algorithm-based study designs such as the PGSA could be properly assessed.

Development of novel measures for Alzheimer's disease prevention trials (NoMAD)

IntroductionAssessment of cognition and everyday function is essential in clinical trials for Alzheimer's disease (AD). Two novel measures of cognition (No Practice Effects (NPE) cognitive battery and Miami Computerized Functional Assessment Scale (CFAS)) were designed to have robust psychometric properties and reduced practice and ceiling effects. This study aims to evaluate if the NPE and CFAS demonstrate stronger psychometric properties and reduced practice effects compared with established measures, including the Preclinical Alzheimer Cognitive Composite (PACC), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Functional Activities Questionnaire (FAQ). MethodsThis parallel group, four-site study will randomize 320 cognitively intact adults aged 60 to 85 years to novel or well-established measures of cognition and function. All participants will receive assessments at baseline (week 0), 3-months, and 12-months, as well as a brain MRI scan and Apolipoprotein E genetic test at study entry. Analyses will determine psychometric properties of the NPE and CFAS, compare the sensitivity of measures to AD risk markers, and identify cognitive domains within the NPE. DiscussionPractice effects have been a major limitation of Alzheimer's disease clinical trials that typically assess cognitive changes over serial assessments. Detection of functional impairment in cognitively normal individuals with biomarkers for Alzheimer's disease requires instruments sensitive to very subtle functional changes. This study is intended to support the validation of two new composite measures, the NPE battery and the CFAS, which may advance clinical testing of interventions for individuals across the spectrum of early stage Alzheimer's disease.Trial Registration: NCT03900273

Cognitive and clinical outcome measures for Alzheimer's disease prevention trials in adults with Down syndrome

AbstractBackgroundAdults with Down syndrome (DS) are at ultra‐high risk for developing Alzheimer’s disease (AD) due to APP gene triplication on chromosome 21. There is interest in conducting trials of treatment that can delay or prevent onset of disease in at‐risk individuals with DS. Reliable outcome measures are required to demonstrate clinical benefit of treatment in a population with premorbid cognitive impairments that affect their performance on cognitive outcome measures. We aimed to identify the most efficient clinical and cognitive outcomes for prevention trials of AD in DS.MethodsAnalysis of cognitive data based on different test batteries from several recent longitudinal cohort studies of AD in DS in Europe and the US (n &gt;300 with 2 years of follow‐up data), using staging and E‐Max models and other statistical methods.ResultsThe age range within which cognitive decline can be first reliably observed in DS adults who do not yet have dementia is around age 45; this varies by outcome measure, with memory, attention, orientation and some verbal tasks being the most feasible and reliable tests for prevention trials. We will report effect sizes for these outcome measures to inform trial design.ConclusionsTrials of treatment to prevent or delay AD in DS individuals using cognitive measures as primary outcomes are feasible if targeted at individuals within age ranges where decline can be first observed, but effect sizes (and sample sizes) vary by outcome measures selected.

Optimal age and outcome measures for Alzheimer's disease prevention trials in people with Down syndrome.

People with Down syndrome (DS) typically develop Alzheimer's disease (AD) neuropathology before age 40, but a lack of outcome measures and longitudinal data have impeded their inclusion in randomized controlled trials (RCTs). Cohort study. Event-based and dose-response Emax models were fitted to longitudinal cognitive data, to stage AD and determine the earliest ages of decline. Results informed sample size estimations for hypothetical RCTs of disease-modifying treatments that reduced decline by 35% or 75%. Seventy-five percent of participants progressed or remained stable in the AD staging model; effect sizes varied by age group and tests. Varied treatment effects could be detected with 50-200 people per arm when using sensitive cognitive outcome measures and targeting recruitment to ages 36 to 45 years. Efficient RCTs of AD preventative treatments can be conducted in the DS population using sensitive outcome measures to monitor early decline. Dose-response models could help tailor future RCTs.

Using Direct-to-Consumer Genetic Testing Results to Accelerate Alzheimer Disease Clinical Trial Recruitment.

The apolipoprotein E (APOE) gene is the strongest known genetic risk factor for sporadic Alzheimer disease (AD). APOE can be used as an enrichment strategy or inclusion criterion for AD prevention trials. Personal genomics companies market direct-to-consumer (DTC) genetic tests, including APOE. We assessed DTC APOE testing usage among enrollees of the University of California Irvine Consent-to-Contact Registry, an online recruitment registry, and attitudes toward using this information in clinical trial recruitment. We emailed links to an electronic survey to registry enrollees age 50 years or older. We assessed participants' use of DTC services, willingness to learn APOE status, and willingness to share genetic information. Logistic regression models assessed relationships between DTC testing usage and demographic characteristics, and with willingness to share results to assist trial recruitment. Among 1312 responders (57% response rate), few (7%) had used DTC testing for APOE. Non-Hispanic Asian enrollees were 93% less likely to have used DTC testing, compared with non-Hispanic Whites [95% confidence interval: (0.01, 0.67)]. Willingness to share APOE information for study recruitment was >90% for both users and nonusers. Matching participants to trials on the basis of DTC APOE information may be an effective way to streamline AD prevention trial recruitment.

Association of Vascular Risk Factors With β-Amyloid Peptide and Tau Burdens in Cognitively Unimpaired Individuals and Its Interaction With Vascular Medication Use

Vascular risk factors are associated with increased risk of Alzheimer disease (AD), but it is unclear whether there is a direct association of these risk factors with AD pathogenesis. To assess the associations of vascular risk factors with AD pathogenesis in asymptomatic individuals, and to test whether this association is moderated among individuals who use vascular medications. This cross-sectional study used data from the Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease (PREVENT-AD) cohort of cognitively unimpaired individuals aged 55 to 82 years with a parental or multiple-sibling history of sporadic AD, who were recruited via advertisement from the greater Montreal, Quebec, Canada, metropolitan area. Participants were enrolled between September 9, 2011, to May, 3, 2017, and stratified by use vs no use of vascular medications. Data were analyzed July 1, 2018, to April 5, 2019. Principal analyses investigated associations of total, high-density lipoprotein, and low-density lipoprotein cholesterol levels, systolic and diastolic blood pressure, pulse pressure, and a combined vascular risk score (measured using the Framingham Coronary Risk Profile) with global β-amyloid peptide (Aβ) and entorhinal tau burden as measured by positron emission tomography (PET). Potential moderating associations of use of vascular medications with these associations were examined. Secondary similar analyses considered cerebrospinal fluid (CSF) Aβ1-42 and phosphorylated tau levels. Among 215 participants (mean [SD] age, 62.3 [5.0] years; 161 [74.8%] women), 120 participants underwent PET, including 75 participants (62.5%) who were not using vascular medications, and 162 participants underwent CSF assessment, including 113 participants (69.8%) who were not using vascular medications. There was an overlap of 67 participants who underwent PET and CSF assessment. Interaction analyses showed that among participants not using vascular medications, higher Aβ deposition as measured by PET was associated with higher total cholesterol level (β = -0.002 [SE, 0.001]; P = .02), low-density lipoprotein cholesterol level (β = -0.002 [SE, 0.001]; P = .006), systolic blood pressure (β = -0.006 [SE, 0.002]; P = .02), pulse pressure (β = -0.007 [SE, 0.002]; P = .004), and Framingham Coronary Risk Profile score (β = -0.038 [SE, 0.011]; P = .001), but such associations were absent in participants who used vascular medications. Interactions were also found between vascular medication use and high-density lipoprotein cholesterol (β = -3.302 [SE, 1.540]; P = .03), low-density lipoprotein cholesterol (β = 1.546 [SE, 0.754]; P = .04), and Framingham Coronary Risk Profile score (β = 23.102 [SE, 10.993]; P = .04) on Aβ1-42 burden as measured in CSF. Higher Framingham Coronary Risk Profile scores were associated with reduced tau burden among participants using vascular medications but not among participants not using vascular medications (interaction, β = -0.010 [SE, 0.005]; P = .046). These findings corroborate previously reported associations of vascular risk factors with Aβ burden but not tau burden. However, these associations were found only among individuals who were not using vascular medications. These results suggest that medication use or other control of vascular risk factors should be considered in Alzheimer disease prevention trials.

Prescreening for European Prevention of Alzheimer Dementia (EPAD) trial-ready cohort: impact of AD risk factors and recruitment settings

BackgroundRecruitment is often a bottleneck in secondary prevention trials in Alzheimer disease (AD). Furthermore, screen-failure rates in these trials are typically high due to relatively low prevalence of AD pathology in individuals without dementia, especially among cognitively unimpaired. Prescreening on AD risk factors may facilitate recruitment, but the efficiency will depend on how these factors link to participation rates and AD pathology. We investigated whether common AD-related factors predict trial-ready cohort participation and amyloid status across different prescreen settings.MethodsWe monitored the prescreening in four cohorts linked to the European Prevention of Alzheimer Dementia (EPAD) Registry (n = 16,877; mean ± SD age = 64 ± 8 years). These included a clinical cohort, a research in-person cohort, a research online cohort, and a population-based cohort. Individuals were asked to participate in the EPAD longitudinal cohort study (EPAD-LCS), which serves as a trial-ready cohort for secondary prevention trials. Amyloid positivity was measured in cerebrospinal fluid as part of the EPAD-LCS assessment. We calculated participation rates and numbers needed to prescreen (NNPS) per participant that was amyloid-positive. We tested if age, sex, education level, APOE status, family history for dementia, memory complaints or memory scores, previously collected in these cohorts, could predict participation and amyloid status.ResultsA total of 2595 participants were contacted for participation in the EPAD-LCS. Participation rates varied by setting between 3 and 59%. The NNPS were 6.9 (clinical cohort), 7.5 (research in-person cohort), 8.4 (research online cohort), and 88.5 (population-based cohort). Participation in the EPAD-LCS (n = 413 (16%)) was associated with lower age (odds ratio (OR) age = 0.97 [0.95–0.99]), high education (OR = 1.64 [1.23–2.17]), male sex (OR = 1.56 [1.19–2.04]), and positive family history of dementia (OR = 1.66 [1.19–2.31]). Among participants in the EPAD-LCS, amyloid positivity (33%) was associated with higher age (OR = 1.06 [1.02–1.10]) and APOE ɛ4 allele carriership (OR = 2.99 [1.81–4.94]). These results were similar across prescreen settings.ConclusionsNumbers needed to prescreen varied greatly between settings. Understanding how common AD risk factors link to study participation and amyloid positivity is informative for recruitment strategy of studies on secondary prevention of AD.

Recruitment into the Alzheimer Prevention Trials (APT) Webstudy for a Trial-Ready Cohort for Preclinical and Prodromal Alzheimer\u2019s Disease (TRC-PAD)

BackgroundThe Alzheimer Prevention Trials (APT) Webstudy is the first stage in establishing a Trial-ready Cohort for Preclinical and Prodromal Alzheimer’s disease (TRC-PAD). This paper describes recruitment approaches for the APT Webstudy.ObjectivesTo remotely enroll a cohort of individuals into a web-based longitudinal observational study. Participants are followed quarterly with brief cognitive and functional assessments, and referred to Sites for in-clinic testing and biomarker confirmation prior to enrolling in the Trial-ready Cohort (TRC).DesignParticipants are referred to the APT Webstudy from existing registries of individuals interested in brain health and Alzheimer’s disease research, as well as through central and site recruitment efforts. The study team utilizes Urchin Tracking Modules (UTM) codes to better understand the impact of electronic recruitment methods.SettingA remotely enrolled online study.ParticipantsVolunteers who are at least 50 years old and interested in Alzheimer’s research.MeasurementsDemographics and recruitment source of participant where measured by UTM.Results30,650 participants consented to the APT Webstudy as of April 2020, with 69.7% resulting from referrals from online registries. Emails sent by the registry to participants were the most effective means of recruitment. Participants are distributed across the US, and the demographics of the APT Webstudy reflect the referral registries, with 73.1% female, 85.0% highly educated, and 92.5% Caucasian.ConclusionsWe have demonstrated the feasibility of enrolling a remote web-based study utilizing existing registries as a primary referral source. The next priority of the study team is to engage in recruitment initiatives that will improve the diversity of the cohort, towards the goal of clinical trials that better represent the US population.