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JPAD Volume 8, N°04 - 2021

 

HOW WILL ADUCANUMAB APPROVAL IMPACT AD RESEARCH?

M.W. Weiner, P.S. Aisen, L.A. Beckett, R.C. Green, W. Jagust, J.C. Morris, O. Okonkwo, R.J. Perrin, R.C. Petersen, M. Rivera Mindt, A.J. Saykin, L.M. Shaw, A.W. Toga, J.Q. Trojanowski, and the Alzheimer’s Disease Neuroimaging Initiative (ADNI)

J Prev Alz Dis 2021;4(8):391-392

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CITATION:
M.W. Weiner ; P.S. Aisen ; L.A. Beckett ; R.C. Green ; W. Jagust ; J.C. Morris ; O. Okonkwo ; R.J. Perrin ; R.C. Petersen ; M. Rivera Mindt ; A.J. Saykin ; L.M. Shaw ; A.W. Toga ; J.Q. Trojanowski ; and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (2021): How Will Aducanumab Approval Impact AD Research?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.46

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CONSEQUENCES OF THE FDA DECISION ON ADUCANUMAB FOR PATIENT CARE AND RESEARCH

R. Doody

J Prev Alz Dis 2021;4(8):393-395

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CITATION:
R. Doody (2021): Consequences of the FDA Decision on Aducanumab for Patient Care and Research. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.43

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IMPACT OF ADUHELM APPROVAL ON CARE AND POLICY

B. Kallmyer, M. Daven, L. Thornhill, K. Clifford, R. Conant, M. Carrillo

J Prev Alz Dis 2021;4(8):396-397

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CITATION:
B. Kallmyer ; M. Daven ; L. Thornhill ; K. Clifford ; R. Conant ; M. Carrillo (2021): Impact of Aduhelm Approval on Care and Policy. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.42

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ADUCANUMAB: APPROPRIATE USE RECOMMENDATIONS

J. Cummings, P. Aisen, L.G. Apostolova, A. Atri, S. Salloway, M. Weiner

J Prev Alz Dis 2021;4(8):398-410

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Aducanumab has been approved by the US Food and Drug Administration for treatment of Alzheimer’s disease (AD). Clinicians require guidance on the appropriate use of this new therapy. An Expert Panel was assembled to construct Appropriate Use Recommendations based on the participant populations, conduct of the pivotal trials of aducanumab, updated Prescribing Information, and expert consensus. Aducanumab is an amyloid-targeting monoclonal antibody delivered by monthly intravenous infusions. The pivotal trials included patients with early AD (mild cognitive impairment due to AD and mild AD dementia) who had confirmed brain amyloid using amyloid positron tomography. The Expert Panel recommends that use of aducanumab be restricted to this population in which efficacy and safety have been studied. Aducanumab is titrated to a dose of 10 mg/kg over a 6-month period. The Expert Panel recommends that the aducanumab be titrated to the highest dose to maximize the opportunity for efficacy. Aducanumab can substantially increase the incidence of amyloid-related imaging abnormalities (ARIA) with brain effusion or hemorrhage. Dose interruption or treatment discontinuation is recommended for symptomatic ARIA and for moderate-severe ARIA. The Expert Panel recommends MRIs prior to initiating therapy, during the titration of the drug, and at any time the patient has symptoms suggestive of ARIA. Recommendations are made for measures less cumbersome than those used in trials for the assessment of effectiveness in the practice setting. The Expert Panel emphasized the critical importance of engaging in a process of patient-centered informed decision-making that includes comprehensive discussions and clear communication with the patient and care partner regarding the requirements for therapy, the expected outcome of therapy, potential risks and side effects, and the required safety monitoring, as well as uncertainties regarding individual responses and benefits.

CITATION:
J. Cummings ; P. Aisen ; L.G. Apostolova ; A. Atri ; S. Salloway ; M. Weiner ; (2021): Aducanumab: Appropriate Use Recommendations. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.41

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THE US EXPERT PANEL ON THE APPROPRIATE USE RECOMMENDATIONS OF ADUCANUMAB IN CLINICAL PRACTICE

S. Gauthier, P. Rosa-Neto

J Prev Alz Dis 2021;4(8):411

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CITATION:
S. Gauthier ; P. Rosa-Neto ; (2021): The US Expert Panel on the Appropriate Use Recommendations of Aducanumab in Clinical Practice. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.44

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ADUCANUMAB: APPROPRIATE USE RECOMMENDATIONS

P. Scheltens, E.G.B. Vijverberg

J Prev Alz Dis 2021;4(8):412-413

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CITATION:
P. Scheltens ; E.G.B. Vijverberg (2021): Aducanumab: Appropriate Use Recommendations. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.45

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DONANEMAB (LY3002813) PHASE 1B STUDY IN ALZHEIMER’S DISEASE: RAPID AND SUSTAINED REDUCTION OF BRAIN AMYLOID MEASURED BY FLORBETAPIR F18 IMAGING

S.L Lowe, C. Duggan Evans, S. Shcherbinin, Y.-J. Cheng, B.A. Willis, I. Gueorguieva, A.C. Lo, A.S. Fleisher, J.L. Dage, P. Ardayfio, G. Aguiar, M. Ishibai, G. Takaichi, L. Chua, G. Mullins, J.R. Sims, on behalf of AACD Investigators

J Prev Alz Dis 2021;4(8):414-424

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Background: Donanemab (LY3002813) is an IgG1 antibody directed at an N‑terminal pyroglutamate of amyloid beta epitope that is present only in brain amyloid plaques. Objectives: To assess effects of donanemab on brain amyloid plaque load after single and multiple intravenous doses, as well as pharmacokinetics, safety/tolerability, and immunogenicity. Design: Phase 1b, investigator- and patient-blind, randomized, placebo-controlled study. Setting: Patients recruited at clinical research sites in the United States and Japan. Participants: 61 amyloid plaque-positive patients with mild cognitive impairment due to Alzheimer’s disease and mild-to-moderate Alzheimer’s disease dementia. Intervention: Six cohorts were dosed with donanemab: single dose 10-, 20- or 40- mg/kg (N = 18), multiple doses of 10-mg/kg every 2 weeks for 24 weeks (N = 10), and 10- or 20-mg/kg every 4 weeks for 72 weeks (N=18) or placebo (N = 15). Measurements: Brain amyloid plaque load, using florbetapir positron emission tomography, was assessed up to 72 weeks. Safety was evaluated by occurrence of adverse events, magnetic resonance imaging, electrocardiogram, vital signs, laboratory testing, neurological monitoring, and immunogenicity. Results: Treatment with donanemab resulted in rapid reduction of amyloid, even after a single dose. By 24 weeks, amyloid positron emission tomography mean changes from baseline for single donanemab doses in Centiloids were: -16.5 (standard error 11.22) 10-mg/kg intravenous; 40.0 (standard error 11.23) 20 mg/kg intravenous; and -49.6 (standard error 15.10) 40-mg/kg intravenous. Mean reduction of amyloid plaque in multiple dose cohorts by 24 weeks in Centiloids were: 55.8 (standard error 9.51) 10-mg/kg every 2 weeks; -50.2 (standard error 10.54) 10-mg/kg every 4 weeks; and -58.4 (standard error 9.66) 20-mg/kg every 4 weeks. Amyloid on average remained below baseline levels up to 72 weeks after a single dose of donanemab. Repeated dosing resulted in continued florbetapir positron emission tomography reductions over time compared to single dosing with 6 out of 28 patients attaining complete amyloid clearance within 24 weeks. Within these, 5 out of 10 patients in the 20 mg/kg every 4 weeks cohort attained complete amyloid clearance within 36 weeks. When dosing with donanemab was stopped after 24 weeks of repeat dosing in the 10 mg every 2 weeks cohort, florbetapir positron emission tomography reductions were sustained up to 72 weeks. For the single dose cohorts on day 1, dose proportional increases in donanemab pharmacokinetics were observed from 10 to 40 mg/kg. Dose proportional increases in pharmacokinetics were also observed at steady state with the multiple dose cohorts. Donanemab clearance was comparable across the dose levels. Mean donanemab elimination-half-life following 20 mg/kg single dose was 9.3 days with range of 5.6 to 16.2 days. Greater than 90% of patients had positive treatment-emergent antidrug antibodies with donanemab. However, overall, the treatment-emergent antidrug antibodies did not have a significant impact on pharmacokinetics. Donanemab was generally well tolerated. Amongst the 46 participants treated with donanemab, the following amyloid-related imaging abnormalities, common to the drug class, were observed: 12 vasogenic cerebral edema events (12 [19.7%] patients), 10 cerebral microhemorrhage events (6 [13.0%] patients), and 2 superficial siderosis events (2 [4.3%] patients). Conclusions: Single and multiple doses of donanemab demonstrated a rapid, robust, and sustained reduction up to 72 weeks in brain amyloid plaque despite treatment-emergent antidrug antibodies detected in most patients. Amyloid-related imaging abnormalities were the most common treatment-emergent event.

CITATION:
S.L Lowe ; C. Duggan Evans ; S. Shcherbinin ; Y.-J. Cheng ; B.A. Willis ; I. Gueorguieva ; A.C. Lo ; A.S. Fleisher ; J.L. Dage ; P. Ardayfio ; G. Aguiar ; M. Ishibai ; G. Takaichi ; L. Chua ; G. Mullins ; J.R. Sims ; (2021): Donanemab (LY3002813) Phase 1b Study in Alzheimer’s Disease: Rapid and Sustained Reduction of Brain Amyloid Measured by Florbetapir F18 Imaging. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.56

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THE COST-EFFECTIVENESS OF THREE PREVENTION STRATEGIES IN ALZHEIMER\'S DISEASE: RESULTS FROM THE MULTIDOMAIN ALZHEIMER PREVENTIVE TRIAL (MAPT)

N. Costa, M. Mounié, A. Pagès, H. Derumeaux, T. Rapp, S. Guyonnet, N. Coley, C. Cantet, I. Carrié, S. Andrieu, L. Molinier, and on behalf of the MAPT/DSA Group

J Prev Alz Dis 2021;4(8):425-435

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BACKGROUND: To date, no curative treatment is available for Alzheimer’s disease (AD). Therefore, efforts should focus on prevention strategies to improve the efficiency of healthcare systems. Objective: Our aim was to assess the cost-effectiveness of three preventive strategies for AD compared to a placebo. Design: The Multidomain Alzheimer Preventive Trial (MAPT) study was a multicenter, randomized, placebo-controlled superiority trial with four parallel groups, including three intervention groups (one group with Multidomain Intervention (MI) plus a placebo, one group with Polyunsaturated Fatty Acids (PFA), one group with a combination of PFA and MI) and one placebo group. Setting: Participants were recruited and included in 13 memory centers in France and Monaco. Participants: Community-dwelling subject aged 70 years and older were followed during 3 years. Interventions: We used data from the MAPT study which aims to test the efficacy of a MI along PFA, the MI plus a placebo, PFA alone, or a placebo alone. Measurement: Direct medical and non-medical costs were calculated from a payer’s perspective during the 3 years of follow-up. The base case incremental Cost-Effectiveness Ratio (ICER) represents the cost per improved cognitive Z-score point. Sensitivity analyses were performed using different interpretation of the effectiveness criteria. Results: Analyses were conducted on 1,525 participants. The ICER at year 3 that compares the MI + PFA and the MI alone to the placebo amounted to €21,443 and €21,543 respectively, per improved Z score point. PFA alone amounted to €111,720 per improved Z score point. Conclusion: Our study shows that ICERS of PFA combined with MI and MI alone amounted to €21,443 and €21,543 respectively per improved Z score point compared to the placebo and are below the WTP of €50,000 while the ICER of PFA alone amounted to €111,720 per improved Z score point. This information may help decision makers and serve as a basis for the implementation of a lifetime decision analytic model.

CITATION:
N. Costa ; M. Mounié ; A. Pagès ; H. Derumeaux ; T. Rapp ; S. Guyonnet ; N. Coley ; C. Cantet ; I. Carrié ; S. Andrieu ; L. Molinier ; and on behalf of the MAPT/DSA Group (2021): The Cost-Effectiveness of Three Prevention Strategies in Alzheimer's Disease: Results from the Multidomain Alzheimer Preventive Trial (MAPT). The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.47

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THE ASSOCIATION BETWEEN PEANUT AND PEANUT BUTTER CONSUMPTION AND COGNITIVE FUNCTION AMONG COMMUNITY-DWELLING OLDER ADULTS

E.W. Katzman, S.J. Nielsen

J Prev Alz Dis 2021;4(8):436-441

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Background: Many studies have focused on the association between diet and cognitive function. While a subset of these studies focused on a diet that includes tree nuts (TN), there is limited data on the association between peanut and peanut butter consumption (P/PB) and cognitive health. Objective: This study investigated the association of P/PB consumption and cognitive function. Design: This was a cross-sectional study using 2011-2014 NHANES data. Participants/setting: Individuals 60-80 years old in 2011-2014 NHANES who had two 24-hour dietary recalls, cognitive function tests, and education level and with no history of stroke. Measurements: P/PB and TN consumption was measured as well as participant performance on the CERAD Word Learning subtest (CERAD W-L), Animal Fluency test (AFT), and the Digit Symbol Substitution test (DSST). Scores from the three cognitive tests were dichotomized. Individuals were classified as either P/PB consumers or non-consumers and TN consumers or non-consumers. Logistic regression models examined associations between P/PB consumption, tree nut consumption, and cognitive function with adjusted models including age, sex, and education as covariates. Results: A total of 2,454 adults, aged 60-80 years old (mean age=69.4) participated. Approximately half were male (48%), 18% were P/PB consumers, and 14% consumed TN. Participants who did not consume P/PB were more likely to do poorly on the CERAD W-L (adjusted OR=1.56, 95% CI 1.24-1.97; p<0.05), AFT (adjusted OR=1.29, 95% CI 1.03-1.61; p<0.05), and DSST (adjusted OR=1.43, 95% CI 1.12-1.82; p<0.05) when compared to those who did consume P/PB. Conclusions: These findings suggest an association between P/PB consumption and cognitive function; however, this is a cross sectional study and a causal relationship cannot be established. More studies are needed to determine causality.

CITATION:
E.W. Katzman ; S.J. Nielsen ; (2021): The Association between Peanut and Peanut Butter Consumption and Cognitive Function among Community-Dwelling Older Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.32

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EARLY-ONSET SUBGROUP OF TYPE 2 DIABETES AND RISK OF DEMENTIA, ALZHEIMER’S DISEASE AND STROKE: A COHORT STUDY

K. Wang, H. Liu

J Prev Alz Dis 2021;4(8):442-447

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BACKGROUND: This study aimed to assess the relation of early-onset type 2 diabetes (age<55years) versus later in life to the risk of dementia, Alzheimer Disease (AD) dementia and stroke. Methods: This study was based on the Framingham Heart Study Offspring cohort (FHS-OS) which is a community-based prospective cohort. Glycemic status was ascertained at serial examinations over six decades among participants who initially did not have diabetes. Surveillance for incident events including dementia and stroke has been continued for approximately 30 years. Results: At baseline, there were 142 (5%) subjects with onset of diabetes prior to age 55 years, 172 (6%) subjects with 55-64 years, 349 (11%) subjects over 65 years and 2389 (78%) subjects without diabetes. The risk of dementia, AD and stroke increased with decreasing age of diabetes onset (P<0.05, for trend). Compared with never developing diabetes, early-onset diabetes conferred a higher risk of all dementia, AD dementia and stroke [HR 2.86(1.16-5.51) for dementia; HR 2.42(1.63-4.33) for AD; HR 2.85(1.37-3.98) for stroke]. Whereas later-onset diabetes was only associated with greater risk for stroke, neither dementia nor AD. Conclusion: Early-onset diabetes was stronger associated with an increased risk of all dementia, AD dementia and stroke than later-onset.

CITATION:
K. Wang ; H. Liu ; (2021): Early-Onset Subgroup of Type 2 Diabetes and Risk of Dementia, Alzheimer’s disease and Stroke: A Cohort Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.35

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A UK-WIDE STUDY EMPLOYING NATURAL LANGUAGE PROCESSING TO DETERMINE WHAT MATTERS TO PEOPLE ABOUT BRAIN HEALTH TO IMPROVE DRUG DEVELOPMENT: THE ELECTRONIC PERSON-SPECIFIC OUTCOME MEASURE (EPSOM) PROGRAMME

S. Saunders, G. Muniz-Terrera, S. Sheehan, C.W. Ritchie, S. Luz

J Prev Alz Dis 2021;4(8):448-456

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BACKGROUND: It is important to use outcome measures for novel interventions in Alzheimer’s disease (AD) that capture the research participants’ views of effectiveness. The electronic Person-Specific Outcome Measure (ePSOM) development programme is underpinned by the need to identify and detect change in early disease manifestations and the possibilities of incorporating artificial intelligence in outcome measures. Objectives: The aim of the ePSOM programme is to better understand what outcomes matter to patients in the AD population with a focus on those at the pre-dementia stages of disease. Ultimately, we aim to develop an app with robust psychometric properties to be used as a patient reported outcome measure in AD clinical trials. Design: We designed and ran a nationwide study (Aug 2019 – Nov 2019, UK), collecting primarily free text responses in five pre-defined domains. We collected self-reported clinical details and sociodemographic data to analyse responses by key variables whilst keeping the survey short (around 15 minutes). We used clustering and Natural Language Processing techniques to identify themes which matter most to individuals when developing new treatments for AD. Results: The study was completed by 5,808 respondents, yielding over 80,000 free text answers. The analysis resulted in 184 themes of importance. An analysis focusing on key demographics to explore how priorities differed by age, gender and education revealed that there are significant differences in what groups consider important about their brain health. Discussion: The ePSOM data has generated evidence on what matters to people when developing new treatments for AD that target secondary prevention and therein maintenance of brain health. These results will form the basis for an electronic outcome measure to be used in AD clinical research and clinical practice.

CITATION:
S. Saunders ; G. Muniz-Terrera ; S. Sheehan ; C.W. Ritchie ; S. Luz (2021): The Japan-Multimodal Intervention Trial for Prevention of Dementia (J-MINT): The Study Protocol for an 18-MA UK-Wide Study Employing Natural Language Processing to Determine What Matters to People about Brain Health to Improve Drug Development: The Electronic Person-Specific Outcome Measure (ePSOM) Programmeonth, Multicenter, Randomized, Controlled Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.30

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A FAY-HERRIOT MODEL FOR ESTIMATING SUBJECTIVE COGNITIVE DECLINE AMONG MILITARY VETERANS

J.T. McDaniel, R.J. McDermott, T. Schneider

J Prev Alz Dis 2021;4(8):457-461

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BACKGROUND: Although studies have examined the geographic distribution of dementia among the general population in order to develop geographically targeted interventions, no studies have examined the geographic distribution of subjective cognitive decline (SCD) among military veterans specifically. Objectives: To map the geographic distribution of subjective cognitive decline from 2011-2019 in the United States among military veterans. Design: Cross-sectional. Setting: United States. Participants: Individuals reporting previous service in the United States Armed Forces. Measurements: Using 2011 Behavioral Risk Factor Surveillance System (BRFSS) data, which is last year for which geocoded SCD data is publicly available, we estimated the survey-weighted county-level prevalence of veteran SCD for counties with >30 veterans (43 counties in 7 states). We then developed a Fay-Herriot small area estimation linear model using auxiliary data from the Census, with county-level veteran-specific covariates including % >65 years old, % female, % college educated, and median income. Following model validation, we created beta-weighted predictions of veteran SCD for all USA counties for 2011-2019 using relevant time-specific Census auxiliary data. We provide choropleth maps of our predictions. Results: Results of our model on 43 counties showed that county-level rates of SCD were significantly associated with all auxiliary variables except annual income (F = 1.49, df = 4, 38). Direct survey-weighted rates were correlated with model-predicted rates in 43 counties (Pearson r = 0.32). Regarding predicted rates for the entire USA, the average county-level prevalence rate of veteran SCD in 2011 was 13.83% (SD = 7.35), but 29.13% in 2019 (SD = 14.71) – although variation in these rates were evident across counties. Conclusions: SCD has increased since 2011 among veterans. Veterans Affairs hospitals should implement plans that include cognitive assessments, referral to resources, and monitoring patient progress, especially in rural areas.

CITATION:
J.T. McDaniel ; R.J. McDermott ; T. Schneider (2021): A Fay-Herriot Model for Estimating Subjective Cognitive Decline among Military Veterans. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.28

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ALZHEIMER’S DISEASE RESEARCH IN JAPAN: A SHORT HISTORY, CURRENT STATUS AND FUTURE PERSPECTIVES TOWARD PREVENTION

T. Iwatsubo, Y. Niimi, H. Akiyama

J Prev Alz Dis 2021;4(8):462-464

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CITATION:
T. Iwatsubo ; Y. Niimi ; H. Akiyama (2021): Alzheimer’s Disease Research in Japan: A Short History, Current Status and Future Perspectives toward Prevention. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.38

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THE JAPAN-MULTIMODAL INTERVENTION TRIAL FOR PREVENTION OF DEMENTIA (J-MINT): THE STUDY PROTOCOL FOR AN 18-MONTH, MULTICENTER, RANDOMIZED, CONTROLLED TRIAL

T. Sugimoto, T. Sakurai, H. Akatsu, T. Doi, Y. Fujiwara, A. Hirakawa, F. Kinoshita, M. Kuzuya, S. Lee, K. Matsuo, M. Michikawa, S. Ogawa, R. Otsuka, K. Sato, H. Shimada, H. Suzuki, H. Suzuki, H. Takechi, S. Takeda, H. Umegaki, S. Wakayama, H. Arai, On behalf of the J-MINT investigators

J Prev Alz Dis 2021;4(8):465-476

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Background/Objectives: The Japan-multimodal intervention trial for prevention of dementia (J-MINT) is intended to verify the effectiveness of multi-domain interventions and to clarify the mechanism of cognitive improvement and deterioration by carrying out assessment of dementia-related biomarkers, omics analysis and brain imaging analysis among older adults at high risk of dementia. Moreover, the J-MINT trial collaborates with partnering private enterprises in the implementation of relevant interventional measures. This manuscript describes the study protocol. Design/Setting: Eighteen-month, multi-centered, randomized controlled trial. Participants: We plan to recruit 500 older adults aged 65-85 years with mild cognitive impairment. Subjects will be centrally randomized into intervention and control groups at a 1:1 allocation ratio using the dynamic allocation method with all subjects stratified by age, sex, and cognition. Intervention: The multi-domain intervention program includes: (1) management of vascular risk factors; (2) group-based physical exercise and self-monitoring of physical activity; (3) nutritional counseling; and (4) cognitive training. Health-related information will be provided to the control group every two months. Measurements: The primary and secondary outcomes will be assessed at baseline, 6-, 12-, and 18-month follow-up. The primary outcome is the change from baseline to 18 months in a global composite score combining several neuropsychological domains. Secondary outcomes include: cognitive change in each neuropsychological test, incident dementia, changes in blood and dementia-related biomarkers, changes in geriatric assessment including activities of daily living, frailty status and neuroimaging, and number of medications taken. Conclusions: This trial that enlist the support of private enterprises will lead to the creation of new services for dementia prevention as well as to verify the effectiveness of multi-domain interventions for dementia prevention.

CITATION:
T. Sugimoto ; T. Sakurai ; H. Akatsu ; T. Doi ; Y. Fujiwara ; A. Hirakawa ; F. Kinoshita ; M. Kuzuya ; S. Lee ; K. Matsuo ; M. Michikawa ; S. Ogawa ; R. Otsuka ; K. Sato ; H. Shimada ; H. Suzuki ; H. Suzuki ; H. Takechi ; S. Takeda ; H. Umegaki ; S. Wakayama ; H. Arai (2021): The Japan-Multimodal Intervention Trial for Prevention of Dementia (J-MINT): The Study Protocol for an 18-Month, Multicenter, Randomized, Controlled Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.29

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PERIPHERAL BLOOD BRCA1 METHYLATION POSITIVELY CORRELATES WITH MAJOR ALZHEIMER’S DISEASE RISK FACTORS

T. Mano, K. Sato, T. Ikeuchi, T. Toda, T. Iwatsubo, A. Iwata, Japanese Alzheimer’s Disease Neuroimaging Initiative

J Prev Alz Dis 2021;4(8):477-482

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BACKGROUND: Recent biomarker studies demonstrated that the central nervous system (CNS) environment can be observed from peripherally-derived samples. In a previous study, we demonstrated significant hypomethylation of the BRCA1 promoter region in neuronal cells from post-mortem brains of Alzheimer’s disease patients through neuron-specific methylome analysis. Thus, we investigate the methylation changes in the BRCA1 promoter region in the blood samples. OBJECTIVES: To analyze the methylation level of the BRCA1 promoter in peripheral blood from AD patients and normal controls. DESIGN, SETTING, PARTICIPANTS: Genomic DNA samples from peripheral blood were obtained from the J-ADNI repository, and their biomarker data were obtained J-ADNI from the National Bioscience Database Center. Genomic DNA samples from an independent cohort for validation was obtained from Niigata University Hospital (Niigata, Japan). Amyloid positivity was defied by visual inspection of amyloid PET or a CSF Aβ42 value ≤ 333 pg/mL at the baseline. MEASUREMENTS: Methylation level of the BRCA1 promoter was analyzed by pyrosequencing. RESULTS: Compared to normal controls, methylation of the BRCA1 promoter in AD patients was not significantly changed; however, in AD patients, it showed a positive correlation with AD risk factors. CONCLUSIONS: Our data confirmed the importance of cell-type specific methylome analysis and also suggested that environmental changes in the CNS can be detected by observing the peripheral blood, implying that the peripheral BRCA1 methylation level can be a surrogate for AD.

CITATION:
T. Mano ; K. Sato ; T. Ikeuchi ; T. Toda ; T. Iwatsubo ; A. Iwata ; Japanese Alzheimer’s Disease Neuroimaging Initiative ; (2021): Peripheral Blood BRCA1 Methylation Positively Correlates with Major Alzheimer’s Disease Risk Factors. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.31

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TAUROURSODEOXYCHOLIC ACID ATTENUATES DIET-INDUCED AND AGE-RELATED PERIPHERAL ENDOPLASMIC RETICULUM STRESS AND CEREBRAL AMYLOID PATHOLOGY IN A MOUSE MODEL OF ALZHEIMER’S DISEASE

T. Ochiai, T. Nagayama, K. Matsui, K. Amano, T. Sano, T. Wakabayashi, T. Iwatsubo

J Prev Alz Dis 2021;4(8):483-494

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BACKGROUND: Obesity and diabetes are well-established risk factors of Alzheimer’s disease (AD). In the brains of patients with AD and model mice, diabetes-related factors have been implicated in the pathological changes of AD. However, the molecular mechanistic link between the peripheral metabolic state and AD pathophysiology have remained elusive. Endoplasmic reticulum (ER) stress is known as one of the major contributors to the metabolic abnormalities in obesity and diabetes. Interventions aimed at reducing ER stress have been shown to improve the systemic metabolic abnormalities, although their effects on the AD pathology have not been extensively studied. OBJECTIVES: We examined whether interventions targeting ER stress attenuate the obesity/diabetes-induced Aβ accumulation in brains. We also aimed to determine whether ER stress that took place in the peripheral tissues or central nervous system was more important in the Aβ neuropathology. Furthermore, we explored if age-related metabolic abnormalities and Aβ accumulation could be suppressed by reducing ER stress. METHODS: APP transgenic mice (A7-Tg), which exhibit Aβ accumulation in the brain, were used as a model of AD to analyze parameters of peripheral metabolic state, ER stress, and Aβ pathology in the brain. Intraperitoneal or intracerebroventricular administration of taurodeoxycholic acid (TUDCA), a chemical chaperone, was performed in high-fat diet (HFD)-fed A7-Tg mice for ~1 month, followed by analyses at 9 months of age. Mice fed a normal diet were treated with TUDCA by drinking water for 4 months and intraperitoneally for 1 month in parallel, and analyzed at 15 months of age. RESULTS: Intraperitoneal administration of TUDCA suppressed ER stress in the peripheral tissues and ameliorated the HFD-induced obesity and insulin resistance. Concomitantly, Aβ levels in the brain were significantly reduced. In contrast, intracerebroventricular administration of TUDCA had no effect on the Aβ levels. Peripheral administration of TUDCA was also effective against the age-related obesity and insulin resistance, and markedly reduced amyloid accumulation. CONCLUSIONS: Interventions that target peripheral ER stress might be beneficial therapeutic and prevention strategies against brain Aβ pathology associated with metabolic overload and aging.

CITATION:
T. Ochiai ; T. Nagayama ; K. Matsui ; K. Amano ; T. Sano ; T. Wakabayashi ; T. Iwatsubo (2021): Tauroursodeoxycholic Acid Attenuates Diet-Induced and Age-Related Peripheral Endoplasmic Reticulum Stress and Cerebral Amyloid Pathology in a Mouse Model of Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.33

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A JAPANESE MULTICENTER STUDY ON PET AND OTHER BIOMARKERS FOR SUBJECTS WITH POTENTIAL PRECLINICAL AND PRODROMAL ALZHEIMER’S DISEASE

M. Senda, K. Ishii, K. Ito, T. Ikeuchi, H. Matsuda, T. Iwatsubo, A. Iwata, R. Ihara, K. Suzuki, K. Kasuga, Y. Ikari, Y. Niimi, H. Arai, A. Tamaoka, Y. Arahata, Y. Itoh, H. Tachibana, Y. Ichimiya, S. Washizuka, T. Odawara, K. Ishii, K. Ono, T. Yokota, A. Nakanishi, E. Matsubara, H. Mori, H. Shimada

J Prev Alz Dis 2021;4(8):495-502

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BACKGROUND: PET (positron emission tomography) and CSF (cerebrospinal fluid) provide the “ATN” (Amyloid, Tau, Neurodegeneration) classification and play an essential role in early and differential diagnosis of Alzheimer’s disease (AD). OBJECTIVE: Biomarkers were evaluated in a Japanese multicenter study on cognitively unimpaired subjects (CU) and early (E) and late (L) mild cognitive impairment (MCI) patients. MEASUREMENTS: A total of 38 (26 CU, 7 EMCI, 5 LMCI) subjects with the age of 65-84 were enrolled. Amyloid-PET and FDG-PET as well as structural MRI were acquired on all of them, with an additional tau-PET with 18F-flortaucipir on 15 and CSF measurement of Aβ1-42, P-tau, and T-tau on 18 subjects. Positivity of amyloid and tau was determined based on the positive result of either PET or CSF. RESULTS: The amyloid positivity was 13/38, with discordance between PET and CSF in 6/18. Cortical tau deposition quantified with PET was significantly correlated with CSF P-tau, in spite of discordance in the binary positivity between visual PET interpretation and CSF P-tau in 5/8 (PET-/CSF+). Tau was positive in 7/9 amyloid positive and 8/16 amyloid negative subjects who underwent tau measurement, respectively. Overall, a large number of subjects presented quantitative measures and/or visual read that are close to the borderline of binary positivity, which caused, at least partly, the discordance between PET and CSF in amyloid and/or tau. Nine subjects presented either tau or FDG-PET positive while amyloid was negative, suggesting the possibility of non-AD disorders. CONCLUSION: Positivity rate of amyloid and tau, together with their relationship, was consistent with previous reports. Multicenter study on subjects with very mild or no cognitive impairment may need refining the positivity criteria and cutoff level as well as strict quality control of the measurements.

CITATION:
M. Senda ; K. Ishii ; K. Ito ; T. Ikeuchi ; H. Matsuda ; T. Iwatsubo ; A. Iwata ; R. Ihara ; K. Suzuki ; K. Kasuga ; Y. Ikari ; Y. Niimi ; H. Arai ; A. Tamaoka ; Y. Arahata ; Y. Itoh ; H. Tachibana ; Y. Ichimiya ; S. Washizuka ; T. Odawara ; K. Ishii ; K. Ono ; T. Yokota ; A. Nakanishi ; E. Matsubara ; H. Mori ; H. Shimada (2021): A Japanese Multicenter Study on PET and Other Biomarkers for Subjects with Potential Preclinical and Prodromal Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.37

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COHORT-SPECIFIC OPTIMIZATION OF MODELS PREDICTING PRECLINICAL ALZHEIMER’S DISEASE, TO ENHANCE SCREENING PERFORMANCE IN THE MIDDLE OF PRECLINICAL ALZHEIMER’S DISEASE CLINICAL STUDIES

K. Sato, T. Mano, R. Ihara, K. Suzuki, Y. Niimi, T. Toda, T. Iwatsubo, A. Iwata

J Prev Alz Dis 2021;4(8):503-512

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Background: Models that can predict brain amyloid beta (Aβ) status more accurately have been desired to identify participants for clinical trials of preclinical Alzheimer’s disease (AD). However, potential heterogeneity between different cohorts and the limited cohort size have been the reasons preventing the development of reliable models applicable to the Asian population, including Japan. Objectives: We aim to propose a novel approach to predict preclinical AD while overcoming these constraints, by building models specifically optimized for ADNI or for J-ADNI, based on the larger samples from A4 study data. Design & Participants: This is a retrospective study including cognitive normal participants (CDR-global = 0) from A4 study, Alzheimer Disease Neuroimaging Initiative (ADNI), and Japanese-ADNI (J-ADNI) cohorts. Measurements: The model is made up of age, sex, education years, history of AD, Clinical Dementia Rating-Sum of Boxes, Preclinical Alzheimer Cognitive Composite score, and APOE genotype, to predict the degree of amyloid accumulation in amyloid PET as Standardized Uptake Value ratio (SUVr). The model was at first built based on A4 data, and we can choose at which SUVr threshold configuration the A4-based model may achieve the best performance area under the curve (AUC) when applied to the random-split half ADNI or J-ADNI subset. We then evaluated whether the selected model may also achieve better performance in the remaining ADNI or J-ADNI subsets. Result: When compared to the results without optimization, this procedure showed efficacy of AUC improvement of up to approximately 0.10 when applied to the models “without APOE;” the degree of AUC improvement was larger in the ADNI cohort than in the J-ADNI cohort. Conclusions: The obtained AUC had improved mildly when compared to the AUC in case of literature-based predetermined SUVr threshold configuration. This means our procedure allowed us to predict preclinical AD among ADNI or J-ADNI second-half samples with slightly better predictive performance. Our optimizing method may be practically useful in the middle of the ongoing clinical study of preclinical AD, as a screening to further increase the prior probability of preclinical AD before amyloid testing.

CITATION:
K. Sato ; T. Mano ; R. Ihara ; K. Suzuki ; Y. Niimi ; T. Toda ; T. Iwatsubo ; A. Iwata ; for Alzheimer’s disease Neuroimaging Initiative, Japanese Alzheimer’s disease Neuroimaging Initiative, and The A4 Study Team ; (2021): Cohort-Specific Optimization of Models Predicting Preclinical Alzheimer’s Disease, to Enhance Screening Performance in the Middle of Preclinical Alzheimer’s Disease Clinical Studies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.39

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USING DIGITAL TOOLS TO ADVANCE ALZHEIMER’S DRUG TRIALS DURING A PANDEMIC: THE EU/US CTAD TASK FORCE

J. Kaye, P. Aisen, R. Amariglio, R. Au, C. Ballard, M. Carrillo, H. Fillit, T. Iwatsubo, G. Jimenez-Maggiora, S. Lovestone, F. Natanegara, K. Papp, M.E. Soto, M. Weiner, B. Vellas

J Prev Alz Dis 2021;4(8):513-519

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The 2020 COVID-19 pandemic has disrupted Alzheimer’s disease (AD) clinical studies worldwide. Digital technologies may help minimize disruptions by enabling remote assessment of subtle cognitive and functional changes over the course of the disease. The EU/US Clinical Trials in Alzheimer’s Disease (CTAD) Task Force met virtually in November 2020 to explore the opportunities and challenges associated with the use of digital technologies in AD clinical research. While recognizing the potential of digital tools to accelerate clinical trials, improve the engagement of diverse populations, capture clinically meaningful data, and lower costs, questions remain regarding the stability, validity, generalizability, and reproducibility of digital data. Substantial concerns also exist regarding regulatory acceptance and privacy. Nonetheless, the Task Force supported further exploration of digital technologies through collaboration and data sharing, noting the need for standardization of digital readouts. They also concluded that while it may be premature to employ remote assessments for trials of novel experimental medications, remote studies of non-invasive, multi-domain approaches may be feasible at this time.

CITATION:
J. Kaye ; P. Aisen ; R. Amariglio ; R. Au ; C. Ballard ; M. Carrillo ; H. Fillit ; T. Iwatsubo ; G. Jimenez-Maggiora ; S. Lovestone ; F. Natanegara ; K. Papp ; M.E. Soto ; M. Weiner ; B. Vellas (2021): Using Digital Tools to Advance Alzheimer’s Drug Trials During a Pandemic: The EU/US CTAD Task Force. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.36

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COMPARATIVE EFFICACY, SAFETY, TOLERABILITY, AND EFFECTIVENESS OF ANTIPSYCHOTICS IN THE TREATMENT OF DEMENTIA-RELATED PSYCHOSIS (DRP): A SYSTEMATIC LITERATURE REVIEW

I. Yunusa, N. Rashid, V. Abler, K. Rajagopalan

J Prev Alz Dis 2021;4(8):520-533

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Objectives: To evaluate the comparative efficacy, safety, tolerability, and effectiveness of atypical antipsychotics (AAPs) for the treatment of dementia related psychosis (DRP) in older adults. Methods: In this systematic literature review (SLR), we qualitatively synthesized evidence on the comparative efficacy (based on neuropsychiatric inventory), tolerability (weight gain), and safety (cerebrovascular adverse events [CVAE], cardiovascular events, mortality, somnolence, extrapyramidal symptoms [EPS]) of AAPs used to treat DRP. We also assessed effectiveness based on all-cause discontinuations and discontinuations due to lack of efficacy or adverse events (AE). Published articles from through March 2021 from PubMed, EMBASE, PsycINFO, and Cochrane databases evaluated. We included double-blind, active-comparator/placebo-controlled randomized trials, open-label trials, and observational studies. Results: This qualitative synthesis included 51 eligible studies with sample size of 13,334 and mean age of 79.36 years. Risperidone, olanzapine, quetiapine, and aripiprazole demonstrated numerically small improvement in psychotic symptoms among patients with DRP. Somnolence was the most reported AE for all the AAPs, with weight gain and tardive dyskinesia more common with olanzapine and risperidone, respectively. These AAPs are associated with falls, EPS, cognitive declines, CVAE, and mortality. Aripiprazole and olanzapine had lower odds of discontinuation due to lack of efficacy, with olanzapine having greater discontinuation odds due to AEs. Conclusion: This SLR demonstrated that AAPs used off-label to treat DRP are associated with small numerical symptom improvement but with a high risk of AEs, including cognitive decline and potentially higher mortality. These results underscore the need for new treatments with a favorable benefit-risk profile for treating DRP.

CITATION:
I. Yunusa ; N. Rashid ; V. Abler ; K. Rajagopalan (2021): Comparative Efficacy, Safety, Tolerability, and Effectiveness of Antipsychotics in The Treatment of Dementia-Related Psychosis (DRP): A Systematic Literature Review. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.48

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IMMUNOTHERAPY FOR ALZHEIMER’S DISEASE: CURRENT SCENARIO AND FUTURE PERSPECTIVES

M.B. Usman, S. Bhardwaj, S. Roychoudhury, D. Kumar, A. Alexiou, P. Kumar, R.K. Ambasta, P. Prasher, S. Shukla, V. Upadhye, F.A. Khan, R. Awasthi, M.D. Shastri, S.K. Singh, G. Gupta, D.K. Chellappan, K. Dua, S.K. Jha, J. Ruokolainen, K.K. Kesari, S. Ojha, N.K. Jha

J Prev Alz Dis 2021;4(8):534-551

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Alzheimer’s disease (AD) is a global health concern owing to its complexity, which often poses a great challenge to the development of therapeutic approaches. No single theory has yet accounted for the various risk factors leading to the pathological and clinical manifestations of dementia-type AD. Therefore, treatment options targeting various molecules involved in the pathogenesis of the disease have been unsuccessful. However, the exploration of various immunotherapeutic avenues revitalizes hope after decades of disappointment. The hallmark of a good immunotherapeutic candidate is not only to remove amyloid plaques but also to slow cognitive decline. In line with this, both active and passive immunotherapy have shown success and limitations. Recent approval of aducanumab for the treatment of AD demonstrates how close passive immunotherapy is to being successful. However, several major bottlenecks still need to be resolved. This review outlines recent successes and challenges in the pursuit of an AD vaccine.

CITATION:
M.B. Usman ; S. Bhardwaj ; S. Roychoudhury ; D. Kumar ; A. Alexiou ; P. Kumar ; R.K. Ambasta ; P. Prasher ; S. Shukla ; V. Upadhye ; F.A. Khan ; R. Awasthi ; M.D. Shastri ; S.K. Singh ; G. Gupta ; D.K. Chellappan ; K. Dua ; S.K. Jha ; J. Ruokolainen ; K.K. Kesari ; S. Ojha ; N.K. Jha ; (2021): Immunotherapy for Alzheimer’s Disease: Current Scenario and Future Perspectives. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.52

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CHILDHOOD SECONDHAND SMOKE EXPOSURE AND RISK OF DEMENTIA IN ADULTHOOD

T. Kawada

J Prev Alz Dis 2021;4(8):552

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CITATION:
T. Kawada ; (2021): Childhood Secondhand Smoke Exposure and Risk of Dementia in Adulthood. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.51

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