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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.

CITATION:
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

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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.

CITATION:
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

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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.

CITATION:
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

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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.

CITATION:
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

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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.

CITATION:
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

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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.

CITATION:
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

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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.

CITATION:
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

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JPAD Volume 7, N°04 - 2020

 

Editorials

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):202-203

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CITATION:
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

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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):204-205

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CITATION:
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

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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):206-207

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CITATION:
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

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Original Research

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):208-212

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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..

CITATION:
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

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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):213-218

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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.

CITATION:
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

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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):219-225

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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.

CITATION:
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

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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):226-233

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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.

CITATION:
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

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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):234-241

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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.

CITATION:
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

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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):242-250

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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.

CITATION:
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

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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):251-255

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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.

CITATION:
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

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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):256-264

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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.

CITATION:
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

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Review Articles

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):265-273

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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.

CITATION:
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

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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):274-282

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CITATION:
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

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Brief Report

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):283-287

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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.

CITATION:
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

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Viewpoint

THE ROLE OF CLINICAL TRIALS IN PRECLINICAL ALZHEIMER’S DISEASE DRUG DEVELOPMENT PROGRAMS

J. Cummings

J Prev Alz Dis 2020;4(7):288-290

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CITATION:
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

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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):291-293

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CITATION:
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

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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):294-298

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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.

CITATION:
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

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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

D. Umbricht

J Prev Alz Dis 2020;4(7):299-300

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CITATION:
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

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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):300

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CITATION:
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

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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):301-304

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CITATION:
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

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