Ahead of print articles
SAFETY AND EFFICACY OF LEMBOREXANT IN PATIENTS WITH IRREGULAR SLEEP-WAKE RHYTHM DISORDER AND ALZHEIMER’S DISEASE DEMENTIA: RESULTS FROM A PHASE 2 RANDOMIZED CLINICAL TRIAL
M. Moline, S. Thein, M. Bsharat, N. Rabbee, M. Kemethofer-Waliczky, G. Filippov, N. Kubota, S. Dhadda
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BACKGROUND: Irregular sleep-wake rhythm disorder (ISWRD) is a common sleep disorder in individuals with Alzheimer’s disease dementia (AD-D).
OBJECTIVES: This exploratory phase 2 proof-of-concept and dose-finding clinical trial evaluated the effects of lemborexant compared with placebo on circadian rhythm parameters, nighttime sleep, daytime wakefulness and other clinical measures of ISWRD in individuals with ISWRD and mild to moderate AD-D.
DESIGN: Multicenter, randomized, double-blind, placebo-controlled, parallel-group study.
SETTING: Sites in the United States, Japan and the United Kingdom.
PARTICIPANTS: Men and women 60 to 90 years of age with documentation of diagnosis with AD-D and Mini-Mental State Exam (MMSE) score 10 to 26.
INTERVENTION: Subjects were randomized to placebo or one of four lemborexant treatment arms (2.5 mg, 5 mg, 10 mg or
15 mg) once nightly at bedtime for 4 weeks.
MEASUREMENTS: An actigraph was used to collect subject rest-activity data, which were used to calculate sleep-related, wake-related and circadian rhythm–related parameters. These parameters included least active 5 hours (L5), relative amplitude of the rest-activity rhythm (RA) and mean duration of sleep bouts (MDSB) during the daytime. The MMSE and the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) were used to assess for changes in cognitive function.
RESULTS: Sixty-two subjects were randomized and provided data for circadian, daytime and nighttime parameters (placebo, n = 12; lemborexant 2.5 mg [LEM2.5], n = 12; lemborexant
5 mg [LEM5], n = 13, lemborexant 10 mg [LEM10], n = 13 and lemborexant 15 mg [LEM15], n = 12). Mean L5 showed a decrease from baseline to week 4 for LEM2.5, LEM5 and LEM15 that was significantly greater than with placebo (all p < 0.05), suggesting a reduction in restlessness. For RA, LS mean change from baseline to week 4 versus placebo indicated greater distinction between night and day with all dose levels of lemborexant, with significant improvements seen with LEM5 and LEM15 compared with placebo (both p < 0.05). The median percentage change from baseline to week 4 in MDSB during the daytime indicated a numerical decrease in duration for LEM5, LEM10 and LEM15, which was significantly different from placebo for LEM5 and LEM15 (p < 0.01 and p = 0.002, respectively).
There were no serious treatment-emergent adverse events or worsening of cognitive function, as assessed by the MMSE and ADAS-Cog. Lemborexant was well tolerated. No subjects discontinued treatment.
CONCLUSIONS: This study provides preliminary evidence of the potential utility of lemborexant as a treatment to address both nighttime and daytime symptoms in patients with ISWRD and AD-D.
M. Moline ; S. Thein ; M. Bsharat ; N. Rabbee ; M. Kemethofer-Waliczky ; G. Filippov ; N. Kubota ; S. Dhadda (2020): Safety and Efficacy of Lemborexant in Patients With Irregular Sleep-Wake Rhythm Disorder and Alzheimer’s Disease Dementia: Results From a Phase 2 Randomized Clinical Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.69
THIRTY-SIX-MONTH AMYLOID POSITRON EMISSION TOMOGRAPHY RESULTS SHOW CONTINUED REDUCTION IN AMYLOID BURDEN WITH SUBCUTANEOUS GANTENERUMAB
G. Klein, P. Delmar, G.A. Kerchner, C. Hofmann, D. Abi-Saab, A. Davis, N. Voyle, M. Baudler, P. Fontoura, R. Doody
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Previous findings from the positron emission tomography (PET) substudy of the SCarlet RoAD and Marguerite RoAD open-label extension (OLE) showed gantenerumab doses up to 1200 mg every 4 weeks administered subcutaneously resulted in robust beta-amyloid (Aβ) plaque removal over 24 months in people with prodromal-to-moderate Alzheimer’s disease (AD). In this 36-month update, we demonstrate continued reduction, with mean (standard error) centiloid values at
36 months of -4.3 (7.5), 0.8 (6.7), and 4.7 (8.0) in the SCarlet RoAD (double-blind pooled placebo and active groups), Marguerite RoAD double-blind placebo, and Marguerite RoAD double-blind active groups respectively, representing a change of -57.0 (10.3), -90.3 (9.0), and -74.9 (10.5) centiloids respectively. These results demonstrate that prolonged gantenerumab treatment, at doses up to 1200 mg, reduces amyloid plaque levels below the amyloid positivity threshold. The ongoing GRADUATE Phase III trials will evaluate potential clinical benefits associated with gantenerumab-induced amyloid-lowering in people with early (prodromal-to-mild) AD.
G. Klein ; P. Delmar ; G.A. Kerchner ; C. Hofmann ; D. Abi-Saab ; A. Davis ; N. Voyle ; M. Baudler ; P. Fontoura ; R. Doody (2020): Thirty-Six-Month Amyloid Positron Emission Tomography Results Show Continued Reduction in Amyloid Burden with Subcutaneous Gantenerumab. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.68
DOES TEA DRINKING PROMOTE HEALTH OF OLDER ADULTS: EVIDENCE FROM THE CHINA HEALTH AND NUTRITION SURVEY
J. Wang, Q. Wei, X. Wan
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Objective: This study selects the health indicators of older adults to analyze the impact of tea drinking on health. Design: This is a panel data.
Setting: This study uses data from China Health and Nutrition Survey (CHNS), which covers nine provinces and ten waves, between 1997 and 2015.
Participants: a total of 706 old adults are consistently surveyed in six surveys on issues such as health and nutrition.
Measurements: Health of old adults is assessed by self-reported health (SRH), tea drinking is 0-1 dummy variable, and also analyze with the frequency of tea drinking. This study uses ordered probit model to analyze the influence of tea drinking on SRH.
Results: Findings reveal a significant negative correlation between tea drinking and SRH of older adults. It is shows that the significant positive correlation exists between the tea drinking frequency and SRH, but the quadratic term of tea frequency shows the significant negative correlation. It means drinking tea benefits older adults in terms of improved health, but excessive consumption of tea is not healthy for them. The heterogeneity analyses reveal that there are no significant geographic, tea-drinking pattern or gender differences in the conclusion that tea drinking is good for older adults’ health.
Conclusion: In this study, we find correlation between tea drinking and SRH of older adults, and tea drinking is beneficial toward the improvement of SRH, but drinking tea in excess is not good for older adults’ health.
J. Wang ; Q. Wei ; X. Wan (2020): Does Tea Drinking Promote Health of Older Adults: Evidence from the China Health and Nutrition Survey. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.67
LONGITUDINAL COURSE OF AGITATION AND AGGRESSION IN PATIENTS WITH ALZHEIMER’S DISEASE IN A COHORT STUDY: METHODS, BASELINE AND LONGITUDINAL RESULTS OF THE A3C STUDY
A. De Mauleon, J. Delrieu, C. Cantet, B. Vellas, S. Andrieu, P.B. Rosenberg, C.G. Lyketsos, M. Soto Martin
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BACKGROUND: To present methodology, baseline results and longitudinal course of the Agitation and Aggression in patients with Alzheimer’s Disease Cohort (A3C) study.
Objectives: The central objective of A3C was to study the course, over 12 months of clinically significant Agitation and Aggression symptoms based on validated measures, and to assess relationships between symptoms and clinical significance based on global ratings.
Design: A3C is a longitudinal, prospective, multicenter observational cohort study performed at eight memory clinics in France, and their associated long-term care facilities.
Setting: Clinical visits were scheduled at baseline, monthly during the first 3 months, at 6 months, at 9 months and at 12 months. The first three months intended to simulate a classic randomized control trial 12-week treatment design.
Participants: Alzheimer’s Disease patients with clinically significant Agitation and Aggression symptoms lived at home or in long-term care facilities.
Measurements: Clinically significant Agitation and Aggression symptoms were rated on Neuropsychiatric Inventory (NPI), NPI-Clinician rating (NPI-C) Agitation and Aggression domains, and Cohen Mansfield Agitation Inventory. Global rating of agitation over time was based on the modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change. International Psychogeriatric Association “Provisional Diagnostic Criteria for Agitation”, socio-demographics, non-pharmacological approaches, psychotropic medication use, resource utilization, quality of life, cognitive and physical status were assessed.
Results: A3C enrolled 262 AD patients with a mean age of 82.4 years (SD ±7.2 years), 58.4% women, 69.9% at home. At baseline, mean MMSE score was 10.0 (SD±8.0), Cohen Mansfield Agitation Inventory score was 62.0 (SD±15.8) and NPI-C Agitation and Aggression clinician severity score was 15.8 (SD±10.8). According to the International Psychogeriatric Association agitation definition, more than 70% of participants showed excessive motor activity (n=199, 76.3%) and/or a verbal aggression (n=199, 76.3%) while 115 (44.1%) displayed physical aggression. The change of the CMAI score and the NPI-C Agitation and Aggression at 1-year follow-up period was respectively -11.36 (Standard Error (SE)=1.32; p<0.001) and -6.72 (SE=0.77; p<0.001).
Conclusion: Little is known about the longitudinal course of clinically significant agitation symptoms in Alzheimer’s Disease about the variability in different outcome measures over time, or the definition of a clinically meaningful improvement. A3C may provide useful data to optimize future clinical trials and guide treatment development for Agitation and Aggression in Alzheimer’s Disease.
A. De Mauleon ; J. Delrieu ; C. Cantet ; B. Vellas ; S. Andrieu ; P.B. Rosenberg ; C.G. Lyketsos ; M. Soto Martin (2020): Longitudinal Course of Agitation and Aggression in Patients with Alzheimer’s Disease in a Cohort study: Methods, Baseline and Longitudinal Results of the A3C Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.66
MOLECULAR SUBTYPING OF MILD COGNITIVE IMPAIRMENT BASED ON GENETIC POLYMORPHISM AND GENE EXPRESSION
H.-T. Li, S.-X. Yuan, J.-S. Wu, X.-Z. Zhang, Y. Liu, X. Sun, For the Alzheimer’s Disease Neuroimaging Initiative
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Background: Alzheimer’s Disease (AD) is a neurodegenerative brain disease in the elderly. Recent studies have revealed the heterogeneous nature of AD. Mild Cognitive Impairment (MCI) is the prodromal stage of AD.
Objectives: In this study, we identified subtypes of MCI based on genetic polymorphism and gene expression.
Methods: We utilized the two types of omics data, namely genetic polymorphism and gene expression profiling, derived from 125 MCI patients’ peripheral blood samples from the ADNI-1 dataset. Similarity network fusion (SNF) algorithm was implemented to cluster MCI patient subtypes. And 185 MCI patients in ADNI-2 were utilized to evaluate the effectiveness of this method. Two MCI subtypes were identified by implementing the SNF algorithm.
Results: We used Kaplan-Meier analysis and log-rank testing for the conversion from MCI to AD between two subtypes, and p-value is 4.58×10-3. In addition, we compared patients among two MCI subtypes by the following factors: the changes in Alzheimer’s Disease cognitive scales and MRI image; significantly enriched pathways based on differentially expressed genes. This study proved that MCI is a heterogeneous disease by concluding that AD development in two MCI subtypes is significantly different.
Conclusions: MCI patients with different molecular characteristics have different risks converting to AD. In addition to evaluating statistics, genetic polymorphism and gene expression profiling from MCI patients’ peripheral blood are non-invasiveness and cost-effectiveness markers to identify MCI subtypes for clinical application.
H.-T. Li ; S.-X. Yuan ; J.-S. Wu ; X.-Z. Zhang ; Y. Liu ; X. Sun ; and For the Alzheimer’s Disease Neuroimaging Initiative (2020): Molecular Subtyping of Mild Cognitive Impairment based on Genetic Polymorphism and Gene Expression. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.65
SUGAR IN BEVERAGE AND THE RISK OF INCIDENT DEMENTIA, ALZHEIMER’S DISEASE AND STROKE: A PROSPECTIVE COHORT STUDY
H. Miao, K. Chen, X. Yan, F. Chen
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Background: This study aimed to investigate the association between sugar in beverage and dementia, Alzheimer Disease (AD) dementia and stroke.
Methods: This prospective cohort study were based on the US community-based Framingham Heart Study (FHS). Sugar in beverage was assessed between 1991 and 1995 (5th exam). Surveillance for incident events including dementia and stroke commenced at examination 9 through 2014 and continued for 15-20 years.
Results: At baseline, a total of 1865 (63%) subjects consumed no sugar in beverage, whereas 525 (18%) subjects consumed it in 1-7 servings/week and 593 (29%) in over 7 servings/week. Over an average follow-up of 19 years in 1384 participants, there were 275 dementia events of which 73 were AD dementia. And 103 of 1831 participants occurred stroke during the follow-up nearly 16 years. After multivariate adjustments, individuals with the highest intakes of sugar in beverage had a higher risk of all dementia, AD dementia and stroke relative to individuals with no intakes, with HRs of 2.80(95%CI 2.24-3.50) for all dementia, 2.55(95%CI 1.55-4.18) for AD dementia, and 2.11(95%CI 1.48-3.00) for stroke. And the same results were shown in the subgroup for individuals with median intakes of sugar in beverage.
Conclusion: Higher consumption of sugar in beverage was associated with an increased risk of all dementia, AD dementia and stroke.
H. Miao ; K. Chen ; X. Yan ; F. Chen (2020): Sugar in Beverage and the Risk of Incident Dementia, Alzheimer’s disease and Stroke: A Prospective Cohort Study . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.62
POLYGENIC RISK SCORING IS AN EFFECTIVE APPROACH TO PREDICT THOSE INDIVIDUALS MOST LIKELY TO DECLINE COGNITIVELY DUE TO ALZHEIMER’S DISEASE
P. Daunt, C.G. Ballard, B. Creese, G. Davidson, J. Hardy, O. Oshota, R.J. Pither, A.M. Gibson, for the Alzheimer’s Disease Neuroimaging Initiative
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BACKGROUND: There is a clear need for simple and effective tests to identify individuals who are most likely to develop Alzheimer’s Disease (AD) both for the purposes of clinical trial recruitment but also for improved management of patients who may be experiencing early pre-clinical symptoms or who have clinical concerns.
OBJECTIVES: To predict individuals at greatest risk of progression of cognitive impairment due to Alzheimer’s Disease in individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) using a polygenic risk scoring algorithm. To compare the performance of a PRS algorithm in predicting cognitive decline against that of using the pTau/Aß1-42 ratio CSF biomarker profile.
DESIGN: A longitudinal analysis of data from the Alzheimer’s Disease Neuroimaging Initiative study conducted across over 50 sites in the US and Canada.
SETTING: Multi-center genetics study.
PARTICPANTS: 515 subjects who upon entry to the study were diagnosed as cognitively normal or with mild cognitive impairment.
MEASUREMENTS: Use of genotyping and/or whole genome sequencing data to calculate polygenic risk scores and assess ability to predict subsequent cognitive decline as measured by CDR-SB and ADAS-Cog13 over 4 years
RESULTS: The overall performance for predicting those individuals who would decline by at least 15 ADAS-Cog13 points from a baseline mild cognitive impairment in 4 years was 72.8% (CI:67.9-77.7) AUC increasing to 79.1% (CI: 75.6-82.6) when also including cognitively normal participants. Assessing mild cognitive impaired subjects only and using a threshold of greater than 0.6, the high genetic risk participant group declined, on average, by 1.4 points (CDR-SB) more than the low risk group over 4 years. The performance of the PRS algorithm tested was similar to that of the pTau/Aß1-42 ratio CSF biomarker profile in predicting cognitive decline.
CONCLUSION: Calculating polygenic risk scores offers a simple and effective way, using DNA extracted from a simple mouth swab, to select mild cognitively impaired patients who are most likely to decline cognitively over the next four years.
P. Daunt ; C.G. Ballard ; B. Creese ; G. Davidson ; J. Hardy ; O. Oshota ; R.J. Pither ; A.M. Gibson ; for the Alzheimer’s Disease Neuroimaging Initiative (2020): Polygenic Risk Scoring is an Effective Approach to Predict Those Individuals Most Likely to Decline Cognitively Due to Alzheimer’s Disease . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.64
APPLICATION OF DIGITAL COGNITIVE BIOMARKERS FOR ALZHEIMER’S DISEASE: IDENTIFYING COGNITIVE PROCESS CHANGES AND IMPENDING COGNITIVE DECLINE
J.R. Bock, J. Hara, D. Fortier, M.D. Lee, R.C. Petersen, W.R. Shankle, The Alzheimer’s Disease Neuroimaging Initiative
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Background: Recent Alzheimer’s disease (AD) trials have faced significant challenges to enroll pre-symptomatic or early stage AD subjects with biomarker positivity, minimal or no cognitive impairment, and likelihood to decline cognitively during a short trial period. Our previous study showed that digital cognitive biomarkers (DCB), generated by a hierarchical Bayesian cognitive process (HBCP) model, were able to distinguish groups of cognitively normal individuals with impending cognitive decline from those without. We generated DCBs using only baseline Auditory Verbal Learning Test’s wordlist memory (WLM) item response data from the Mayo Clinic Alzheimer’s Disease Patient Registry.
Objectives: To replicate our previous findings, using baseline ADAS-Cog WLM item response data from the Alzheimer’s Disease Neuroimaging Initiative, and compare DCBs to traditional approaches for scoring word-list memory tests.
Design: Classified decliner subjects (n = 61) as those who developed amnestic MCI or AD dementia within 3 years of normal baseline assessment and non-decliner (n = 442) as those who did not.
Measures: Evaluated the relative value of DCBs compared to traditional measures, using three analytic approaches to group differences: 1) logistic regression of summary scores per ADAS-Cog WLM task; 2) Bayesian modeling of summary scores; and 3) HBCP modeling to generate DCBs from item-level responses.
Results: The HBCP model produced posterior distributions of group differences, of which Bayes factor assessment identified three DCBs with notable group differences: Immediate Retrieval from Durable Storage, (BFds = 11.8, strong evidence); One-Shot Learning, (BFds = 4.5, moderate evidence); and Partial Learning (BFds = 2.9, weak evidence). In contrast, logistic regression of summary scores did not significantly discriminate between groups, and the Bayes factor assessment of modeled summary scores provided moderate evidence that the groups were equivalent (BFsd = 3.4, 3.1, 2.9, and 1.4, respectively).
Conclusions: This study demonstrated DCBs’ ability to distinguish , at baseline, between impending cognitive decline and non-decline groups where individuals in both groups were classified as cognitively normal. This validated findings from our previous study, demonstrating DCBs’ advantages over traditional approaches. This study warrants further refinement of the HBCP DCBs to predict impending cognitive decline in individuals and other factors associated with AD, such as physical biomarker load.
J.R. Bock ; J. Hara ; D. Fortier ; M.D. Lee ; R.C. Petersen ; W.R. Shankle ; The Alzheimer’s Disease Neuroimaging Initiative (2020): Application of Digital Cognitive Biomarkers for Alzheimer’s Disease: Identifying Cognitive Process Changes and Impending Cognitive Decline. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.63
EXECUTIVE FUNCTION PREDICTS THE VALIDITY OF SUBJECTIVE MEMORY COMPLAINTS IN OLDER ADULTS BEYOND DEMOGRAPHIC, EMOTIONAL, AND CLINICAL FACTORS
R.-Y. Chao, T.-F. Chen, Y.-L. Chang
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Background: Although evidence suggests that subjective memory complaints (SMCs) could be a risk factor for dementia, the relationship between SMCs and objective memory performance remains controversial. Old adults with or without mild cognitive impairment (MCI) may represent a highly heterogeneous group, based partly on the demonstrated variability in the level of executive function among those individuals. It is reasonable to speculate that the accuracy of the memory-monitoring ability could be affected by the level of executive function in old adults.
Objective: This study investigated the effects of executive function level on the consistency between SMCs and objective memory performance while simultaneously considering demographic and clinical variables in nondemented older adults.
Setting: Participants were recruited from both the memory clinics and local communities.
Participants: Participants comprised 65 cognitively normal (CN) older adults and 54 patients with MCI.
Measurements: Discrepancy scores between subjective memory evaluation and objective memory performance were calculated to determine the degree and directionality of the concordance between subjective and objective measures. Demographic, emotional, genetic, and clinical information as well as several executive function measurements were collected.
Results: The CN and MCI groups exhibited similar degrees of SMC; however, the patients with MCI were more likely to overestimate their objective memory ability, whereas the CN adults were more likely to underestimate their objective memory ability. The results also revealed that symptoms of depression, group membership, and the executive function level together predicted the discrepancy between the subjective and objective measures of memory function; however, the executive function level retained its unique predictive ability even after the symptoms of depression, group membership, and other factors were controlled for.
Conclusion: Although both noncognitive and cognitive factors were necessary for consideration, the level of executive function may play a unique role in understanding the equivocal relationship of the concurrence between subjective complaints and objective function measures. Through a comprehensive evaluation, high-risk individuals (i.e., CN individuals heightened self-awareness of memory changes) may possibly be identified or provided with the necessary intervention during stages at which objective cognitive impairment remains clinically unapparent.
R.-Y. Chao ; T.-F. Chen ; Y.-L. Chang (2020): Executive Function Predicts the Validity of Subjective Memory Complaints in Older Adults beyond Demographic, Emotional, and Clinical Factors. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.61
PROSPECTIVE ASSOCIATIONS BETWEEN PLASMA AMYLOIDBETA 42/40 AND FRAILTY IN COMMUNITY-DWELLING OLDER ADULTS
W.-H. Lu, K.V. Giudici, Y. Rolland, S. Guyonnet, Y. Li, R.J. Bateman, P. de Souto Barreto, B. Vellas, for the MAPT/DSA Group
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Background: Brain amyloid-beta (Aβ) plaques, a hallmark of the pathophysiology of Alzheimer’s disease, have been associated with frailty. Whether the plasma Aβ markers show similar relationship with frailty is unknown.
OBJECTIVES: To investigate the prospective associations between plasma Aβ42/40 ratio and overtime frailty in community-dwelling older adults.
METHODS: From the 5-year Multidomain Alzheimer Preventive Trial (MAPT), we included 477 adults ≥70 years with available data on plasma Aβ42/40 ratio (lower is worse). Fried frailty phenotype (robust, pre-frail and frail) was assessed at the same time-point of plasma Aβ measures and after until the end of follow-up. The outcomes of interest were the change in the frailty phenotype over time (examined by mixed-effect ordinal logistic regressions) and incident frailty (examined by Cox proportional hazard models).
RESULTS: Plasma Aβ42/40 did not show significant associations with incident frailty; however, after adjusting for Apolipoprotein E (APOE) ε4 genotype, people in the lower quartile of plasma Aβ42/40 (≤0.103) had higher risk of incident frailty (HR=2.63; 95% CI, 1.00 to 6.89), compared to those in the upper quartile (>0.123). Exploratory analysis found a significant association between the lower quartile of plasma Aβ42/40 and incident frailty among APOE ε4 non-carriers (HR=3.48; 95% CI, 1.19 to 10.16), but not among carriers. No associations between plasma Aβ42/40 and evolution of frailty were observed.
CONCLUSION: No significant associations between plasma Aβ42/40 and frailty were found when APOE ε4 status was not accounted into the model. Nevertheless, APOE ε4 non-carriers with high Aβ burden might be more susceptible to develop frailty.
W.-H. Lu ; K.V. Giudici ; Y. Rolland ; S. Guyonnet ; Y. Li ; R.J. Bateman ; P. de Souto Barreto ; B. Vellas ; for the MAPT/DSA Group* (2020): Prospective Associations between Plasma Amyloid-Beta 42/40 and Frailty in Community-Dwelling Older Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.60
COMPARATIVE EFFECTIVENESS OF BEHAVIORAL INTERVENTIONS TO PREVENT OR DELAY DEMENTIA: ONEYEAR PARTNER OUTCOMES
P.A. Amofa, D.E.C. Locke, M. Chandler, J.E. Crook, C.T. Ball, V. Phatak, G.E. Smith
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Background/Objective: Various behavioral interventions are recommended to combat the distress experienced by caregivers of those with cognitive decline, but their comparative effectiveness is poorly understood.
Design/Setting: Caregivers in a comparative intervention study randomly had 1 of 5 possible interventions suppressed while receiving the other four. Caregivers in a full clinical program received all 5 intervention components. Care partner outcomes in the study group were compared to participants enrolled in a full clinical program.
Participants: Two hundred and seventy-two dyads of persons with amnestic mild cognitive impairment (pwMCI) and care partners enrolled in the comparative intervention study. 265 dyads participated in the full clinical program.
Intervention: Behavioral intervention components included: memory compensation training, computerized cognitive training, yoga, support group, and wellness education. Each was administered for 10 sessions over 2 weeks.
Measurements: A longitudinal mixed-effect regression model was used to analyze the effects of the interventions on partner burden, quality of life (QoL), mood, anxiety, and self-efficacy at 12 months follow-up.
Results: At 12 months, withholding wellness education or yoga had a significantly negative impact on partner anxiety compared to partners in the clinical program (ES=0.55 and 0.44, respectively). Although not statistically significant, withholding yoga had a negative impact on partner burden and mood compared to partners in the full clinical program (ES=0.32 and 0.36, respectively).
Conclusion: Our results support the benefits of wellness education and yoga for improving partner’s burden, mood, and anxiety at one year. Our findings are the first to provide an exploration of the impact of multicomponent interventions in care partners of pwMCI.
P.A. Amofa ; D.E.C. Locke ; M. Chandler ; J.E. Crook ; C.T. Ball ; V. Phatak ; G.E. Smith (2020): Comparative Effectiveness of Behavioral Interventions to Prevent or Delay Dementia: One-Year Partner Outcomes. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.59
A SYSTEMATIC REVIEW ON THE FEASIBILITY OF SALIVARY BIOMARKERS FOR ALZHEIMER’S DISEASE
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Early AD diagnosis is critical for ameliorating prognosis and treatment. The analysis of CSF biomarkers yields accurate results, but it necessitates a lumbar puncture procedure. Screening for peripheral biomarkers in saliva is advantageous since this medium is noninvasive and inexpensive to obtain. The objective of this systematic review is to analyze saliva biomarker studies which aim to diagnose AD. Titles, abstracts, and reference lists for publications from January 2004 to February 2020 were screened for by searching Google Scholar and PubMed. The inclusion criteria involved published studies that consisted of both AD and control groups. 88 studies were screened, and 20 publications fulfilled the inclusion criteria. These selected publications were scrutinized and included in this review. Aβ42, tau, certain metabolites, and oral microbiota might serve as reliable biomarkers for AD diagnosis. These results showcase the legitimate feasibility of proteomic, metabolomic, and microbiotic compounds in saliva for AD diagnostics in the near future. Supplemental studies must consider standardizing the analytical methods of measuring salivary biomarkers to establish coherence for the selection of valid AD biomarkers. Validation studies will require a large sample size of biomarker-diagnosed individuals for independent populations. This ensures accuracy and rigidity for receiver operating characteristic (ROC) curves that can be set for the most optimal salivary biomarkers in future clinical settings.
M. Bouftas (2020): A Systematic Review on the Feasibility of Salivary Biomarkers for Alzheimer’s Disease . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.57
PHYSICAL FITNESS AND APOLIPOPROTEIN E GENOTYPE INFLUENCE CORTICAL NETWORKING AND INTELLIGENCE IN ADOLESCENTS
J. Park, Y. Kim, M. Woo
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Aims: This study examined the interactive effect of physical fitness and Apolipoprotein e4 on intelligence and cortical networking in adolescents.
Methods: Participants were middle school students consisting of 10 and 8 high- and low-fit e4 carriers (e4+), respectively, and 14 and 10 high- and low-fit non-carriers (e4−), respectively. Inter- and intra-hemispheric coherences were calculated to examine cortico-cortical communication during intelligence test.
Results: Coherence in low-fit e4+ was lower than in high-fit e4+, while coherence in low-fit e4- was similar to or higher than in high-fit e4-.
Conclusion: the presence of the e4 allele can decrease neural networking 50-60 years before Alzheimer’s disease onset: however, physical fitness may compensate for the negative impact of genotype. Moreover, the beneficial effects of physical fitness may differ depending on functional states of the adolescent brain according to the presence of the e4 allele.
J. Park ; Y. Kim ; M. Woo (2020): Physical Fitness and Apolipoprotein E Genotype Influence Cortical Networking and Intelligence in Adolescents. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.56
THE EFFECT OF BASELINE PERFORMANCE AND AGE ON COGNITIVE TRAINING IMPROVEMENTS IN OLDER ADULTS: A QUALITATIVE REVIEW
J.S. Shaw, S.M.H. Hosseini
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Findings that the brain is capable of plasticity up until old age have led to interest in the use of cognitive training as a potential intervention to delay the onset of dementia. However, individuals participating in training regimens differ greatly with respect to their outcomes, demonstrating the importance of considering individual differences, in particular age and baseline performance in a cognitive domain, when evaluating the effectiveness of cognitive training. In this review, we summarize existing literature on cognitive training in adults across the domains of episodic memory, working memory and the task-switching component of executive functioning to clarify the picture on the impact of age and baseline performance on cognitive training-related improvements. Studies targeting episodic memory induced greater improvements in younger adults with more intact cognitive abilities, explained in part by factors specific to episodic memory training. By contrast, older, lower baseline performance adults improved most in several studies targeting working memory in older individuals as well as in the majority of studies targeting executive functioning, suggesting the preservation of neural plasticity in these domains until very old age. Our findings can have important implications for informing the design of future interventions for enhancing cognitive functions in individuals at the prodromal stage of Alzheimer’s Disease and potentially delaying the clinical onset of Alzheimer’s Disease. Future research should more clearly stratify individuals according to their baseline cognitive abilities and assign specialized, skill-specific cognitive training regimens in order to directly answer the question of how individual differences impact training effectiveness.
J.S. Shaw ; S.M.H. Hosseini ; (2020): The Effect of Baseline Performance and Age on Cognitive Training Improvements in Older Adults: A Qualitative Review . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.55
ASSESSING THE IMPACT OF FACTORS THAT INFLUENCE THE KETOGENIC RESPONSE TO VARYING DOSES OF MEDIUM CHAIN TRIGLYCERIDE (MCT) OIL
A.G. Juby, D.R. Brocks, D.A. Jay, C.M.J. Davis, D.R. Mager
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Objectives, Design, Setting: The ketogenic effect of medium chain triglyceride (MCT) oil offers potential for Alzheimer’s disease prevention and treatment. Limited literature suggests a linear B-hyroxybutyrate (BHB) response to increasing MCT doses. This pharmacokinetic study evaluates factors affecting BHB response in three subject groups.
Participants: Healthy subjects without cognitive deficits <65years, similarly healthy subjects >=65years, and those with Alzheimer’s Disease were assessed.
Intervention: Different doses (0g,14g, 28g, 42g) of MCT oil (99.3% C8:0) were administered, followed by fasting during the study period.
Measurements: BHB measured by finger prick sampling hourly for 5 hours after ingestion. Each subject attended four different days for each ascending dose. Data was also collected on body composition, BMI, waist/hip ratio, grip strength, gait speed, nutrient content of pre-study breakfast and side effects.
Results: Twenty-five participants: eight healthy; average age of 44yr (25-61), nine healthy; 79yr (65-90) and eight with AD; 78.6yr (57-86) respectively. Compiled data showed the expected linear dose response relationship. No group differences, with baseline corrected area under the blood vs. time curve (r2=0.98) and maximum concentrations (r2=0.97). However, there was notable individual variability in maximum BHB response (42g dose: 0.4 -2.1mM), and time to reach maximum BHB response both, within and between individuals. Variability was unrelated to age, sex, sarcopenic or AD status. Visceral fat, BMI, waist/hip ratio and pretest meal CHO and protein content all affected the BHB response (p<0.001).
Conclusion: There was a large inter-individual variability, with phenotype effects identified. This highlights challenges in interpreting clinical responses to MCT intake.
A.G. Juby ; D.R. Brocks ; D.A. Jay ; C.M.J. Davis ; D.R. Mager (2020): Assessing the Impact of Factors that Influence the Ketogenic Response to Varying Doses of Medium Chain Triglyceride (MCT) Oil. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.53
DEVELOPING A SKILLED WORKFORCE: IMPACT OF A POSTGRADUATE PROGRAMME ON DEMENTIA KNOWLEDGE, ATTITUDES AND TRAINING NEEDS
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C. Scerri (2020): Developing a Skilled Workforce: Impact of a Postgraduate Programme on Dementia Knowledge, Attitudes and Training Needs. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.52
COMPARATIVE ANALYSIS OF DIFFERENT DEFINITIONS OF AMYLOID-Β POSITIVITY TO DETECT EARLY DOWNSTREAM PATHOPHYSIOLOGICAL ALTERATIONS IN PRECLINICAL ALZHEIMER
M. Milà-Alomà, G.Salvadó, M. Shekari, O. Grau-Rivera, A. Sala-Vila, G. Sánchez-Benavides, E.M. Arenaza-Urquijo, J.M. González-de-Echávarri, M. Simon, G. Kollmorgen, H. Zetterberg, K. Blennow, J.D. Gispert, M. Suárez-Calvet, J.L. Molinuevo, for the ALFA study
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Amyloid-β (Aβ) positivity is defined using different biomarkers and different criteria. Criteria used in symptomatic patients may conceal meaningful early Aβ pathology in preclinical Alzheimer. Therefore, the description of sensitive cutoffs to study the pathophysiological changes in early stages of the Alzheimer’s continuum is critical. Here, we compare different Aβ classification approaches and we show their performance in detecting pathophysiological changes downstream Aβ pathology.
We studied 368 cognitively unimpaired individuals of the ALFA+ study, many of whom in the preclinical stage of the Alzheimer’s continuum. Participants underwent Aβ PET and CSF biomarkers assessment. We classified participants as Aβ -positive using five approaches: (1) CSF Aβ42 < 1098 pg/ml; (2) CSF Aβ42/40 < 0.071; (3) Aβ PET Centiloid > 12; (4) Aβ PET Centiloid > 30 or (5) Aβ PET Positive visual read. We assessed the correlations between Aβ biomarkers and compared the prevalence of Aβ positivity. We determined which approach significantly detected associations between Aβ pathology and tau/neurodegeneration CSF biomarkers.
We found that CSF-based approaches result in a higher Aβ-positive prevalence than PET-based ones. There was a higher number of discordant participants classified as CSF
Aβ-positive but PET Aβ-negative than CSF Aβ-negative but PET Aβ-positive. The CSF Aβ 42/40 approach allowed optimal detection of significant associations with CSF p-tau and t-tau in the Aβ-positive group.
Altogether, we highlight the need for sensitive Aβ -classifications to study the preclinical Alzheimer’s continuum. Approaches that define Aβ positivity based on optimal discrimination of symptomatic Alzheimer’s disease patients may be suboptimal for the detection of early pathophysiological alterations in preclinical Alzheimer.
M. Milà-Alomà ; G.Salvadó ; M. Shekari ; O. Grau-Rivera ; A. Sala-Vila ; G. Sánchez-Benavides ; E.M. Arenaza-Urquijo ; J.M. González-de-Echávarri ; M. Simon ; G. Kollmorgen ; H. Zetterberg ; K. Blennow ; J.D. Gispert ; M. Suárez-Calvet ; J.L. Molinuevo ; for the ALFA study (2020): Comparative Analysis of Different Definitions of Amyloid-β Positivity to Detect Early Downstream Pathophysiological Alterations in Preclinical Alzheimer. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.51
MENTAL COMPONENT SCORE (MCS) FROM HEALTH-RELATED QUALITY OF LIFE PREDICTS INCIDENCE OF DEMENTIA IN U.S. MALES
X. Ding, E.L. Abner, F.A. Schmitt, J. Crowley, P. Goodman, R.J. Kryscio
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Background: The Medical Outcomes Study Questionnaire Short Form 36 health survey (SF-36) measures health-related quality of life (HRQoL) from the individual’s point of view and is an indicator of overall health status.
Objective: To examine whether HRQoL shows differential changes over time prior to dementia onset and investigate whether HRQoL predicts incidence of dementia.
Design: Prevention of Alzheimer’s Disease (AD) by Vitamin E and Selenium (PREADViSE) trial, which recruited 7,547 non-demented men between 2002 and 2009. A subset of 2,746 PREADViSE participants who completed up to five SF-36 assessments at annual visits was included in the current analysis
Setting: Secondary data analysis of PREADViSE data.
Participants: A subset of 2,746 PREADViSE participants who completed up to five SF-36 assessments at annual visits was included in the current analysis.
Measurements: Two summary T scores were generated for analysis: physical component score (PCS) and mental component score (MCS), each with a mean of 50 (standard deviation of 10); higher scores are better. Linear mixed models (LMM) were applied to determine if mean component scores varied over time or by eventual dementia status. Cox proportional hazards regression was used to determine if the baseline component scores were associated with dementia incidence, adjusting for baseline age, race, APOE-4 carrier status, sleep apnea, and self-reported memory complaint at baseline.
Results: The mean baseline MCS score for participants who later developed dementia (mean± SD: 53.9±9.5) was significantly lower than for those participants who did not develop dementia during the study (mean±SD: 56.4±6.5; p = 0.005). Mean PCS scores at baseline (dementia: 49.3±7.9 vs. non-dementia: 49.8±7.8) were not significantly different (p = 0.5) but LMM analysis showed a significant time effect. For MCS, the indicator for eventual dementia diagnosis was significantly associated with poorer scores after adjusting for baseline age, race, and memory complaint. Adjusted for other baseline risk factors, the Cox model showed that a 10-unit increase in MCS was associated with a 44% decrease in the hazard of a future dementia diagnosis (95% CI: 32%-55%).
Conclusion: The SF-36 MCS summary score may serve as a predictor for future dementia and could be prognostic in longitudinal dementia research.
X. Ding ; E.L. Abner ; F.A. Schmitt ; J. Crowley ; P. Goodman ; R.J. Kryscio (2020): Mental Component Score (MCS) from Health-Related Quality of Life Predicts Incidence of Dementia in U.S. Males. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.50
LONG CHAIN OMEGA-3 FATTY ACID INTERVENTION IN AGEING ADULTS AT RISK OF DEMENTIA FOLLOWING REPEATED HEAD TRAUMA. LOW-LEVEL SUPPORT OR AN OPPORTUNITY FOR AN UNANSWERED QUESTION?
C.S. Patch, E.L Hill-Yardin, L. Ryan, E. Daly, A.J. Pearce
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Emerging evidence of brain injury on risk of neurodegenerative diseases such as Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE) have resulted in interest in therapeutic potential of omega-3 fatty acids (n-3FA). We conducted a systematic review of n-3FA therapeutic efficacy for ageing adults at risk of AD/CTE following a history of repeated head trauma. Databases for articles between 1980-June 2020 were examined for studies reporting on n-3 FAs in adults (≥ 45 years) with a history of repeated brain injury. Following an initial screen of 175 articles, 12 studies were considered but were eventually rejected, as they did not meet inclusion criteria. Our review could find no evidence to support, or disprove, effectiveness of n-3FA intervention in older adults with a history of head trauma. With animal studies showing neuro-restorative potential of n-3FA following brain injury, this review highlights the urgent need for human research in this area.
C.S. Patch ; E.L Hill-Yardin ; L. Ryan ; E. Daly ; A.J. Pearce (2020): Long Chain Omega-3 Fatty Acid Intervention in Ageing Adults at Risk of Dementia Following Repeated Head Trauma. Low-Level Support or an Opportunity for an Unanswered Question? . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.49
NUTRITION TO PREVENT OR TREAT COGNITIVE IMPAIRMENT IN OLDER ADULTS: A GRADE RECOMMENDATION
F. Buckinx, M. Aubertin-Leheudre
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Aging is associated with cognitive declines leading to mild cognitive impairments or Alzheimer disease. Nutrition appear to protect from aging. Some dietary factors could either increase or protect against cognitive declines. This article aimed to provide GRADE recommendations related to nutrition aspects able to prevent or to treat cognitive impairments. A comprehensive literature review was performed using Medline database. The GRADE approach was used to classify quality of the existing evidence (systematic review or meta-analysis).The GRADE process led us to formulate seven key nutritional recommendations to manage cognitive declines, but did not allow us to do it for protein, vitamin B or antioxidants. Thus, 1) adherence to a Mediterranean diet (GRADE 1B); 2) high-level of consumption of mono- or poly- unsaturated fatty acids combined to a low consumption of saturated fatty acids (GRADE 1B); 3) high consumption of fruits and vegetables (GRADE 1B); 4) higher vitamin D intake (GRADE 1C) than the recommended daily allowance. In addition, a ketogenic diet, a low consumption of whole-fat dairy products or a caloric restriction are promising nutritional habits although the evidence does not yet support widespread uptake (GRADE 2C). In conclusion, nutrition is an important modifiable factor to prevent or protect against cognitive decline. Nevertheless, more studies are required to determine specific guidelines such as duration and amounts of nutrients to help older adult to maintain a healthy cognitive life.
F. Buckinx ; M. Aubertin-Leheudre (2020): Nutrition to Prevent or Treat Cognitive Impairment in Older Adults: A GRADE Recommendation. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.40
THE COMPUTERIZED COGNITIVE COMPOSITE (C3) IN A4, AN ALZHEIMER’S DISEASE SECONDARY PREVENTION TRIAL
K.V. Papp, D.M. Rentz, P. Maruff, C.-K. Sun, R. Raman, M.C. Donohue, A. Schembri, C. Stark, M.A. Yassa, A.M. Wessels, R. Yaari, K.C. Holdridge, P.S. Aisen, R.A. Sperling, on behalf of the A4 Study Team
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Background: Computerized cognitive assessments may improve Alzheimer’s disease (AD) secondary prevention trial efficiency and accuracy. However, they require validation against standard outcomes and relevant biomarkers.
Objective: To assess the feasibility and validity of the tablet-based Computerized Cognitive Composite (C3).
Design: Cross-sectional analysis of cognitive screening data from the A4 study (Anti-Amyloid in Asymptomatic AD).
Setting: Multi-center international study.
Participants: Clinically normal (CN) older adults (65-85; n=4486)
Measurements: Participants underwent florbetapir-Positron Emission Tomography for Aβ+/- classification. They completed the C3 and standard paper and pencil measures included in the Preclinical Alzheimer’s Cognitive Composite (PACC). The C3 combines memory measures sensitive to change over time (Cogstate Brief Battery-One Card Learning) and measures shown to be declining early in AD including pattern separation (Behavioral Pattern Separation Test- Object- Lure Discrimination Index) and associative memory (Face Name Associative Memory Exam- Face-Name Matching). C3 acceptability and completion rates were assessed using qualitative and quantitative methods. C3 performance was explored in relation to Aβ+/- groups (n=1323/3163) and PACC.
Results: C3 was feasible for CN older adults to complete. Rates of incomplete or invalid administrations were extremely low, even in the bottom quartile of cognitive performers (PACC). C3 was moderately correlated with PACC (r=0.39). Aβ+ performed worse on C3 compared with Aβ- [unadjusted Cohen’s d=-0.22 (95%CI: -0.31,-0.13) p<0.001] and at a magnitude comparable to the PACC [d=-0.32 (95%CI: -0.41,-0.23) p<0.001]. Better C3 performance was observed in younger, more educated, and female participants.
Conclusions: These findings provide support for both the feasibility and validity of C3 and computerized cognitive outcomes more generally in AD secondary prevention trials.
K.V. Papp ; D.M. Rentz ; P. Maruff ; C.-K. Sun ; R. Raman ; M.C. Donohue ; A. Schembri ; C. Stark ; M.A. Yassa ; A.M. Wessels ; R. Yaari ; K.C. Holdridge ; P.S. Aisen ; R.A. Sperling ; on behalf of the A4 Study Team ; (2020): The Computerized Cognitive Composite (C3) in A4, an Alzheimer’s Disease Secondary Prevention Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.38
IS RELUCTANCE TO SHARE ALZHEIMER’S DISEASE BIOMARKER STATUS WITH A STUDY PARTNER A BARRIER TO PRECLINICAL TRIAL RECRUITMENT?
C.G. Cox, M.M. Ryan, D.L. Gillen, J.D. Grill
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Background: Preclinical Alzheimer’s disease clinical trials test candidate treatments in individuals with biomarker evidence but no cognitive impairment. Participants are required to co-enroll with a knowledgeable study partner, to whom biomarker information is disclosed.
Objective: We investigated whether reluctance to share biomarker results is associated with viewing the study partner requirement as a barrier to preclinical trial enrollment.
Design: We developed a nine-item assessment on views toward the study partner requirement and performed in-person interviews based on a hypothetical clinical trial requiring biomarker testing and disclosure.
Setting: We conducted interviews on campus at the University of California, Irvine.
Participants: Two hundred cognitively unimpaired older adults recruited from the University of California, Irvine Consent-to-Contact Registry participated in the study.
Measurements: We used logistic regression models, adjusting for potential confounders, to examine potential associations with viewing the study partner requirement as a barrier to preclinical trial enrollment.
Results: Eighteen percent of participants reported strong agreement that the study partner requirement was a barrier to enrollment. Ten participants (5%) agreed at any level that they would be reluctant to share their biomarker result with a study partner. The estimated odds of viewing the study partner requirement as a barrier to enrollment were 26 times higher for these participants (OR=26.3, 95% CI 4.0, 172.3), compared to those who strongly disagreed that they would be reluctant to share their biomarker result. Overall, participants more frequently agreed with positive statements than negative statements about the study partner requirement, including 76% indicating they would want their study partner with them when they learned biomarker results.
Conclusions: This is one of the first studies to explore how potential preclinical Alzheimer’s disease trial participants feel about sharing their personal biomarker information with a study partner. Most participants viewed the study partner as an asset to trial enrollment, including having a partner present during biomarker disclosure.
C.G. Cox ; M.M. Ryan ; D.L. Gillen ; J.D. Grill (2020): Is Reluctance to Share Alzheimer’s Disease Biomarker Status with a Study Partner a Barrier to Preclinical Trial Recruitment?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.36
INTEGRATING BIOMARKER OUTCOMES INTO CLINICAL TRIALS FOR ALZHEIMER’S DISEASE IN DOWN SYNDROME
M.S. Rafii, S. Zaman, B.L. Handen
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The NIH-funded Alzheimer’s Biomarker Consortium Down Syndrome (ABC-DS) and the European Horizon 21 Consortium are collecting critical new information on the natural history of Alzheimer’s Disease (AD) biomarkers in adults with Down syndrome (DS), a population genetically predisposed to developing AD. These studies are also providing key insights into which biomarkers best represent clinically meaningful outcomes that are most feasible in clinical trials. This paper considers how these data can be integrated in clinical trials for individuals with DS. The Alzheimer’s Clinical Trial Consortium - Down syndrome (ACTC-DS) is a platform that brings expert researchers from both networks together to conduct clinical trials for AD in DS across international sites while building on their expertise and experience.
M.S. Rafii ; S. Zaman ; B.L. Handen (2020): Integrating Biomarker Outcomes into Clinical Trials for Alzheimer’s Disease in Down Syndrome. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.35
JPAD Volume 7, N°04 - 2020
ESTABLISHING A TRIAL READY COHORT TO ACCELERATE ALZHEIMER’S CLINICAL TRIAL ENROLLMENT AND TREATMENTS
E.A. Meyers, M.C. Carrillo
J Prev Alz Dis 2020;4(7):202-203Show summaryHide summary
E.A. Meyers ; M.C. Carrillo (2020): Establishing a Trial Ready Cohort to Accelerate Alzheimer’s Clinical Trial Enrollment and Treatments. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.42
ACCELERATING PRECLINICAL ALZHEIMER’S CLINICAL TRIALS THROUGH A TRIAL-READY COHORT WITH DIVERSE REPRESENTATION
A.K.W. Lee, S. Correia, S.P. Salloway
J Prev Alz Dis 2020;4(7):204-205Show summaryHide summary
A.K.W. Lee ; S. Correia ; S.P. Salloway (2020): Accelerating Preclinical Alzheimer’s Clinical Trials through a Trial-Ready Cohort with Diverse Representation. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.43
THE TRIAL-READY COHORT FOR PRECLINICAL/PRODROMAL ALZHEIMER’S DISEASE (TRC-PAD) – A FUNDAMENTAL ALLY IN AD PREVENTION RESEARCH
A.P. Porsteinsson, E.D. Clark
J Prev Alz Dis 2020;4(7):206-207Show summaryHide summary
A.P. Porsteinsson ; E.D. Clark (2020): The Trial-Ready Cohort for Preclinical/Prodromal Alzheimer’s Disease (TRC-PAD) – A Fundamental Ally in AD Prevention Research. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.41
THE TRIAL-READY COHORT FOR PRECLINICAL/PRODROMAL ALZHEIMER’S DISEASE (TRC-PAD) PROJECT: AN OVERVIEW
P.S. Aisen, R.A. Sperling, J. Cummings, M.C. Donohue, O. Langford, G.A. Jimenez-Maggiora, P.S. Aisen, R.A. Sperling, J. Cummings, M.C. Donohue, O. Langford, G.A. Jimenez-Maggiora, R.A. Rissman, M.S. Rafii, S. Walter, T. Clanton, R. Raman
J Prev Alz Dis 2020;4(7):208-212Show summaryHide summary
The Trial-Ready Cohort for Preclinical/prodromal Alzheimer’s Disease (TRC-PAD) project is a collaborative effort to establish an efficient mechanism for recruiting participants into very early stage Alzheimer’s disease trials. Clinically normal and mildly symptomatic individuals are followed longitudinally in a web-based component called the Alzheimer’s Prevention Trial Webstudy (APT Webstudy), with quarterly assessment of cognition and subjective concerns. The Webstudy data is used to predict the likelihood of brain amyloid elevation; individuals at relatively high risk are invited for in-person assessment in the TRC screeing phase, during which a cognitive battery is administered and Apolipoprotein E genotype is obtained followed by reassessment of risk of amyloid elevation. After an initial validation study, plasma amyloid peptide ratios will be included in this risk assessment. Based on this second risk calculation, individuals may have amyloid testing by PET scan or lumbar puncture, with those potentially eligible for trials followed in the TRC, while the rest are invited to remain in the APT Webstudy. To date, over 30,000 individuals have participated in the Webstudy; enrollment in the TRC is in its early stage..
P.S. Aisen ; R.A. Sperling ; J. Cummings ; M.C. Donohue ; O. Langford ; G.A. Jimenez-Maggiora ; R.A. Rissman ; M.S. Rafii ; S. Walter ; T. Clanton ; R. Raman (2020): The Trial-Ready Cohort for Preclinical/Prodromal Alzheimer’s Disease (TRC-PAD) Project: An Overview. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.45
PREDICTING AMYLOID BURDEN TO ACCELERATE RECRUITMENT OF SECONDARY PREVENTION CLINICAL TRIALS
O. Langford, R. Raman, R.A. Sperling, J. Cummings, C.-K. Sun, G. Jimenez-Maggiora, P.S. Aisen, M.C. Donohue, the TRC-PAD Investigators
J Prev Alz Dis 2020;4(7):213-218Show summaryHide summary
BACKGROUND: Screening to identify individuals with elevated brain amyloid (Aβ+) for clinical trials in Preclinical Alzheimer’s Disease (PAD), such as the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4) trial, is slow and costly. The Trial-Ready Cohort in Preclinical/Prodromal Alzheimer’s Disease (TRC-PAD) aims to accelerate and reduce costs of AD trial recruitment by maintaining a web-based registry of potential trial participants, and using predictive algorithms to assess their likelihood of suitability for PAD trials.
OBJECTIVES: Here we describe how algorithms used to predict amyloid burden within TRC-PAD project were derived using screening data from the A4 trial.
DESIGN: We apply machine learning techniques to predict amyloid positivity. Demographic variables, APOE genotype, and measures of cognition and function are considered as predictors. Model data were derived from the A4 trial.
SETTING: TRC-PAD data are collected from web-based and in-person assessments and are used to predict the risk of elevated amyloid and assess eligibility for AD trials.
PARTICIPANTS: Pre-randomization, cross-sectional data from the ongoing A4 trial are used to develop statistical models.
MEASUREMENTS: Models use a range of cognitive tests and subjective memory assessments, along with demographic variables. Amyloid positivity in A4 was confirmed using positron emission tomography (PET).
RESULTS: The A4 trial screened N=4,486 participants, of which N=1323 (29%) were classified as Aβ+ (SUVR ≥ 1.15). The Area under the Receiver Operating Characteristic curves for these models ranged from 0.60 (95% CI 0.56 to 0.64) for a web-based battery without APOE to 0.74 (95% CI 0.70 to 0.78) for an in-person battery. The number needed to screen to identify an Aβ+ individual is reduced from 3.39 in A4 to 2.62 in the remote setting without APOE, and 1.61 in the remote setting with APOE.
CONCLUSIONS: Predictive algorithms in a web-based registry can improve the efficiency of screening in future secondary prevention trials. APOE status contributes most to predictive accuracy with cross-sectional data. Blood-based assays of amyloid will likely improve the prediction of amyloid PET positivity.
O. Langford ; R. Raman ; R.A. Sperling ; J. Cummings ; C.-K. Sun ; G. Jimenez-Maggiora ; P.S. Aisen ; M.C. Donohue ; the TRC-PAD Investigators (2020): Predicting Amyloid Burden to Accelerate Recruitment of Secondary Prevention Clinical Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.44
RECRUITMENT INTO THE ALZHEIMER PREVENTION TRIALS (APT) WEBSTUDY FOR A TRIAL-READY COHORT FOR PRECLINICAL AND PRODROMAL ALZHEIMER’S DISEASE (TRCPAD)
S. Walter, T.B. Clanton, O.G. Langford, M.S. Rafii, E.J. Shaffer, J.D. Grill, G.A. Jimenez-Maggiora, R.A. Sperling, J.L. Cummings, P.S. Aisen, the TRC-PAD Investigators*
J Prev Alz Dis 2020;4(7):219-225Show summaryHide summary
Background: The 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.
Objectives: To 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).
Design: Participants 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.
Setting: A remotely enrolled online study.
Participants: Volunteers who are at least 50 years old and interested in Alzheimer’s research.
Measurements: Demographics and recruitment source of participant where measured by UTM.
Results: 30,650 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.
Conclusions: We 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.
S. Walter ; T.B. Clanton ; O.G. Langford ; M.S. Rafii ; E.J. Shaffer ; J.D. Grill ; G.A. Jimenez-Maggiora ; R.A. Sperling ; J.L. Cummings ; P.S. Aisen ; the TRC-PAD Investigators (2020): Recruitment into the Alzheimer Prevention Trials (APT) Webstudy for a Trial-Ready Cohort for Preclinical and Prodromal Alzheimer’s Disease (TRC-PAD). The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.46
TRC-PAD: ACCELERATING RECRUITMENT OF AD CLINICAL TRIALS THROUGH INNOVATIVE INFORMATION TECHNOLOGY
G.A. Jimenez-Maggiora, S. Bruschi, R. Raman, O. Langford, M. Donohue, M.S. Rafii, R.A. Sperling, J.L. Cummings, P.S. Aisen, the TRC-PAD Investigators
J Prev Alz Dis 2020;4(7):226-233Show summaryHide summary
BACKGROUND: The Trial-Ready Cohort for Preclinical/Prodromal Alzheimer’s Disease (TRC-PAD) Informatics Platform (TRC-PAD IP) was developed to facilitate the efficient selection, recruitment, and assessment of study participants in support of the TRC-PAD program.
Objectives: Describe the innovative architecture, workflows, and components of the TRC-PAD IP.
Design: The TRC-PAD IP was conceived as a secure, scalable, multi-tiered information management platform designed to facilitate high-throughput, cost-effective selection, recruitment, and assessment of TRC-PAD study participants and to develop a learning algorithm to select amyloid-bearing participants to participate in trials of early-stage Alzheimer’s disease.
Setting: TRC-PAD participants were evaluated using both web-based and in-person assessments to predict their risk of amyloid biomarker abnormalities and eligibility for preclinical and prodromal clinical trials. Participant data were integrated across multiple stages to inform the prediction of amyloid biomarker elevation.
Participants: TRC-PAD participants were age 50 and above, with an interest in participating in Alzheimer’s research.
Measurements: TRC-PAD participants’ cognitive performance and subjective memory concerns were remotely assessed on a longitudinal basis to predict participant risk of biomarker abnormalities. Those participants determined to be at the highest risk were invited to an in-clinic screening visit for a full battery of clinical and cognitive assessments and amyloid biomarker confirmation using positron emission tomography (PET) or lumbar puncture (LP).
Results: The TRC-PAD IP supported growth in recruitment, screening, and enrollment of TRC-PAD participants by leveraging a secure, scalable, cost-effective cloud-based information technology architecture.
Conclusions: The TRC-PAD program and its underlying information management infrastructure, TRC-PAD IP, have demonstrated feasibility concerning the program aims. The flexible and modular design of the TRC-PAD IP will accommodate the introduction of emerging diagnostic technologies.
G.A. Jimenez-Maggiora ; S. Bruschi ; R. Raman ; O. Langford ; M. Donohue ; M.S. Rafii ; R.A. Sperling ; J.L. Cummings ; P.S. Aisen ; and the TRC-PAD Investigators (2020): TRC-PAD: Accelerating Recruitment of AD Clinical Trials through Innovative Information Technology. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.48
THE TRIAL-READY COHORT FOR PRECLINICAL AND PRODROMAL ALZHEIMER’S DISEASE (TRC-PAD): EXPERIENCE FROM THE FIRST 3 YEARS
S. Walter, O.G. Langford, T.B. Clanton, G.A. Jimenez-Maggiora, R. Raman, M.S. Rafii, E.J. Shaffer, R.A. Sperling, J.L. Cummings, P.S. Aisen, the TRC-PAD Investigators
J Prev Alz Dis 2020;4(7):234-241Show summaryHide summary
BACKGROUND: The Trial-Ready Cohort for Preclinical and Prodromal Alzheimer’s disease (TRC-PAD) aims to accelerate enrollment for Alzheimer’s disease (AD) clinical trials by remotely identifying and tracking individuals who are at high risk for developing symptoms of AD, and referring these individuals to in-person cognitive and biomarker evaluation with the purpose of engaging them in clinical trials. A risk algorithm using statistical modeling to predict brain amyloidosis will be refined as TRC-PAD advances with a maturing data set.
Objectives: To provide a summary of the steps taken to build this Trial-Ready cohort (TRC) and share results of the first 3 years of enrollment into the program.
Design: Participants are remotely enrolled in the Alzheimer Prevention Trials (APT) Webstudy with quarterly assessments, and through an algorithm identified as potentially at high risk, referred to clinical sites for biomarker confirmation, and enrolled into the TRC.
Setting: Both an online study and in-clinic non-interventional cohort study.
Participants: APT Webstudy participants are aged 50 or older, with an interest in participation in AD therapeutic trials. TRC participants must have a study partner, stable medical condition, and elevated brain amyloid, as measured by amyloid positron emission tomography or cerebrospinal fluid analysis. Additional risk assessments include apolipoprotein E genotyping.
Measurements: In the APT Webstudy, participants complete the Cognitive Function Index and Cogstate Brief Battery. The TRC includes the Preclinical Alzheimer’s Cognitive Composite, comprised of the Free and Cued Selective Reminding Test, the Delayed Paragraph Recall score on the Logical Memory IIa test from the Wechsler Memory Scale, the Digit-Symbol Substitution test from the Wechsler Adult Intelligence Scale-Revised, and the Mini Mental State Examination total score (1).
Results: During the first 3 years of this program, the APT Webstudy has 30,650 consented participants, with 23 sites approved for in person screening, 112 participants have been referred for in-clinic screening visits with eighteen enrolled to the TRC. The majority of participants consented to APT Webstudy have a family history of AD (62%), identify as Caucasian (92.5%), have over twelve years of formal education (85%), and are women (73%). Follow up rates for the first quarterly assessment were 38.2% with 29.5% completing the follow up Cogstate Battery.
Conclusions: After successfully designing and implementing this program, the study team’s priority is to improve diversity of participants both in the APT Webstudy and TRC, to continue enrollment into the TRC to our target of 2,000, and to improve longitudinal retention, while beginning the process of referring TRC participants into clinical trials.
S. Walter ; O.G. Langford ; T.B. Clanton ; G.A. Jimenez-Maggiora ; R. Raman ; M.S. Rafii ; E.J. Shaffer ; R.A. Sperling ; J.L. Cummings ; P.S. Aisen ; and the TRC-PAD Investigators ; (2020): The Trial-Ready Cohort for Preclinical and Prodromal Alzheimer’s Disease (TRC-PAD): Experience from the First 3 Years. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.47
THE ALZHEIMER’S PREVENTION REGISTRY: A LARGE INTERNET-BASED PARTICIPANT RECRUITMENT REGISTRY TO ACCELERATE REFERRALS TO ALZHEIMER’S-FOCUSED STUDIES
J.B. Langbaum, N. High, J. Nichols, C. Kettenhoven, E.M. Reiman, P.N. Tariot
J Prev Alz Dis 2020;4(7):242-250Show summaryHide summary
Background: Recruitment for Alzheimer’s disease (AD)-focused studies, particularly prevention studies, is challenging due to the public’s lack of awareness about study opportunities coupled with studies’ inclusion and exclusion criteria, resulting in a high screen fail rate.
Objectives: To develop an internet-based participant recruitment registry for efficiently and effectively raising awareness about AD-focused study opportunities and connecting potentially eligible volunteers to studies in their communities.
Methods: Individuals age 18 and older are eligible to join the Alzheimer’s Prevention Registry (APR). Individuals provide first and last name, year of birth, country, and zip/postal code to join the APR; for questions regarding race, ethnicity, sex, family history of AD or other dementia, and diagnosis of cognitive impairment, individuals have the option to select “prefer not to answer.” The APR website maintains a list of recruiting studies and contacts members who have opted in by email when new studies are available for enrollment.
Results: As of December 1, 2019, 346,661 individuals had joined the APR. Members had a mean age of 63.3 (SD 11.7) years and were predominately women (75%). 94% were cognitively unimpaired, 50% reported a family history of AD or other dementia, and of those who provided race, 76% were white. 39% joined the APR as a result of a paid social media advertisement. To date, the APR helped recruit for 82 studies.
Conclusions: The APR is a large, internet-based participant recruitment registry designed to raise awareness about AD prevention research and connect members with enrolling studies in their communities. It has demonstrated the ability to recruit and engage a large number of highly motivated members and assist researchers in meeting their recruitment goals. Future publications will report on the effectiveness of APR for accelerating recruitment and enrollment into AD-focused studies.
J.B. Langbaum ; N. High ; J. Nichols ; C. Kettenhoven ; E.M. Reiman ; P.N. Tariot (2020): The Alzheimer’s Prevention Registry: A Large Internet-Based Participant Recruitment Registry to Accelerate Referrals to Alzheimer’s-Focused Studies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.31
EFFECTIVENESS OF THE OPEN SCREENING PROGRAMS IN RECRUITING SUBJECTS TO PRODROMAL AND MILD ALZHEIMER’S DISEASE CLINICAL TRIALS
D. Wójcik, K. Szczechowiak, M. Zboch, M. Pikala
J Prev Alz Dis 2020;4(7):251-255Show summaryHide summary
BACKGROUND AND OBJECTIVES: Due to the lack of scientific data comparing the success and cost-effectiveness of trial recruiting strategies, the main goal of this paper is to present our results and experiences in recruiting participants to prodromal and mild AD clinical trials from an open-access screening program.
DESIGN: The screening procedure includes the interview, and combined tests administration conducted by experienced neuropsychologist: Mini-Mental State Examination (MMSE) and Auditory-Verbal Learning Test (AVLT). The clinical evaluation was based on test scores, patient and/or caregiver interview, and the health questionnaire.
SETTINGS AND PARTICIPANTS: The open-access screening program was conducted in Wroclaw Alzheimer’s Center for 18 months (2018-2019). We invited individuals age 50 or older with the caregivers. The total number of subjects was 730 (N=730).
MEASUREMENTS AND RESULTS: Due to our research, the detection rates in the screened population were 0,7% for severe dementia, 4,1% for moderate dementia, 18,6% for mild dementia, and 28,9% for mild cognitive impairment (MCI). From 347 individuals classified in our open-access screening programs as MCI or mild dementia patients, as many as 248 patients were screened in Alzheimer’s disease clinical trials, which is 71,47%. Moreover, 63 from 347 individuals selected from our program as MCI or mild dementia patients were randomized into the clinical trials, which is 18,16%. Furthermore, 63 from total 730 (8,6%) patients were randomized in clinical trials.
CONCLUSIONS: Open-access screening programs can improve detection of MCI and dementia in society, help to distinguish demented from non-demented elderly, and improve recruitment of prodromal AD patients who would probably not have come to the memory clinic otherwise.
D. Wójcik ; K. Szczechowiak ; M. Zboch ; M. Pikala (2020): Effectiveness of the Open Screening Programs in Recruiting Subjects to Prodromal and Mild Alzheimer’s Disease Clinical Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.15
PTI-125 REDUCES BIOMARKERS OF ALZHEIMER’S DISEASE IN PATIENTS
H.-Y. Wang, Z. Pei, K.-C. Lee, E. Lopez-Brignoni, B. Nikolov, C.A. Crowley, M.R. Marsman, R. Barbier, N. Friedmann, L.H. Burns
J Prev Alz Dis 2020;4(7):256-264Show summaryHide summary
BACKGROUND: The most common dementia worldwide, Alzheimer’s disease is often diagnosed via biomarkers in cerebrospinal fluid, including reduced levels of Aβ1–42, and increases in total tau and phosphorylated tau-181. Here we describe results of a Phase 2a study of a promising new drug candidate that significantly reversed all measured biomarkers of Alzheimer’s disease, neurodegeneration and neuroinflammation. PTI-125 is an oral small molecule drug candidate that binds and reverses an altered conformation of the scaffolding protein filamin A found in Alzheimer’s disease brain. Altered filamin A links to the α7-nicotinic acetylcholine receptor to allow Aβ42’s toxic signaling through this receptor to hyperphosphorylate tau. Altered filamin A also links to toll-like receptor 4 to enable Aβ-induced persistent activation of this receptor and inflammatory cytokine release. Restoring the native shape of filamin A prevents or reverses filamin A’s linkages to the α7-nicotinic acetylcholine receptor and toll-like receptor 4, thereby blocking Aβ42’s activation of these receptors. The result is reduced tau hyperphosphorylation and neuroinflammation, with multiple functional improvements demonstrated in transgenic mice and postmortem Alzheimer’s disease brain.
OBJECTIVES: Safety, pharmacokinetics, and cerebrospinal fluid and plasma biomarkers were assessed following treatment with PTI-125 for 28 days. Target engagement and mechanism of action were assessed in patient lymphocytes by measuring 1) the reversal of filamin A’s altered conformation, 2) linkages of filamin A with α7-nicotinic acetylcholine receptor or toll-like receptor 4, and 3) levels of Aβ42 bound to α7-nicotinic acetylcholine receptor or CD14, the co-receptor for toll-like receptor 4.
DESIGN: This was a first-in-patient, open-label Phase 2a safety, pharmacokinetics and biomarker study.
SETTING: Five clinical trial sites in the U.S. under an Investigational New Drug application.
PARTICIPANTS: This study included 13 mild-to-moderate Alzheimer’s disease patients, age 50-85, Mini Mental State Exam ≥16 and ≤24 with a cerebrospinal fluid total tau/Aβ42 ratio ≥0.30.
INTERVENTION: PTI-125 oral tablets (100 mg) were administered twice daily for 28 consecutive days.
MEASUREMENTS: Safety was assessed by electrocardiograms, clinical laboratory analyses and adverse event monitoring. Plasma levels of PTI-125 were measured in blood samples taken over 12 h after the first and last doses; cerebrospinal fluid levels were measured after the last dose. Commercial enzyme linked immunosorbent assays assessed levels of biomarkers of Alzheimer’s disease in cerebrospinal fluid and plasma before and after treatment with PTI-125. The study measured biomarkers of pathology (pT181 tau, total tau and Aβ42), neurodegeneration (neurofilament light chain and neurogranin) and neuroinflammation (YKL-40, interleukin-6, interleukin-1β and tumor necrosis factor α). Plasma levels of phosphorylated and nitrated tau were assessed by immunoprecipitation of tau followed by immunoblotting of three different phospho-epitopes elevated in AD (pT181-tau, pS202-tau and pT231-tau) and nY29-tau. Changes in conformation of filamin A in lymphocytes were measured by isoelectric focusing point. Filamin A linkages to α7-nicotinic acetylcholine receptor and toll-like receptor 4 were assessed by immunoblot detection of α7-nicotinic acetylcholine receptor and toll-like receptor 4 in anti-filamin A immunoprecipitates from lymphocytes. Aβ42 complexed with α7-nicotinic acetylcholine receptor or CD14 in lymphocytes was also measured by co-immunoprecipitation. The trial did not measure cognition.
RESULTS: Consistent with the drug’s mechanism of action and preclinical data, PTI-125 reduced cerebrospinal fluid biomarkers of Alzheimer’s disease pathology, neurodegeneration and neuroinflammation from baseline to Day 28. All patients showed a biomarker response to PTI-125. Total tau, neurogranin, and neurofilament light chain decreased by 20%, 32% and 22%, respectively. Phospho-tau (pT181) decreased 34%, evidence that PTI-125 suppresses tau hyperphosphorylation induced by Aβ42’s signaling through α7-nicotinic acetylcholine receptor. Cerebrospinal fluid biomarkers of neuroinflammation (YKL-40 and inflammatory cytokines) decreased by 5-14%. Biomarker effects were similar in plasma. Aβ42 increased slightly – a desirable result because low Aβ42 indicates Alzheimer’s disease. This increase is consistent with PTI-125’s 1,000-fold reduction of Aβ42’s femtomolar binding affinity to α7-nicotinic acetylcholine receptor. Biomarker reductions were at least p ≤ 0.001 by paired t test. Target engagement was shown in lymphocytes by a shift in filamin A’s conformation from aberrant to native: 93% was aberrant on Day 1 vs. 40% on Day 28. As a result, filamin A linkages with α7-nicotinic acetylcholine receptor and toll-like receptor 4, and Aβ42 complexes with α7-nicotinic acetylcholine receptor and CD14, were all significantly reduced by PTI-125. PTI-125 was safe and well-tolerated in all patients. Plasma half-life was 4.5 h and approximately 30% drug accumulation was observed on Day 28 vs. Day 1.
CONCLUSIONS: PTI-125 significantly reduced biomarkers of Alzheimer’s disease pathology, neurodegeneration, and neuroinflammation in both cerebrospinal fluid and plasma. All patients responded to treatment. The magnitude and consistency of reductions in established, objective biomarkers imply that PTI-125 treatment counteracted disease processes and reduced the rate of neurodegeneration. Based on encouraging biomarker data and safety profile, approximately 60 patients with mild-to-moderate AD are currently being enrolled in a Phase 2b randomized, placebo-controlled confirmatory study to assess the safety, tolerability and efficacy of PTI-125.
H.-Y. Wang ; Z. Pei ; K.-C. Lee ; E. Lopez-Brignoni ; B. Nikolov ; C.A. Crowley ; M.R. Marsman ; R. Barbier ; N. Friedmann ; L.H. Burns (2020): PTI-125 Reduces Biomarkers of Alzheimer’s Disease in Patients. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.6
THE INTERRELATIONSHIP BETWEEN INSULIN-LIKE GROWTH FACTOR 1, APOLIPOPROTEIN E Ε4, LIFESTYLE FACTORS, AND THE AGING BODY AND BRAIN
S.A. Galle, I.K. Geraedts, J.B. Deijen, M.V. Milders, M.L. Drent
J Prev Alz Dis 2020;4(7):265-273Show summaryHide summary
Aging is associated with a decrease in body and brain function and with a decline in insulin-like growth factor 1 levels. The observed associations between alterations in insulin-like growth factor 1 levels and cognitive functioning and Mild Cognitive Impairment suggest that altered insulin-like growth factor 1 signaling may accompany Alzheimer’s disease or is involved in the pathogenesis of the disease. Recent animal research has suggested a possible association between insulin-like growth factor 1 levels and the Apolipoprotein E ε4 allele, a genetic predisposition to Alzheimer’s disease. It is therefore hypothesized that a reduction in insulin-like growth factor 1 signaling may moderate the vulnerability to Alzheimer’s disease of human Apolipoprotein E ε4 carriers. We address the impact of age-related decline of insulin-like growth factor 1 levels on physical and brain function in healthy aging and Alzheimer’s disease and discuss the links between insulin-like growth factor 1 and the Apolipoprotein E ε4 polymorphism. Furthermore, we discuss lifestyle interventions that may increase insulin-like growth factor 1 serum levels, including physical activity and adherence to a protein rich diet and the possible benefits to the physical fitness and cognitive functioning of the aging population.
S.A. Galle ; I.K. Geraedts ; J.B. Deijen ; M.V. Milders ; M.L. Drent (2020): The Interrelationship between Insulin-Like Growth Factor 1, Apolipoprotein E ε4, Lifestyle Factors, and the Aging Body and Brain. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.11
A FRAMEWORK FOR DEVELOPING PHARMACOTHERAPY FOR AGITATION IN ALZHEIMER’S DISEASE: RECOMMENDATIONS OF THE ISCTM* WORKING GROUP
C. O’Gorman, R. Khoury, A. Anderson, M. Carter, F. DiCesare, S. Dubé, L. Ereshefsky, G. Grossberg, N. Hefting, S. Khan, S. Lind, H. Moebius, T. Shiovitz, P. Rosenberg
J Prev Alz Dis 2020;4(7):274-282Show summaryHide summary
C. O’Gorman ; R. Khoury ; A. Anderson ; M. Carter ; F. DiCesare ; S. Dubé ; L. Ereshefsky ; G. Grossberg ; N. Hefting ; S. Khan ; S. Lind ; H. Moebius ; T. Shiovitz ; P. Rosenberg (2020): A Framework for Developing Pharmacotherapy for Agitation in Alzheimer’s disease: Recommendations of the ISCTM* Working Group . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.37
SELF-ADMINISTERED COGNITIVE TESTING BY OLDER ADULTS AT-RISK FOR COGNITIVE DECLINE
E. Tsoy, K.L. Possin, N. Thompson, K. Patel, S.K. Garrigues, I. Maravilla, S.J. Erlhoff, C.S. Ritchie
J Prev Alz Dis 2020;4(7):283-287Show summaryHide summary
Self-administered computerized cognitive testing could effectively monitor older individuals at-risk for cognitive decline at home. In this study, we tested the feasibility and reliability of 3 tablet-based executive functioning measures and an executive composite score in a sample of 30 older adults (age 80±6) with high multimorbidity. The tests were examiner-administered at baseline and then self-administered by the participants at home across 2 subsequent days. Eight of the participants reported no prior experience with touchscreen technology. Twenty-seven participants completed both self-administered assessments, and 28 completed at least one. Cronbach’s alpha (individual tests: .87-.89, composite: .93) and correlations between examiner-administered and self-administered performances (individual tests: .72-.91, composite: .93) were high. The participants who had never used a smartphone or a tablet computer showed comparable consistency. Remote self-administered tablet-based testing in older adults at-risk for cognitive decline is feasible and reliable, even among participants without prior technology experience.
E. Tsoy ; K.L. Possin ; N. Thompson ; K. Patel ; S.K. Garrigues ; I. Maravilla ; S.J. Erlhoff ; C.S. Ritchie (2020): Self-Administered Cognitive Testing by Older Adults At-Risk for Cognitive Decline. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.25
THE ROLE OF CLINICAL TRIALS IN PRECLINICAL ALZHEIMER’S DISEASE DRUG DEVELOPMENT PROGRAMS
J Prev Alz Dis 2020;4(7):288-290Show summaryHide summary
J. Cummings (2020): The Role of Clinical Trials in Preclinical Alzheimer’s Disease Drug Development Programs. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.28
A MISSED OPPORTUNITY FOR DEMENTIA PREVENTION? CURRENT CHALLENGES FOR EARLY DETECTION AND MODERN-DAY SOLUTIONS
R. Isaacson, N. Saif
J Prev Alz Dis 2020;4(7):291-293Show summaryHide summary
R. Isaacson ; N. Saif (2020): A Missed Opportunity for Dementia Prevention? Current Challenges for Early Detection and Modern-Day Solutions. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.23
THE SARS-COV-2 PANDEMIC AND THE BRAVE NEW DIGITAL WORLD OF ENVIRONMENTAL ENRICHMENT TO PREVENT BRAIN AGING AND COGNITIVE DECLINE
H. Hampel, A. Vergallo
J Prev Alz Dis 2020;4(7):294-298Show summaryHide summary
Individuals experiencing brain aging, cognitive decline, and dementia are currently confronted with several more complex challenges due to the current Sars-Cov-2 pandemic as compared to younger and cognitively healthy people. During the first six months of the pandemic, we are experiencing critical issues related to the management of mild cognitive impairment (MCI) and dementia. The evolving, highly contagious global viral spread has created a pressure test of unprecedented proportions for the existing brain health care infrastructure and related services for management, diagnosis, treatment, and prevention. Social distancing and lock-down measures are catalyzing and accelerating a technological paradigm shift, away from a traditional model of brain healthcare focused on late symptomatic disease stages and towards optimized preventive strategies to slow brain aging and increase resilience at preclinical asymptomatic stages. Digital technologies transform global healthcare for accessible equality of opportunities in order to generate better outcomes for brain aging aligned with the paradigm of preventive medicine.
H. Hampel ; A. Vergallo (2020): The Sars-Cov-2 Pandemic and the Brave New Digital World of Environmental Enrichment to Prevent Brain Aging and Cognitive Decline. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.39
Letter to the Editor
LETTER TO THE EDITOR REFERRING TO AISEN, P.S. AND R. RAMAN, FUTILITY ANALYSES IN ALZHEIMER’S DISEASE (AD) CLINICAL TRIALS: A RISKY BUSINESS. THE JOURNAL OF PREVENTION OF ALZHEIMER’S DISEASE, 2020
J Prev Alz Dis 2020;4(7):299-300Show summaryHide summary
D. Umbricht ; (2020): Letter to the editor referring to Aisen, P.S. and R. Raman, Futility Analyses in Alzheimer’s Disease (AD) Clinical Trials: A Risky Business. The Journal of Prevention of Alzheimer’s Disease, 2020. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.34
AUTHORS RESPONSE TO UMBRICHT D, LETTER TO THE EDITOR REFERRING FUTILITY ANALYSES IN ALZHEIMER’S DISEASE (AD) CLINICAL TRIALS: A RISKY BUSINESS. THE JOURNAL OF PREVENTION OF ALZHEIMER’S DISEASE, 2020
P.S. Aisen, R. Raman
J Prev Alz Dis 2020;4(7):300Show summaryHide summary
P.S. Aisen ; R. Raman (2020): Authors response to Umbricht D, letter to the editor referring Futility Analyses in Alzheimer’s Disease (AD) Clinical Trials: A Risky Business. The Journal of Prevention of Alzheimer’s Disease, 2020. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.33
TOULOUSE ALZHEIMER’S CLINICAL RESEARCH CENTER RECOVERY AFTER THE COVID-19 CRISIS: TELEMEDICINE AN INNOVATIVE SOLUTION FOR CLINICAL RESEARCH DURING THE CORONAVIRUS PANDEMIC
C. Takeda, S. Guyonnet, P.J. Ousset, M. Soto, B. Vellas
J Prev Alz Dis 2020;4(7):301-304Show summaryHide summary
C. Takeda ; S. Guyonnet ; P.J. Ousset ; M. Soto ; B. Vellas (2020): Toulouse Alzheimer’s Clinical Research Center Recovery after the COVID-19 Crisis: Telemedicine an Innovative Solution for Clinical Research during the Coronavirus Pandemic. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.32
13th Clinical Trials on Alzheimer's Disease (CTAD) November 4-7, 2020
Clinical Trials and Aging: 13th Conference Clinical Trials Alzheimer’s Disease, November 4-7, 2020
CTAD: SYMPOSIA, ORAL COMMUNICATIONS
J Prev Alz Dis 2020;7(S1):S2-S54Show summaryHide summary
(2020): Clinical Trials and Aging: 13th Conference Clinical Trials Alzheimer’s Disease, November 4-7, 2020. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.54
Clinical Trials and Aging: 13th Conference Clinical Trials Alzheimer’s Disease, November 4-7, 2020
J Prev Alz Dis 2020;7(S1):S55-S119Show summaryHide summary
Posters (2020): Clinical Trials and Aging: 13th Conference Clinical Trials Alzheimer’s Disease, November 4-7, 2020. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.58