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TACKLING A MAJOR DEFICIENCY OF DIVERSITY IN ALZHEIMER’S DISEASE THERAPEUTIC TRIALS: AN CTAD TASK FORCE REPORT

R. Raman, P. Aisen, M.C. Carillo, M. Detke, J.D. Grill, O.C. Okonkwo, M. Rivera-Mindt, M. Sabbagh, B. Vellas, M. Weiner, R. Sperlin, and CTAD Task Force

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As the last opportunity to assess treatment effect modification in a controlled setting prior to formal approval, clinical trials are a critical tool for understanding the safety and efficacy of new treatments in diverse populations. Recruitment of diverse participants in Alzheimer’s Disease (AD) clinical trials are therefore essential to increase the generalizability of study results, with diversity broadly described to be representative and inclusive. This representation of study participants is equally critical in longitudinal cohort (observational) studies, which will be key to understanding disease disparities and are often used to design adequately powered AD clinical trials. New and innovative recruitment initiatives and enhanced infrastructure facilitate increased participant diversity in AD clinical studies.

CITATION:
R. Raman ; P. Aisen ; M.C. Carillo ; M. Detke ; J.D. Grill ; O.C. Okonkwo ; M. Rivera-Mindt ; M. Sabbagh ; B. Vellas ; M. Weiner ; R. Sperling ; and CTAD Task Force* ; (2022): Tackling a Major Deficiency of Diversity in Alzheimer’s Disease Therapeutic Trials: An CTAD Task Force Report. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.50

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THE FUTURE OF AD CLINICAL TRIALS WITH THE ADVENT OF ANTI-AMYLOID THERAPIES: AN CTAD TASK FORCE REPORT

J. Delrieu, R.J. Bateman, J. Touchon, M. Sabbagh, J. Cummings

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BACKGROUND: Aducanumab (ADUHELMTM) was approved for the treatment of Alzheimer's disease (AD) in the US. This approval was supported by an effect on the cerebral amyloid plaque load and evidence of cognitive efficacy to be confirmed in post-marketing trials. Other anti-amyloid antibodies are under investigation in phase III (donanemab, lecanemab, gantenerumab) and have shown preliminary evidence of a cognitive benefit in phase II trials. Although these agents target a small segment of patients with mild cognitive impairment due to AD or mild AD dementia, their advent will change the design of future clinical trials both for anti-amyloid and non-amyloid drugs. These changes will promote the selection of patients in clinical trials by amyloid and tau biomarkers that identify patients with appropriate biology and may follow the treatment response to approved amyloid antibodies. The use of these agents creates the opportunity to test combined drug therapies and to conduct comparative assessments with innovative therapies and newly approved drugs available in clinical practice. Blood-based AD biomarkers should be implemented in research and could facilitate the recruitment into clinical trials. Anti-amyloid antibodies will have positive (e.g., more early diagnosis) and negative impacts (some subjects will be reluctant to participate in trials and risk assignment to placebo) on AD trials in the immediate future. We present the results of the CTAD Task Force on this topic, in Boston, November 6, 2021.

CITATION:
J. Delrieu ; R.J. Bateman ; J. Touchon ; M. Sabbagh ; J. Cummings ; (2022): The Future of AD Clinical Trials with the Advent of Anti-Amyloid Therapies: An CTAD Task Force Report. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.48

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PREDICTION OF COGNITIVE DECLINE FOR ENRICHMENT OF ALZHEIMER’S DISEASE CLINICAL TRIALS

A. Tam, C. Laurent, S. Gauthier, C. Dansereau, for the Alzheimer’s Disease Neuroimaging Initiative

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Background: A key issue to Alzheimer’s disease clinical trial failures is poor participant selection. Participants have heterogeneous cognitive trajectories and many do not decline during trials, which reduces a study’s power to detect treatment effects. Trials need enrichment strategies to enroll individuals who are more likely to decline. Objectives: To develop machine learning models to predict cognitive trajectories in participants with early Alzheimer’s disease and presymptomatic individuals over 24 and 48 months respectively. Design: Prognostic machine learning models were trained from a combination of demographics, cognitive tests, APOE genotype, and brain imaging data. Setting: Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), National Alzheimer’s Coordinating Center (NACC), Open Access Series of Imaging Studies (OASIS-3), PharmaCog, and a Phase 3 clinical trial in early Alzheimer’s disease were used for this study. Participants: A total of 2098 participants who had demographics, cognitive tests, APOE genotype, and brain imaging data, as well as follow-up visits for 24-48 months were included. Measurements: Baseline magnetic resonance imaging, cognitive tests, demographics, and APOE genotype were used to separate decliners, defined as individuals whose CDR-Sum of Boxes scores increased during a predefined time window, from stable individuals. A prognostic model to predict decline at 24 months in early Alzheimer’s disease was trained on 1151 individuals who had baseline diagnoses of mild cognitive impairment and Alzheimer’s dementia from ADNI and NACC. This model was validated on 115 individuals from a placebo arm of a Phase 3 clinical trial and 76 individuals from the PharmaCog dataset. A second prognostic model to predict decline at 48 months in presymptomatic populations was trained on 628 individuals from ADNI and NACC who were cognitively unimpaired at baseline. This model was validated on 128 individuals from OASIS-3. Results: The models achieved up to 79% area under the curve (cross-validated and out-of-sample). Power analyses showed that using prognostic models to recruit enriched cohorts of predicted decliners can reduce clinical trial sample sizes by as much as 51% while maintaining the same detection power. Conclusions: Prognostic tools for predicting cognitive decline and enriching clinical trials with participants at the highest risk of decline can improve trial quality, derisk endpoint failures, and accelerate therapeutic development in Alzheimer’s disease.

CITATION:
A. Tam ; C. Laurent ; S. Gauthier ; C. Dansereau ; for the Alzheimer’s Disease Neuroimaging Initiative ; (2022): Prediction of Cognitive Decline for Enrichment of Alzheimer’s Disease Clinical Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.49

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SEX-DRIVEN DIFFERENCES IN THE EFFECTIVENESS OF INDIVIDUALIZED CLINICAL MANAGEMENT OF ALZHEIMER’S DISEASE RISK

N. Saif, H. Hristov, K. Akiyoshi, K. Akiyoshi, I.E. Ariza, N. Malviya, P. Lee, J. Melendez, G. Sadek, K. Hackett, A. Rahman, J. Meléndez-Cabrero, C.E. Greer, L. Mosconi, R. Krikorian, R.S. Isaacson

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Background: The Comparative Effectiveness Dementia & Alzheimer’s Registry (CEDAR) trial demonstrated that individualized, multi-domain interventions improved cognition and reduced the risk of Alzheimer’s disease (AD). As biological sex is a significant risk factor for AD, it is essential to explore the differential effectiveness of targeted clinical interventions in women vs. men. Methods: Patients were recruited from an Alzheimer’s Prevention Clinic. Subjects with normal cognition, subjective cognitive decline, or asymptomatic preclinical AD were classified as “Prevention”. Subjects with mild cognitive impairment due to AD or mild AD were classified as “Early Treatment.” The primary outcome was the change from baseline to 18-months on the modified-Alzheimer’s Prevention Cognitive Composite. Secondary outcomes included a cognitive aging composite, AD and cardiovascular (CV) risk scales, and serum biomarkers. Subjects who adhered to >60% of recommendations in the CEDAR trial were included in this a priori sub-group analysis to examine whether individualized intervention effects were modified by sex (n=80). Results: In the Prevention group, both women (p=0.0205) and men (p=0.0044) demonstrated improvements in cognition with no sex differences (p=0.5244). In the Early Treatment group, there were also no significant sex differences in cognition (p=0.3299). In the Prevention group, women demonstrated greater improvements in the Multi-Ethnic Study of Atherosclerosis risk score (MESA-RS) than men (difference=1.5, p=0.0013). Women in the Early Treatment group demonstrated greater improvements in CV Risk Factors, Aging and Incidence of Dementia (CAIDE) risk score (difference=2.3, p=0.0067), and the MESA-RS (difference=4.1, p<0.001). Conclusions: Individualized multi-domain interventions are equally effective at improving cognition in women and men. However, personally-tailored interventions led to greater improvements in calculated AD and CV risk, and CV blood biomarkers, in women compared to men. Future study in larger cohorts is necessary to further define sex differences in AD risk reduction in clinical practice.

CITATION:
N. Saif ; H. Hristov ; K. Akiyoshi ; K. Akiyoshi ; I.E. Ariza ; N. Malviya ; P. Lee ; J. Melendez ; G. Sadek ; K. Hackett ; A. Rahman ; J. Meléndez-Cabrero ; C.E. Greer ; L. Mosconi ; R. Krikorian ; R.S. Isaacson ; (2022): Sex-Driven Differences in the Effectiveness of Individualized Clinical Management of Alzheimer’s Disease Risk. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.44

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CLINICAL TRIAL ENDPOINTS AND THEIR CLINICAL MEANINGFULNESS IN EARLY STAGES OF ALZHEIMER’S DISEASE

S. Cohen, J. Cummings, S. Knox, M. Potashman, J. Harrison

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As the focus of Alzheimer’s disease (AD) therapeutic development shifts to the early stages of the disease, the clinical endpoints used in drug trials, and how these might translate into clinical practice, are of increasing importance. The clinical meaningfulness of trial outcome measures is often unclear, with a lack of conclusive evidence as to how these measures correlate to changes in disease progression and treatment response. Clarifying this would benefit all, including patients, care partners, primary care providers, regulators, and payers, and would enhance our understanding of the relationship between clinical trial endpoints and assessments used in everyday practice. At present, there is a wide range of assessment tools used in clinical trials for AD and substantial variability in measures selected as endpoints across these trials. The aim of this review is to summarize the most commonly used assessment tools for early stages of AD, describe their use in clinical trials and clinical practice, and discuss what might constitute clinically meaningful change in these measures in relation to disease progression and treatment response.

CITATION:
S. Cohen ; J. Cummings ; S. Knox ; M. Potashman ; J. Harrison ; (2022): Clinical Trial Endpoints and Their Clinical Meaningfulness in Early Stages of Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.41

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CLINICAL RESEARCH INVESTIGATING ALZHEIMER’S DISEASE IN CHINA: CURRENT STATUS AND FUTURE PERSPECTIVES TOWARD PREVENTION

Q. Wang, F. Gao, L. Dai, J. Zhang, D. Bi, Y. Shen

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Based on the background of research investigating brain aging and neurodegenerative diseases in China, the present review addresses Alzheimer’s disease (AD), one of the most common types of neurodegenerative diseases, clinical research progress, and prospects for future development in China.

CITATION:
Q. Wang ; F. Gao ; L. Dai ; J. Zhang ; D. Bi ; Y. Shen ; (2022): Clinical Research Investigating Alzheimer’s Disease in China: Current Status and Future Perspectives Toward Prevention. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.46

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STANDARDIZING ELECTRONIC HEALTH RECORD DATA ON AD/ADRD TO ACCELERATE HEALTH EQUITY IN PREVENTION, DETECTION, AND TREATMENT

C.G. Lyketsos, S.B. Roberts, E.K. Swift, A. Quina, G. Moon, I. Kremer, P. Tariot, H. Fillit, D.E. Bovenkamp, P.P. Zandi, J.G. Haaga

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Improving the prevention, detection, and treatment of Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) across racial, ethnic, and other diverse populations is a national priority. To this end, this paper proposes the development of the Standard Health Record for Dementia (SHRD, pronounced “shared”) for collecting and sharing AD/ADRD real-world data (RWD). SHRD would replace the current unstandardized, fragmented, or missing state of key RWD with an open source, consensus-based, and interoperable common data standard. This paper describes how SHRD could leverage the best practices of the Minimal Common Oncology Data Elements (mCODETM) initiative to advance prevention, detection, and treatment; gain adoption by clinicians and electronic health record (EHR) vendors; and establish sustainable business and governance models. It describes a range of potential use cases to advance equity, including strengthening public health surveillance by facilitating AD/ADRD registry reporting; improving case detection and staging; and diversifying participation in clinical trials.

CITATION:
C.G. Lyketsos ; S.B. Roberts ; E.K. Swift ; A. Quina ; G. Moon ; I. Kremer ; P. Tariot ; H. Fillit ; D.E. Bovenkamp ; P.P. Zandi ; J.G. Haaga ; (2022): Standardizing Electronic Health Record Data on AD/ADRD to Accelerate Health Equity in Prevention, Detection, and Treatment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.47

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AGING, SENESCENCE, AND DEMENTIA

Q. Behfar, A. Ramirez Zuniga, P.V. Martino-Adami

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The underlying processes occurring in aging are complex, involving numerous biological changes that result in chronic cellular stress and sterile inflammation. One of the main hallmarks of aging is senescence. While originally the term senescence was defined in the field of oncology, further research has established that also microglia, astrocytes and neurons become senescent. Since age is the main risk factor for neurodegenerative diseases, it is reasonable to argue that cellular senescence might play a major role in Alzheimer’s disease. Specific cellular changes seen during Alzheimer’s disease are similar to those observed during senescence across all resident brain cell types. Furthermore, increased levels of senescence-associated secretory phenotype proteins such as IL-6, IGFBP, TGF-β and MMP-10 have been found in both CSF and plasma samples from Alzheimer’s disease patients. In addition, genome-wide association studies have identified that individuals with Alzheimer’s disease carry a high burden of genetic risk variants in genes known to be involved in senescence, including ADAM10, ADAMTS4, and BIN1. Thus, cellular senescence is emerging as a potential underlying disease process operating in Alzheimer’s disease. This has also attracted more attention to exploiting cellular senescence as a therapeutic target. Several senolytic compounds with the capability to eliminate senescent cells have been examined in vivo and in vitro with notable results, suggesting they may provide a novel therapeutic avenue. Here, we reviewed the current knowledge of cellular senescence and discussed the evidence of senescence in various brain cell types and its putative role in inflammaging and neurodegenerative processes.

CITATION:
Q. Behfar ; A. Ramirez Zuniga ; P.V. Martino-Adami ; (2022): Aging, Senescence, and Dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.42

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REPLY TO LETTER TO THE EDITOR: “EARLY-ONSET TYPE 2 DIABETES AND RISK OF DEMENTIA”

K. Wang, H. Liu

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CITATION:
K. Wang ; H. Liu ; (2022): Reply to Letter to the Editor: “Early-Onset Type 2 Diabetes and Risk of Dementia”. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.45

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LETTER TO THE EDITOR: EARLY-ONSET TYPE 2 DIABETES AND RISK OF DEMENTIA

T. Kawada

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CITATION:
T. Kawada (2022): Letter to the Editor: Early-Onset Type 2 Diabetes and Risk of Dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.43

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EVALUATION OF THE FEASIBILITY, SAFETY AND EFFICACY OF THE USE OF INTRAVENOUS INFUSIONS OF ADENOSINE TRIPHOSPHATE (ATP) IN PEOPLE AFFECTED BY MODERATE TO SEVERE ALZHEIMER\'S DISEASE: A DOUBLE-BLIND MASKED CLINICAL TRIAL FOR DOSE FINDING

A. Ruiz, D. Sánchez, A. Lafuente, G. Ortega, M. Buendía, J. Papasey, S.Y. Jimeno, F.P. Badia, M.E. Palacio, C. Abdelnour, F. Ramírez-Toraño, F. Maestú, M.E. Sáez, L. Tárraga, P.C. Dagnelie, M. Boada

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Background: There are currently no drug therapies modifying the natural history of patients suffering Alzheimer’s disease (AD). Most recent clinical trials in the field include only subjects in early stage of the disease, while patients with advanced AD are usually not represented. Objectives: To evaluate the feasibility, safety and efficacy of systemic infusions of adenosine triphosphate (ATP) in patients with moderate to severe AD, and to select the minimum effective dose of infusion. Design: A phase IIb, randomized, double-blind, placebo-controlled clinical trial investigates. Participants: A total of 20 subjects with moderate or severe AD were included, 16 in the treatment group and 4 in the placebo group (4:1 randomization) at two dosage regimens, 6-hour or 24-hour infusions. Results: The proof-of-concept study was successfully conducted, with no significant deviations from the study protocol and no serious adverse events reported. Regarding efficacy, only marginal differences were observed between ATP and placebo arms for H-MRS and MMSE variables. Conclusions: Our study demonstrates that the use of ATP infusion as therapy is feasible and safe. Larger studies are however needed to assess the efficacy of ATP in moderate to severe AD.

CITATION:
A. Ruiz ; D. Sánchez ; A. Lafuente ; G. Ortega ; M. Buendía ; J. Papasey ; S.Y. Jimeno ; F.P. Badia ; M.E. Palacio ; C. Abdelnour ; F. Ramírez-Toraño ; F. Maestú ; M.E. Sáez ; L. Tárraga ; P.C. Dagnelie ; M. Boada ; (2022): Evaluation of the Feasibility, Safety and Efficacy of the Use of Intravenous Infusions of Adenosine Triphosphate (ATP) in People Affected by Moderate to Severe Alzheimer's Disease: A Double-Blind Masked Clinical Trial for Dose Finding. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.38

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EFFECTS OF NON-INVASIVE BRAIN STIMULATION ON ALZHEIMER’S DISEASE

L. Gu, H. Xu, F. Qian

J Prev Alz Dis 2022;2(9):247-254

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Background: Previous meta-analyses did not explore the immediate and long-term effect of non-invasive brain stimulation (NIBS) on different cognitive domains in Alzheimer’s disease (AD). The meta-analysis aimed to assess the therapy effect of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) on different cognitive domains in AD in randomized controlled trials (RCTs). Methods: Studies published before December 2021 and exploring therapy effect of rTMS, tDCS on different cognitive domains in AD were searched in the following databases: PubMed and Web of Science. We used STATA 12.0 software to compute the standard mean difference (SMD) and a 95% confidence interval (CI). Results: The present study included 16 articles (including 372 AD patients treated with rTMS and 310 treated with sham rTMS) for rTMS and 11 articles (including 152 AD patients treated with tDCS and 134 treated with sham tDCS) for tDCS. The present study showed better immediate and long-term general cognitive function increase effects in AD given rTMS, compared to those given sham rTMS with random effects models (immediate effect: SMD = 2.07, 95% CI = 0.37 to 3.77, I2 = 97.8%, p < 0.001; long-term effect: SMD = 5.04, 95% CI = 2.25 to 7.84, I2 = 97.8%, p < 0.001). The present study showed no significant immediate and long-term effects of rTMS on attention, executive, language and memory functions. In addition, the present study showed no significant difference in immediate or long-term effects of tDCS on general cognitive function, attention, language or memory functions between tDCS group and sham tDCS group. Conclusions: RTMS was an effective treatment technique for general cognitive function in AD, whereas tDCS showed no significant therapy effect on cognitive function in AD. More large-scale studies were essential to explore the effect of NIBS on various cognitive function in AD.

CITATION:
L. Gu ; H. Xu ; F. Qian ; (): Effects of Non-Invasive Brain Stimulation on Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad..40

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ASSOCIATION BETWEEN DIETARY THEOBROMINE AND COGNITIVE FUNCTION IN A REPRESENTATIVE AMERICAN POPULATION: A CROSS-SECTIONAL STUDY

L. Gao, W. Ge, C. Peng, J. Guo, N. Chen, L. He

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Background: Despite reports on neuroprotective effects of dietary theobromine intake, whether dietary theobromine has beneficial effects on cognitive function is unclear. Objectives: To investigate the association between dietary theobromine and cognitive function. Design: A cross-sectional study. Setting: Data were collected from the 2011-2014 cycles of the National Health and Nutrition Examination Survey conducted by the Centers for Disease Control and Prevention of the USA. Participants: A representative American population aged ≥60 years. Measurements: L-theobromine was treated as a log transform and dichotomous form (the highest quantile vs. others). Cognitive function was measured using four tests: Consortium to Establish a Registry for Alzheimer's Disease Word Learning tests, Consortium to Establish a Registry for Alzheimer's Disease delayed recall test, animal fluency test, and digit symbol substitution test. We conducted multiple regression analyses and subgroup analyses to study the association between theobromine and cognitive performance. Basic characteristics, lifestyle factors, disease history, and nutritional intake were adjusted for in these models. Results: A total of 2,845 participants were included in the study. The highest quantile of L-theobromine intake was positively associated with sores of delayed recall, animal fluency, and digit symbol substitution tests (β, 95% confidence interval, P: 0.11, -0.00-0.30, 0.049; 0.50, 0.02-0.99, 0.043; 1.55, 0.33-2.77, 0.015; respectively) in the fully adjusted model, but not with immediate recall score (β=0.13, 95% confidence interval -0.16-0.43, P=0.361). Subgroup analyses showed that L-theobromine intake was associated with cognitive performance in the highest quantile of caffeine intake. Conclusions: Daily theobromine intake was associated with cognitive performance in a large nationally representative population. However, further research is needed to corroborate our findings.

CITATION:
L. Gao ; W. Ge ; C. Peng ; J. Guo ; N. Chen ; L. He (2022): Association between Dietary Theobromine and Cognitive Function in a Representative American Population: A Cross-Sectional Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.39

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SITE READINESS FRAMEWORK TO IMPROVE HEALTH SYSTEM PREPAREDNESS FOR A POTENTIAL NEW ALZHEIMER’S DISEASE TREATMENT PARADIGM

M. Anderson, N. Sathe, C. Polacek, J. Vawter, T. Fritz, M. Mann, P. Hernandez, M.C. Nguyen, J. Thompson, J. Penderville, M. Arling, S. Safo, R. Christopher

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New therapies that address the underlying pathophysiology of Alzheimer’s Disease (AD), coupled with the growth of the AD population, will transform the AD care pathway and present significant challenges to health systems. We explored real-world challenges health systems may face in delivering potential new AD therapies with diverse stakeholders. Key challenges in care included integrating primary care providers into assessment and management, availability of memory care specialists, understanding payment and coverage issues and training mid-level providers to help coordinate care and serve as a shared resource across the system. This input informed a novel Site Readiness Framework for AD, comprising self-assessment exercises to identify health system capabilities and gaps and a framework of core strategies and responsive tools to help prepare to integrate new AD therapies. These resources may help health systems improve readiness to modify care pathways to integrate new therapies for AD.

CITATION:
M. Anderson ; N. Sathe ; C. Polacek ; J. Vawter ; T. Fritz ; M. Mann ; P. Hernandez ; M.C. Nguyen ; J. Thompson ; J. Penderville ; M. Arling ; S. Safo ; R. Christopher ; (2022): Site Readiness Framework to Improve Health System Preparedness for a Potential New Alzheimer’s Disease Treatment Paradigm. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.32

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SUBJECTIVE COGNITIVE DECLINE IN A REGISTRY SAMPLE: RELATION TO PSYCHIATRIC HISTORY, LONELINESS, AND PERSONALITY

G.O. Reynolds, L. Manning, D. Kirn, H. Klein, O. Hampton, O. Burke Jr., R. Buckley, D. Rentz, R. Sperling, G.A. Marshall, R.E. Amariglio

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BACKGROUND: With the increasing focus on prevention of Alzheimer’s disease, there is need for characterization of preclinical populations. Local participant registries offer an opportunity to facilitate research engagement via remote data collection, inform recruitment, and characterize preclinical samples, including individuals with subjective cognitive decline. OBJECTIVES: We sought to characterize subjective cognitive decline in a registry sample, as related to psychiatric history and related variables, including personality and loneliness, quality of life, and factors related to dementia risk (e.g., family history of dementia). DESIGN, SETTING, PARTICIPANTS: Participants were 366 individuals (mean age=67.2 (range 50-88), 65% female, 94% white, 97% non-Hispanic or Latino, 82% with at least a bachelor’s degree) with no reported history of mild cognitive impairment or dementia. All participants had expressed interest in research, primarily via community outreach events and prior research involvement. Data was collected via electronic surveys, distributed using REDCap. Electronic questionnaires included questions on demographic variables, subjective cognitive decline, quality of life, loneliness, and personality. RESULTS: There was a high prevalence of risk factors for dementia in the registry sample (68% with family history of dementia, 31% with subjective cognitive decline). Subjective cognitive decline was more common in women and associated with history of depression, but not with family history of dementia. Subjective cognitive decline was also associated with lower conscientiousness and lower emotional stability, as well as higher loneliness and lower quality of life. Among participants who endorsed a psychiatric history, most reported onset more than 10 years prior, rather than within the last 10 years. CONCLUSIONS: Subjective cognitive decline in a registry sample may be more strongly associated with longstanding psychiatric and personality variables, rather than family history of dementia, adding to the literature on characterization of subjective cognitive decline across different settings. These findings highlight the acceptability of remote data collection and the potential of registries to inform recruitment by characterizing registrants, which may help to stratify dementia risk and match participants to eligible trials.

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ELECSYS CEREBROSPINAL FLUID ASSAYS ACCURATELY DISTINGUISH ALZHEIMER’S DISEASE FROM FRONTOTEMPORAL LOBAR DEGENERATION

M. Ortner, O. Goldhardt, J. Diehl-Schmid, I. Yakushev, K. Lanz, D.M. Hedderich

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BACKGROUND: Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) are heterogeneous in their clinical presentation and underlying pathology, but they often have overlapping features. Diagnostic accuracy is critical for guiding patient management. Cerebrospinal fluid (CSF) diagnostic assays for the differentiation of AD and FTLD may increase diagnostic accuracy. OBJECTIVES: In this study, we aimed to understand the potential role of CSF biomarkers and biomarker ratios, measured using Elecsys® CSF immunoassays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland), in the differential diagnosis of AD and FTLD. DESIGN: This study was conducted at a single center in Munich, Germany between July 2019 and July 2020. Patient CSF samples were retrospectively collected from the study center biobank. PARTICIPANTS: A total of 130 patients with cognitive impairment were included in the study; 86 patients were diagnosed with AD and 44 with FTLD (behavioral variant frontotemporal dementia, semantic variant of primary progressive aphasia, and non-fluent variant of primary progressive aphasia), based on core clinical criteria and a non-CSF biomarker, a typical pattern of regional hypometabolism on [18F] fluorodeoxyglucose positron emission tomography. MEASUREMENTS: Patient CSF biomarker concentrations were measured using Elecsys CSF immunoassays. Receiver operating characteristic analyses were conducted to determine areas under the curve (AUCs) for CSF biomarker performance. Sensitivity and specificity analyses were conducted to evaluate the performance of established cut-offs (Aβ42 ≤1000 pg/mL, pTau181/Aβ42 ratio >0.024, and tTau/Aβ42 ratio >0.28) and optimized cut-offs based on Youden’s index. RESULTS: AUC-based performance was similarly good for the pTau181/Aβ42 ratio (AUC=0.841; 95% CI: 0.759−0.923), pTau181/Aβ40 ratio (AUC=0.837; 95% CI: 0.754−0.919), Aβ42/Aβ40 ratio (AUC=0.829; 95% CI: 0.746−0.912), tTau/Aβ42 ratio (AUC=0.822; 95% CI: 0.736−0.908), pTau181/Aβ42/Aβ40 ratio (AUC=0.817; 95% CI: 0.734–0.901), and Aβ42 (AUC=0.812; 95% CI: 0.722−0.902). Performance was slightly lower for the tTau/Aβ42/Aβ40 ratio (AUC=0.799; 95% CI: 0.713−0.885), pTau181 alone (AUC=0.793; 95% CI: 0.707−0.880), tTau/Aβ40 ratio (AUC=0.751; 95% CI: 0.657−0.844), and tTau alone (AUC=0.706; 95% CI: 0.613−0.799). The highest qualitative performance was observed with the pTau181/Aβ42 ratio with an established cut-off value of >0.024 and optimized cut-off value of >0.022: sensitivity and specificity values were 0.892 and 0.773, respectively. CONCLUSIONS: Elecsys CSF immunoassays demonstrate good diagnostic accuracy in differentiating patients with AD from those with FTLD. These immunoassays have the potential to support clinical decision making, i.e. in diagnosing patients with FTLD by excluding patients with amyloid positivity, which is indicative of underlying AD.

CITATION:
M. Ortner ; O. Goldhardt ; J. Diehl-Schmid ; I. Yakushev ; K. Lanz ; D.M. Hedderich ; E. Manuilova ; M. Simon ; J.-P. Weinberger ; T. Grimmer (2022): Elecsys Cerebrospinal Fluid Assays Accurately Distinguish Alzheimer’s Disease from Frontotemporal Lobar Degeneration. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.27

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MESENCHYMAL STEM CELLS MODULATE SIRT1/MIR-134/ GSK3Β SIGNALING PATHWAY IN A RAT MODEL OF ALZHEIMER\'S DISEASE

O.A.R. Abozaid, M.W. Sallam, E.S.A. Ahmed

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Prolonged exposure to environmental aluminum-containing substances is associated with the development of Alzheimer's disease (AD). AD is a brain disorder associated with a gradual weakening in neurocognitive functions. Mesenchymal stem cells (MSCs) transplant as a promising and safe approach is used to treat AD through countless mechanisms. Therefore, this study aims to elucidate how MSCs improve biochemical and histopathological approaches associated with the AD model in rats. MSCs treatment restores the redox status impairment through a notable decline in the malondialdehyde (MDA) levels along with antioxidant enrichment. The anti-inflammatory effect of MSCs through conversion of microglial cells from M1 to M2 and inhibition of pro-inflammatory mediator’s release work in with de-activated GSK-3β. Additionally, the alleviation of autophagy and lysosomal clearance of Aβ and tau aggregates was accompanied by a down-regulation of the mTOR. Moreover, MSCs upregulate the expression of SIRT1 together with a limited expression of miR-134 thereby, improve neurite outgrowth and synaptic loss. Overall, the obtained data confirm the novelty of MSCs in the treatment of AD not only by their antioxidant, anti-inflammatory effect but also by restoring the neural integrity, neurogenesis, improving the neurocognitive function, and modulation of the signal pathways linked to the Aβ hypothesis.

CITATION:
O.A.R. Abozaid ; M.W. Sallam ; E.S.A. Ahmed ; (2022): Mesenchymal Stem Cells Modulate SIRT1/MiR-134/ GSK3β Signaling Pathway in a Rat Model of Alzheimer's Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.26

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DECREASED GRAY–WHITE MATTER CONTRAST OF [11C]-PIB UPTAKE IN COGNITIVELY UNIMPAIRED SUBJECTS WITH SEVERE OBSTRUCTIVE SLEEP APNEA

S. Ylä-Herttuala, M. Hakulinen, P. Poutiainen, J. Lötjönen, M. Könönen, H. Gröhn, R. Vanninen, H. Mussalo, T. Laitinen, E. Mervaala

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Background: Very recently, cognitively normal, middle-aged adults with severe obstructive sleep apnea (OSA) were shown to have regional cortical amyloid-β deposits. In the normal brain, amyloid tracer (e.g., [11C]-PiB) uptake is observed in white matter (WM) but not in cortical gray matter (GM), resulting in clear GM–WM contrast. There are no reports on possible changes in this contrast in severe OSA. Objectives: Evaluate changes in the global [11C]-PiB GM–WM contrast and study if factors reflecting clinical and imaging characteristics are associated with them. Design and setting: Cross-sectional imaging study. Participants: 19 cognitively intact middle-aged (mean 44 years) patients with severe OSA (Apnea–Hypopnea Index >30/h), carefully selected to exclude any other possible factors that could alter brain health. Measurements: Detailed neuroimaging (amyloid PET, MRI). Signs of possible alterations in amyloid tracer GM–WM contrast and kinetics were studied with static and dynamic [11C]-PiB PET and WM structures with detailed 3.0T MRI. Results: Static [11C]-PiB PET uptake showed significantly decreased GM–WM contrast in 5 out of 19 patients. This was already clearly seen in visual evaluation and also detected quantitatively using retention indexes. Dynamic imaging revealed decreased contrast due to alterations in trace accumulation in the late phase of [11C]-PiB kinetics. Decreased GM–WM contrast in the late phase was global in nature. MRI revealed no corresponding alterations in WM structures. Importantly, decreased GM–WM contrast was associated with smoking (p = 0.007) and higher Apnea–Hypopnea Index (p = 0.001). Conclusions: Severe OSA was associated with decreased GM–WM contrast in amyloid tracer uptake, with significant correlation with clinical parameters of smoking and AHI. The results support and further extend the current understanding of the deleterious effect of severe OSA on proper amyloid clearance, possibly reflecting dysfunction of the brain glymphatic system.

CITATION:
S. Ylä-Herttuala ; M. Hakulinen ; P. Poutiainen ; J. Lötjönen ; M. Könönen ; H. Gröhn ; R. Vanninen ; H. Mussalo ; T. Laitinen ; E. Mervaala ; (2022): Decreased Gray–White Matter Contrast of [11C]-PiB Uptake in Cognitively Unimpaired Subjects with Severe Obstructive Sleep Apnea. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.24

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WHAT MATTERS TO PATIENTS WITH ALZHEIMER’S DISEASE AND THEIR CARE PARTNERS? IMPLICATIONS FOR UNDERSTANDING THE VALUE OF FUTURE INTERVENTIONS

F. Jessen, J. Georges, M. Wortmann, S. Benham-Hermetz

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Alzheimer's Disease (AD) is the most common cause of dementia. Recent thinking portrays AD as a continuum consisting of three stages: an asymptomatic preclinical period, a mild cognitive impairment phase, and dementia, which can be further classified as mild, moderate or severe. While many studies explore the cognitive and functional aspects of AD, fully understanding AD pathophysiology, as well as the potential value of pharmacological and psycho-social interventions, requires a deeper understanding of patient and care partner priorities, particularly in the early stages where such interventions may have the greatest impact in slowing or delaying progression. Available studies highlight a diverse range of patient and care partner priorities, including impacts on their emotions, moods, and social lives. These priorities have not been systematically incorporated in the clinical and value assessments of potential interventions. We propose approaches to better understand the humanistic impact of AD including conducting additional research into the impacts of interventions from the point of view of patients and care partners, expanding notions of ‘value’ and improving health system capacity for diagnosis.

CITATION:
F. Jessen ; J. Georges ; M. Wortmann ; S. Benham-Hermetz ; (2022): What Matters to Patients with Alzheimer’s Disease and Their Care Partners? Implications for Understanding the Value of Future Interventions. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.22

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CEREBRAL PHOSPHO-TAU ACTS SYNERGISTICALLY WITH SOLUBLE AΒ42 LEADING TO MILD COGNITIVE IMPAIRMENT IN AAV-AD RATS

B. Souchet, M. Audrain, Y. Gu, M.F. Lindberg, N.S. Orefice, E. Rey, N. Cartier, N. Janel, L. Meijer, J. Braudeau

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BACKGROUND: Alzheimer's disease (AD) is a continuum of events beginning with an increase in brain soluble Aβ42 followed by the appearance of hyperphosphorylated tau (P-tau, asymptomatic stage). Mild Cognitive Impairment (MCI) then appears (prodromal stage). However, the individual contribution of these two soluble proteins in the onset of the first cognitive symptoms remains unclear. OBJECTIVES: We sought to understand the specific impact of p-tau on the development of MCI in the AAV-AD rat model, a model of late-onset Alzheimer's disease (LOAD) predementia. METHODS: We specifically reduced the phosphorylation level of tau while leaving Aβ42 levels unchanged using a DYRK1A protein kinase inhibitor, Leucettine L41, in an adeno-associated virus-based Alzheimer's disease (AAV-AD) rat model. Leucettine L41 was administered by intraperitoneal injection at 20 mg/kg per day in AAV-AD rats from 9 (late asymptomatic phase) to 10 (prodromal phase) months of age. RESULTS: Decreased soluble forms of P-tau induced by chronic administration of Leucettine L41 did not change soluble Aβ42 levels but prevented MCI onset in 10-month-old AAV-AD rats. CONCLUSIONS: The present study argues that P-tau is required to induce the development of MCI. Consistent with our previous findings that soluble Aβ42 is also required for MCI onset, the data obtained in the AAV-AD rat model confirm that the transition from the asymptomatic to the prodromal stage may be caused by the combined presence of both soluble brain forms of Aβ42 and p-tau, suggesting that the development of MCI may be the consequence of their synergistic action.

CITATION:
B. Souchet ; M. Audrain ; Y. Gu ; M.F. Lindberg ; N.S. Orefice ; E. Rey ; N. Cartier ; N. Janel ; L. Meijer ; J. Braudeau (2022): Cerebral Phospho-Tau Acts Synergistically with Soluble Aβ42 Leading to Mild Cognitive Impairment in AAV-AD Rats. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.18

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JPAD Volume 9, N°02 - 2022

 

WHERE DO WE GO FROM HERE?

R.C. Petersen

J Prev Alz Dis 2022;2(9):188-189

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CITATION:
R.C. Petersen (2022): Where Do We Go from Here?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.35

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THE ‘ADUCANUMAB STORY’: WILL THE LAST CHAPTER SPELL THE END OF THE ‘AMYLOID HYPOTHESIS’ OR MARK A NEW BEGINNING?

Z.S. Khachaturian

J Prev Alz Dis 2022;2(9):190-192

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CITATION:
Z.S. Khachaturian ; (2022): The ‘Aducanumab Story’: Will the Last Chapter Spell the End of the ‘Amyloid Hypothesis’ or Mark a New Beginning?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.36

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ADUCANUMAB TRIALS EMERGE BUT DON’T ENGAGE

L.S. Schneider

J Prev Alz Dis 2022;2(9):193-196

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CITATION:
L.S. Schneider ; (2022): Aducanumab Trials EMERGE But Don’t ENGAGE. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.37

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TWO RANDOMIZED PHASE 3 STUDIES OF ADUCANUMAB IN EARLY ALZHEIMER’S DISEASE

S. Budd Haeberlein, P.S. Aisen, F. Barkhof, S. Chalkias, T. Chen, S. Cohen, G. Dent, O. Hansson, K. Harrison, C. von Hehn, T. Iwatsubo, C. Mallinckrodt, C.J. Mummery, K.K. Muralidharan, I. Nestorov, L. Nisenbaum, R. Rajagovindan, L. Skordos, Y. Tian, C.H. van Dyck, B. Vellas, S. Wu, Y. Zhu, A. Sandrock

J Prev Alz Dis 2022;2(9):197-210

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BACKGROUND: Alzheimer’s disease is a progressive, irreversible, and fatal disease for which accumulation of amyloid beta is thought to play a key role in pathogenesis. Aducanumab is a human monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. OBJECTIVES: We evaluated the efficacy and safety of aducanumab in early Alzheimer’s disease. DESIGN: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer’s disease. SETTING: These studies involved 348 sites in 20 countries. PARTICIPANTS: Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50–85 years, confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia, of which 1812 (55.2%) completed the study. INTERVENTION: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (10 mg/kg target dose), or placebo via IV infusion once every 4 weeks over 76 weeks. MEASUREMENTS: The primary outcome measure was change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; and biomarker endpoints. RESULTS: EMERGE and ENGAGE were halted based on futility analysis of data pooled from the first approximately 50% of enrolled patients; subsequent efficacy analyses included data from a larger data set collected up to futility declaration and followed prespecified statistical analyses. The primary endpoint was met in EMERGE (difference of −0.39 for high-dose aducanumab vs placebo [95% CI, −0.69 to −0.09; P=.012; 22% decrease]) but not in ENGAGE (difference of 0.03, [95% CI, −0.26 to 0.33; P=.833; 2% increase]). Results of biomarker substudies confirmed target engagement and dose-dependent reduction in markers of Alzheimer's disease pathophysiology. The most common adverse event was amyloid-related imaging abnormalities-edema. CONCLUSIONS: Data from EMERGE demonstrated a statistically significant change across all four primary and secondary clinical endpoints. ENGAGE did not meet its primary or secondary endpoints. A dose- and time-dependent reduction in pathophysiological markers of Alzheimer’s disease was observed in both trials.

CITATION:
S. Budd Haeberlein ; P.S. Aisen ; F. Barkhof ; S. Chalkias ; T. Chen ; S. Cohen ; G. Dent ; O. Hansson ; K. Harrison ; C. von Hehn ; T. Iwatsubo ; C. Mallinckrodt ; C.J. Mummery ; K.K. Muralidharan ; I. Nestorov ; L. Nisenbaum ; R. Rajagovindan ; L. Skordos ; Y. Tian ; C.H. van Dyck ; B. Vellas ; S. Wu ; Y. Zhu ; A. Sandrock (2022): Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.30

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DETECTION AND MANAGEMENT OF AMYLOID-RELATED IMAGING ABNORMALITIES IN PATIENTS WITH ALZHEIMER’S DISEASE TREATED WITH ANTI-AMYLOID BETA THERAPY

J. Barakos, D. Purcell, J. Suhy, S. Chalkias, P. Burkett, C. Marsica Grassi, C. Castrillo-Viguera, I. Rubino, E. Vijverberg

J Prev Alz Dis 2022;2(9):211-220

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Amyloid-related imaging abnormalities (ARIA) are adverse events reported in Alzheimer’s disease trials of anti-amyloid beta (Aβ) therapies. This review summarizes the existing literature on ARIA, including bapineuzumab, gantenerumab, donanemab, lecanemab, and aducanumab studies, with regard to potential risk factors, detection, and management. The pathophysiology of ARIA is unclear, but it may be related to binding of antibodies to accumulated Aβ in both the cerebral parenchyma and vasculature, resulting in loss of vessel wall integrity and increased leakage into surrounding tissues. Radiographically, ARIA-E is identified as vasogenic edema in the brain parenchyma or sulcal effusions in the leptomeninges/sulci, while ARIA-H is hemosiderin deposits presenting as microhemorrhages or superficial siderosis. ARIA tends to be transient and asymptomatic in most cases, typically occurring early in the course of treatment, with the risk decreasing later in treatment. Limited data are available on continued dosing following radiographic findings of ARIA; hence, in the event of ARIA, treatment should be continued with caution and regular monitoring. Clinical trials have implemented management approaches such as temporary suspension of treatment until symptoms or radiographic signs of ARIA have resolved or permanent discontinuation of treatment. ARIA largely resolves without concomitant treatment, and there are no systematic data on potential treatments for ARIA. Given the availability of an anti-Aβ therapy, ARIA monitoring will now be implemented in routine clinical practice. The simple magnetic resonance imaging sequences used in clinical trials are likely sufficient for effective detection of cases. Increased awareness and education of ARIA among clinicians and radiologists is vital.

CITATION:
J. Barakos ; D. Purcell ; J. Suhy ; S. Chalkias ; P. Burkett ; C. Marsica Grassi ; C. Castrillo-Viguera ; I. Rubino ; E. Vijverberg ; (2022): Detection and Management of Amyloid-Related Imaging Abnormalities in Patients with Alzheimer’s Disease Treated with Anti-Amyloid Beta Therapy. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.21

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ADUCANUMAB: APPROPRIATE USE RECOMMENDATIONS UPDATE

J. Cummings, G.D. Rabinovici, A. Atri, P. Aisen, L.G. Apostolova, S. Hendrix, M. Sabbagh, D. Selkoe, M. Weiner, S. Salloway

J Prev Alz Dis 2022;2(9):221-230

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Aducanumab (Aduhelm) is approved in the United States for the treatment of patients with mild cognitive impairment due to Alzheimer's disease or mild AD dementia. Aducanumab Appropriate Use Recommendations (AURs) have been published and have helped guide best practices for use of aducanumab. As real-world use has occurred and more information has accrued, the AURs require refinement. We update the AURs to better inform appropriate patient selection and improve shared decision-making, safety monitoring, and risk mitigation in treated patients. Based on evolving experience we emphasize the importance of detecting past medical conditions that may predispose to amyloid related imaging abnormalities (ARIA) or may increase the likelihood of ARIA complications including autoimmune or inflammatory conditions, seizures, or disorders associated with extensive white matter pathology. The apolipoprotein E ε4 (APOE4) genotype is strongly associated with ARIA and exhibits a gene dose effect. We recommend that clinicians perform APOE genotyping to better inform patient care decisions, discussions regarding risk, and clinician vigilance concerning ARIA. As most ARIA occurs during the titration period of aducanumab, we suggest performing MRI before the 5th, 7th, 9th, and 12th infusions to improve detection. Uncommonly, ARIA may be recurrent or serious; we suggest additional parameters for treatment discontinuation taking these observations into account. It is important to continue to learn from the real-world use of aducanumab and the AURs will continue to evolve as new information becomes available. This AUR update does not address efficacy, price, or insurance coverage and is provided to assist clinicians to establish best practices for use of aducanumab in the treatment of patients with mild cognitive impairment and mild Alzheimer’s dementia.

CITATION:
J. Cummings ; G.D. Rabinovici ; A. Atri ; P. Aisen ; L.G. Apostolova ; S. Hendrix ; M. Sabbagh ; D. Selkoe ; M. Weiner ; S. Salloway (2022): Aducanumab: Appropriate Use Recommendations Update. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.34

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THERAPEUTIC TARGETS FOR ALZHEIMER’S DISEASE: AMYLOID VS. NON-AMYLOID. WHERE DOES CONSENSUS LIE TODAY? AN CTAD TASK FORCE REPORT

S. Gauthier, A. Boxer, D. Knopman, J. Sims, R. Doody, P. Aisen, T. Iwatsubo, R. Bateman, B. Vellas

J Prev Alz Dis 2022;2(9):231-235

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There was consensus that both amyloid and tau pathologies should be targeted in Alzheimer’s disease, as well as additional pathophysiological mechanisms such as neuroinflammation. The selection of one or both of these targets may depend upon a personalized approach that takes into account the genetic and acquired factors that cause AD in any given person as well as their stage of disease as reflected in a biomarker profile. The validation of this therapeutic approach will be made possible by new methodologies for subdividing into predominant pathology, by efficient methods for identifying people in the earliest stages of disease, and by combination studies.

CITATION:
S. Gauthier ; A. Boxer ; D. Knopman ; J. Sims ; R. Doody ; P. Aisen ; T. Iwatsubo ; R. Bateman ; B. Vellas ; (2022): Therapeutic Targets for Alzheimer’s Disease: Amyloid Vs. Non-Amyloid. Where Does Consensus Lie Today? An CTAD Task Force Report. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.29

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DIGITAL THERAPEUTICS FOR MCI AND ALZHEIMER’S DISEASE: A REGULATORY PERSPECTIVE - HIGHLIGHTS FROM THE CLINICAL TRIALS ON ALZHEIMER’S DISEASE CONFERENCE (CTAD)

J. Shuren, P.M. Doraiswamy

J Prev Alz Dis 2022;2(9):236-240

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CITATION:
J. Shuren ; P.M. Doraiswamy ; (2022): Digital Therapeutics for MCI and Alzheimer’s disease: A Regulatory Perspective - Highlights From The Clinical Trials on Alzheimer’s Disease conference (CTAD). The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.28

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PUBLIC POLICY SHOULD FOSTER ALZHEIMER’S TREATMENT AVAILABILITY: COMMENT ON THE DRAFT US MEDICARE DECISION TO LIMIT PAYMENT FOR ADUCANUMAB (ADUHELMTM) TO PATIENTS PARTICIPATING IN CLINICAL TRIALS

J. Cummings

J Prev Alz Dis 2022;2(9):241-246

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CITATION:
J. Cummings (2022): Public Policy Should Foster Alzheimer’s Treatment Availability: Comment on the Draft US Medicare Decision to Limit Payment for Aducanumab (AduhelmTM) to Patients Participating in Clinical Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.25

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A POLYMORPHISM CLUSTER AT THE 2Q12 LOCUS MAY PREDICT RESPONSE TO PIROMELATINE IN PATIENTS WITH MILD ALZHEIMER\'S DISEASE

L.S. Schneider, M. Laudon, T. Nir, J. Caceres, G. Ianniciello, M. Capulli, N. Zisapel

J Prev Alz Dis 2022;2(9):255-261

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Background: Piromelatine is a novel melatonin MT1/2/3 and serotonin 5-HT-1A/1D receptors agonist developed for mild Alzheimer’s disease (AD). In a randomized, placebo-controlled, dose-ranging study (ReCognition) of piromelatine (5, 20, and 50 mg daily for 6 months) in participants with mild dementia due to AD (n=371, age 60-85 years), no statistically significant differences were found between the piromelatine and placebo-treated groups on the primary (i.e., computerized neuropsychological test battery (cNTB)) and secondary outcomes (ADCS-CGIC, ADCS-MCI-ADL, ADAS-cog14, NPI, and Pittsburgh Sleep Quality Index (PSQI)) nor were there safety concerns (https://clinicaltrials.gov/ct2/show/NCT02615002). Objectives: This study was aimed at identifying genetic markers predicting piromelatine treatment response using a genome-wide association approach (GWAS). Design: Variant genotyping of a combined whole genome and whole exome sequencing was performed using DNA extracted from lymphocytes from consenting participants. The general case-control allelic test was performed on piromelatine-treated participants, taking “responders” (i.e., >0.125 change from baseline in the cNTB) as cases and “non responders” as controls, using a Cochran-Armitage trend test. Setting: 58 outpatient clinics in the US. Participants: 371 participants were randomized in the trial; 107 provided informed consent for genotyping. Results: The GWAS sample did not differ from the full study cohort in demographics, baseline characteristics, or response to piromelatine. Six single-nucleotide polymorphisms (SNPs) in chromosome 2q12 (2:107,510,000-107,540,000) were associated with response (p-value < 1x10 -4 each). Post hoc analyses suggested that the carriers of the 2q12 polymorphism cluster (27% of the GWAS sample) improved significantly on the cNTB on piromelatine as compared to placebo but significantly worsened on the ADAS-Cog14 and PSQI. By contrast, “non-carriers” improved significantly with piromelatine compared to placebo on the ADAS-Cog14 ( 2.91 (N=23) with piromelatine 20 mg vs 1.65 (N=19) with placebo (p=0.03)) and PSQI. Conclusions: The 2q12 (2:107,510,000-107,540,000) 5-6 SNPs cluster may predict efficacy of piromelatine for mild AD. These findings warrant further investigation in a larger, prospective early-stage AD clinical trial for patients who are non-carriers of the 2q12 polymorphism cluster.

CITATION:
L.S. Schneider ; M. Laudon ; T. Nir ; J. Caceres ; G. Ianniciello ; M. Capulli ; N. Zisapel ; (2021): A Polymorphism Cluster at the 2q12 locus May Predict Response to Piromelatine in Patients with Mild Alzheimer's Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.61

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SENSITIVITY OF THE PRECLINICAL ALZHEIMER’S COGNITIVE COMPOSITE (PACC), PACC5, AND REPEATABLE BATTERY FOR NEUROPSYCHOLOGICAL STATUS (RBANS) TO AMYLOID STATUS IN PRECLINICAL ALZHEIMER’S DISEASE -ATABECESTAT PHASE 2B/3 EARLY CLINICAL TRIAL

K.V. Papp, H. Rofael, A.E. Veroff, M.C. Donohue, S. Wang, C. Randolph, E. Grober, H.R. Brashear, G. Novak, K. Ernstrom, R. Raman, P.S. Aisen, R. Sperling, G. Romano, D. Henley

J Prev Alz Dis 2022;2(9):255-261

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Background: Cognitive composites commonly serve as primary outcomes in Alzheimer’s disease (AD) secondary prevention trials. Objective: To evaluate the association between amyloid (Aβ) burden level (+/-) and performance on three separate composite endpoints: Preclinical Alzheimer’s Cognitive Composite (PACC), PACC+Semantic Fluency (PACC5), and Repeatable Battery for Neuropsychological Status (RBANS). Design: Screening data from the randomized, double-blind, placebo-controlled, phase 2b/3 atabecestat EARLY study in preclinical AD participants were used in this analysis. Setting: The EARLY study was conducted at 143 centers across 14 countries. Participants: 3,569 cognitively unimpaired older adults (Clinical Dementia Rating of 0; aged 60-85 years) screened for inclusion in the EARLY study with Aβ status and at least PACC or RBANS at screening were included. Participants were categorized as those with non-pathological Aβ levels (Aβ-, n=2,824) and those with pathological Aβ levels (Aβ+, n=745) based on florbetapir uptake or levels of cerebrospinal fluid Aβ1-42. Measurements: Analysis of Covariance models controlling for age, sex, and education were used to examine the difference in PACC, PACC5, and RBANS between Aβ groups. Nonparametric bootstrap was used to compare sensitivity of composites to differentiate between Aβ status. Results: Of 3,569 participants, 2,116 were women (59%); 3,006 were Caucasian (84%); mean (SD) age was 68.98 (5.28) years. Aβ+ participants performed worse versus Aβ- participants on all cognitive composites though the magnitude of the Aβ effect was generally small. The Aβ+/- effect size for the PACC (Cohen’s d=-0.15) was significantly greater than the RBANS (d=-0.097) while the PACC5 effect size (d=-0.139) was numerically larger than the RBANS. When examining subscores from the composites, memory tests (i.e., Free and Cued Selective Reminding Test, Figure Recall) and speed of processing (i.e., Digit-Symbol/Coding on the PACC/RBANS) exhibited the largest Aβ+/- effect sizes. Conclusions: Cross-sectional relationships between Aβ and cognition among clinically unimpaired older adults are detectable on multi-domain cognitive composites but are relatively small in magnitude. The Aβ+/- group effect was statistically larger for PACC and marginally larger for PACC5 versus RBANS. However, interpretation of composite sensitivity to Aβ status cross-sectionally cannot be generalized to sensitivity to change over time.

CITATION:
K.V. Papp ; H. Rofael ; A.E. Veroff ; M.C. Donohue ; S. Wang ; C. Randolph ; E. Grober ; H.R. Brashear ; G. Novak ; K. Ernstrom ; R. Raman ; P.S. Aisen ; R. Sperling ; G. Romano ; D. Henley ; (2022): Sensitivity of the Preclinical Alzheimer’s Cognitive Composite (PACC), PACC5, and Repeatable Battery for Neuropsychological Status (RBANS) to Amyloid Status in Preclinical Alzheimer’s Disease -Atabecestat Phase 2b/3 EARLY Clinical Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.17

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UNSUPERVISED PERFORMANCE OF THE COGSTATE BRIEF BATTERY IN THE BRAIN HEALTH REGISTRY: IMPLICATIONS FOR DETECTING COGNITIVE DECLINE

T. Banh, C. Jin, J. Neuhaus, R.S. Mackin, P. Maruff, N. Stricker, M.W. Weiner, R.L. Nosheny

J Prev Alz Dis 2022;2(9):262-268

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Introduction: The feasibility and validity of unsupervised, longitudinal brief computerized cognitive batteries is unknown. Methods: Participants aged 56-90 (N = 19476) from the Brain Health Registry (BHR) completed the CogState Brief Battery (CBB) at 6-month intervals over a period of 5 years. We used linear mixed-effects models to assess whether cross-sectional and longitudinal performance on CBB within BHR was associated with demographic and cognitive characteristics. We also defined a group of CBB decliners based on subject-specific slopes and estimated associations between decliner status and participant characteristics. Results: We found weak associations between longitudinal change in CBB and participant characteristics. Cross-sectional CBB scores were significantly associated with participant characteristics such as age, gender, ethnicity, self-reported disease status, and memory concern. CBB decliners were more likely to self-report mild cognitive impairment (MCI) and memory concerns. Discussion: Cross-sectional, remote CBB shows evidence of construct validity, but our results suggest that longitudinal assessment may not provide additional value for identifying those at risk for and with cognitive impairment.

CITATION:
T. Banh ; C. Jin ; J. Neuhaus ; R.S. Mackin ; P. Maruff ; N. Stricker ; M.W. Weiner ; R.L. Nosheny (2021): Unsupervised Performance of the CogState Brief Battery in the Brain Health Registry: Implications for Detecting Cognitive Decline. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.68

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VALIDITY OF ONLINE VERSUS IN-CLINIC SELF-REPORTED EVERYDAY COGNITION SCALE

T. Howell, J. Neuhaus, M.M. Glymour, M.W. Weiner, R.L Nosheny

J Prev Alz Dis 2022;2(9):269-276

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BACKGROUND: Online cognitive assessments are alternatives to in-clinic assessments. Objectives: We evaluated the relationship between online and in-clinic self-reported Everyday Cognition Scale (ECog). Methods: In 94 Alzheimer’s Disease Neuroimaging Initiative and Brain Health Registry (ADNI-BHR) participants, we estimated associations between online and in-clinic Everyday Cognition using Bland-Altman plots and regression. In 472 ADNI participants, we estimated reliability of in-clinic Everyday Cognition completed six months apart using Bland-Altman plots and regression. Results: Online Everyday Cognition associations: Mean difference was 0.11 (95% limits of agreement: -0.41 to 0.64). In-clinic Everyday Cognition score increased by 0.81 for each online Everyday Cognition score unit increase (R2=0.60). In-clinic Everyday Cognition reliability: Mean difference was 0.01 (95% limits of agreement: -0.61 to 0.62). In-clinic Everyday Cognition score at enrollment increased by 0.79 for each in-clinic Everyday Cognition score unit increase at six months (R2=0.61). Conclusion: Online Everyday Cognition closely corresponded with in-clinic Everyday Cognition, supporting validity of using online cognitive assessments to more efficiently facilitate Alzheimer’s disease research.

CITATION:
T. Howell ; J. Neuhaus ; M.M. Glymour ; M.W. Weiner ; R.L Nosheny (2022): Validity of Online Versus In-Clinic Self-Reported Everyday Cognition Scale. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.19

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ALZHEIMER\'S DISEASE PREVENTION HEALTH COACHING

A. Rhodes, J. Inker, J. Richardson, F. Zanjani

J Prev Alz Dis 2022;2(9):277-285

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Background: Widespread lifestyle risk reduction at the community level is considered effective in decreasing Alzheimer's disease (AD). To address the limited use of risk deduction in AD, this study aimed to explore the feasibility of community-level implementation. Diverse older adults (60+) living in Richmond, VA, with incomes below $12,000/year and managing diabetic/cardiovascular symptoms were offered weekly lifestyle telephone-health coaching for 12-weeks in 2019-2020 (Phase 1). The health coaching sessions were framed to provide AD lifestyle risk reduction education, goal setting, and support: motivations and self-efficacy. The study sample (n=40, mean age 68 years (range: 60-76 years)) was 90% African American/Black (n=36), 100% Non-Hispanic, and 45% males (n=18). Twenty-five participants (60%) reported experiencing some/often memory problems in the last 12-months. Thirty-nine (95%) of subjects successfully participated in coaching sessions; on average, 11 (91.9%) sessions per subject were completed. Participants provided positive anecdotal feedback and stated the need for continued health coaching. Consequently, n=30 (75%) of the original sample consented to continued health coaching during the 2020-2021 COVID-19 pandemic (Phase 2). All study subjects were examined at baseline (Time 1), 3-month (Time 2), covid-baseline (Time 3), and 3-months postcovid-baseline (Time 4). Repeated Measures ANOVAs were done to examine Time and Time*Memory Status effects. RESULTS: There was a total risk reduction at Phase 1 (F=9.26; p=.004; effect size=.19). At Phase 2, alcohol use decreased (p=.05), quadratic time effects were observed in physical activity (p=.01-.02), and cubic time effects were observed in depression (p=.02). Overall, total risk reduction in Phase 2 was observed at F=5.05; p=.03 effect size=.16. Pre/post-test analyses indicated improvement in Memory Problem Time Interaction (p=.007), AD knowledge (p=.01-.03), and Tired Days (p=.04) across Phase 1. There was also improvement in Social Isolation Time Interaction (p=.03); Tobacco Addiction (p=.001); Poor Mental Health Days (p=.05), and Worried Days Time Interaction (p=.02-.01) across Phase 2. Between subject Memory Status effects, indicating poorer baseline levels for individuals reporting memory problems had greater improvement seen in memory complaints (p=.001), poor mental health days (.02), and tired days (.003-.01). CONCLUSIONS: This preliminary work creates the impetus for future large-scale lifestyle AD risk reduction investigations to mitigate and improve modifiable AD risk among low-income, diverse older adults, including individuals reporting memory problems. Our findings surrounding participant engagement and positive trends in AD risk reduction support the hypothesis that telephone-based health coaching is a practical and feasible AD risk reduction intervention.

CITATION:
A. Rhodes ; J. Inker ; J. Richardson ; F. Zanjani ; (2022): Alzheimer's Disease Prevention Health Coaching. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.33

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ANXIETY AND DEPRESSIVE SYMPTOMS AND CORTICAL AMYLOID-Β BURDEN IN COGNITIVELY UNIMPAIRED OLDER ADULTS

C.K. Lewis, O.M. Bernstein, J.D. Grill, D.L. Gillen, D.L. Sultzer

J Prev Alz Dis 2022;2(9):286-296

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Background: There is evidence of relationships between behavioral symptoms and increased risk for Alzheimer’s Disease and/or Alzheimer’s Disease biomarkers. However, the nature of this relationship is currently unknown. Objectives: To evaluate the relationship between anxiety and depressive symptoms and amyloid-β deposition in cognitively unimpaired older adults, and to assess mediating effects of either objective or subjective cognitive skills. Design: Cross-sectional analysis of screening data from participants enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study (ClinicalTrials.gov Identifier: NCT02008357) Setting: Data analysis Participants: 4492 cognitively unimpaired adults, age 65-85, enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study Measurements: We used linear regression to estimate the associations between amyloid-β standard uptake value ratio (SUVR) and Geriatric Depression Scale (GDS) and State Trait Anxiety Inventory (STAI) scores while adjusting for potential confounding factors as well as for Cognitive Function Index (CFI) or Preclinical Alzheimer’s Cognitive Composite (PACC) scores as possible mediational variables. Results: 4399 subjects with complete covariates were included (mean age: 71.3, 59% female), GDS ranged 0-13 (mean: 1.0), and STAI ranged 6-24 (mean: 9.9). Amyloid-β SUVR was modestly associated with STAI; mean STAI score was estimated to be 0.275 points higher (95% CI: 0.038, 0.526; p-value = 0.023) for each 0.5-point increase in cortical amyloid-β SUVR. Subjective cognitive decline (CFI) attenuated the relationship between SUVR and STAI, while objective cognitive function (PACC) did not. No statistically significant relationship between SUVR and GDS was observed (p = 0.326). Conclusions: In cognitively unimpaired adults with low levels of depression and anxiety, cortical amyloid-β deposition is associated with anxiety but not depressive symptoms. Attenuation of this relationship by subjective cognitive difficulties suggests that anxiety may be partly due to such a perception resulting from cortical amyloid-β deposition.

CITATION:
C.K. Lewis ; O.M. Bernstein ; J.D. Grill ; D.L. Gillen ; D.L. Sultzer (2022): Anxiety and Depressive Symptoms and Cortical Amyloid-β Burden in Cognitively Unimpaired Older Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.13

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DUAL TASK PERFORMANCE IS ASSOCIATED WITH AMYLOIDOSIS IN COGNITIVELY HEALTHY ADULTS

J.K. Longhurst, J.L. Cummings, S.E. John, B. Poston, J.V. Rider, A.M. Salazar, V.R. Mishra, A. Ritter, J.Z. Caldwell, J.B. Miller, J.W. Kinney, M.R. Landers

J Prev Alz Dis 2022;2(9):297-305

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Background: Preclinical Alzheimer’s disease (AD) provides an opportunity for the study and implementation of interventions and strategies aimed at delaying, mitigating, and preventing AD. While this preclinical state is an ideal target, it is difficult to identify efficiently and cost-effectively. Recent findings have suggested that cognitive-motor dual task paradigms may provide additional inference. OBJECTIVES: Investigate the relationship between dual task performance and amyloidosis, suggestive of preclinical Alzheimer’s disease and whether dual task performance provides additional information beyond a cognitive composite, to help in the identification of amyloidosis. DESIGN: Cross-sectional. SETTING: Outpatient specialty brain health clinical research institution in the United States. PARTICIPANTS: 52 cognitively healthy adults. MEASUREMENTS: The data included demographics, amyloid standardized uptake value ratio obtained via florbetapir-PET, neuropsychological testing, apolipoprotien E genotype, and dual task performance measures. Data were analyzed via hierarchal multiple linear regression or logistic regression, controlling for age, education, and apolipoprotien E genotype. Receiver operating characteristic curves were plotted, and sensitivity and specificity calculated via 2x2 contingency tables. RESULTS: There was a moderate relationship (rs>.30) between motor and cognitive dual task effects and amyloid standardized uptake value ratio (ps<.042). A strong relationship (r=.58) was found between combined dual task effect, a measure of automaticity derived from dual task performance, and amyloid standardized uptake value ratio (p<.001). Additionally, combined dual task effect showed promise in its unique contributions to amyloid standardized uptake value ratio, accounting for 7.8% of amyloid standardized uptake value ratio variance beyond cognitive composite scores (p=.018). Additionally, when incorporated into the cognitive composite, combined dual task effect resulted in improved diagnostic accuracy for determining elevated amyloid standardized uptake value ratio, and increased the sensitivity and specificity of the cognitive composite. CONCLUSSION: Dual task performance using the combined dual task effect, a measure of automaticity, was a moderate predictor of cerebral amyloidosis, which suggests that it has utility in the screening and diagnosis of individuals for preclinical AD. Additionally, when combined with the cognitive composite, the combined dual task effect improves diagnostic accuracy. Further research is warranted.

CITATION:
J.K. Longhurst ; J.L. Cummings ; S.E. John ; B. Poston ; J.V. Rider ; A.M. Salazar ; V.R. Mishra ; A. Ritter ; J.Z. Caldwell ; J.B. Miller ; J.W. Kinney ; M.R. Landers ; (2022): Dual Task Performance Is Associated with Amyloidosis in Cognitively Healthy Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.1

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DISEASE BURDEN AND ATTRIBUTABLE RISK FACTORS OF ALZHEIMER’S DISEASE AND DEMENTIA IN CHINA FROM 1990 TO 2019

R. Li, J. Qi, Y. Yang, Y. Wu, P. Yin, M. Zhou, Z. Qian, M.H. LeBaig, S.E. McMillin, H. Guo, H. Lin

J Prev Alz Dis 2022;2(9):306-314

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Background: Updated information on the burden of Alzheimer’s disease and other forms of dementia are of great importance for evidence-based health care planning. However, such an estimate has been lacking in Chinese populations at both national and provincial levels. Objective: To estimate the temporal trends and the attributable burdens of selected risk factors of Alzheimer’s disease and other forms of dementia in China. Design, Setting, and Participants: This is an observational description of the Global Burden of Diseases Study 2019 (GBD 2019). Data on incidence, mortality, prevalence, disability-adjusted life years (DALYs), years lived with disability (YLDs), and years of life lost (YLLs) of Alzheimer’s disease and other forms of dementia were derived from the GBD 2019 study at both national and provincial levels in China. Measurements: Six indicators were used: incidence, mortality, prevalence, DALYs, YLLs, and YLDs. Absolute numbers in detail by age, sex, region, and age-standardized rates (with 95% uncertainty intervals) were calculated. Results: There were notable increasing trends in the number of deaths (247·9%), incidence (264·8%), prevalence (296·5%), DALYs (228·1%), YLDs (308·7%) and YLLs (201·7%) from 1990 to 2019, respectively. The corresponding age-standardized rates increased by 6·2%, 19·3%, 33·6%, 10·7%, 33·4% and 3·1%. Smoking, high body mass index, high fasting plasma glucose levels, and metabolic risks were the four leading risk factors. Higher burden was observed among females versus males and in the more developed regions. Conclusions: The disease burden in China were increasing substantially. Regional differences of the disease burden are accompanied by discrepancies of economic level and geographical location, as well as different levels of exposure to risk factors. Targeted prevention and control strategies are urgently needed to reduce the disease burden.

CITATION:
R. Li ; J. Qi ; Y. Yang ; Y. Wu ; P. Yin ; M. Zhou ; Z. Qian ; M.H. LeBaige ; S.E. McMillin ; H. Guo ; H. Lin (2021): Disease Burden and Attributable Risk Factors of Alzheimer’s Disease and Dementia in China from 1990 to 2019. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.69

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THE ASSOCIATION OF HEART/VASCULAR AGING WITH MILD COGNITIVE IMPAIRMENT IN A RURAL MULTIETHNIC COHORT: THE PROJECT FRONTIER STUDY

D. Appiah, G. Ashworth, A. Boles, N. Nair

J Prev Alz Dis 2022;2(9):315-322

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BACKGROUND: Cardiovascular disease (CVD) and Alzheimer’s disease and related dementias (ADRD) disproportionately affect rural communities. Identifying strategies to effectively communicate CVD risk to prevent these conditions remains a high priority. OBJECTIVE: We assessed the relation between predicted heart/vascular age (PHA), an easily communicated metric of CVD risk, and mild cognitive impairment (MCI), an early manifestation of ADRD. DESIGN, SETTING, PARTICIPANTS: Data were from 967 rural West Texas residents aged ≥40 years without CVD at baseline (2009-2012) enrolled in Project FRONTIER, an ongoing, multi-ethnic cohort study on cognitive aging. MEASUREMENTS: MCI was diagnosed using the standardized consensus review criteria. PHA was calculated using the Framingham CVD risk equation. High excess PHA (HEPHA) was defined as the difference between PHA and chronological age >5 years. Logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: At baseline, the mean age of participants (70% women and 64% Hispanics) was 55 years. Almost 13% had MCI and 65% had HEPHA. After adjusting for socio-demographic and health factors, HEPHA was positively associated with MCI (OR=2.98; 95%CI: 1.72-5.15). Among participants without MCI at baseline who returned for follow-up exam after three years (n=238), a three-year negative change in PHA was seemingly associated with reduced odds for MCI (OR=0.98; 95%CI: 0.96-1.01). CONCLUSIONS: In this study, PHA was positively associated with MCI, with improvement in CVD risk profile seemingly related to reduced odds for MCI. PHA may provide a low-cost means of communicating CVD risk in rural settings to prevent both CVD and ADRD.

CITATION:
D. Appiah ; G. Ashworth ; A. Boles ; N. Nair ; (2022): The Association of Heart/Vascular Aging with Mild Cognitive Impairment in a Rural Multiethnic Cohort: The Project FRONTIER Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.15

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THE ASSOCIATION BETWEEN SUGAR-SWEETENED BEVERAGES AND COGNITIVE FUNCTION IN MIDDLE-AGED AND OLDER PEOPLE: A META-ANALYSIS

Q. Sun, Y. Yang, X. Wang, R. Yang, X. Li

J Prev Alz Dis 2022;2(9):323-330

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Objective: To explore the association between the intake of sugar-sweetened beverages and cognitive dysfunction in middle-aged and older adults, so as to provide an evidence-based basis for the early prevention of cognitive dysfunction. Methods: A comprehensive search of relevant literature was conducted in PubMed, EMBase, Cochrane, ScienceDirect, and Web of Science from the inception until January 2021. Odds ratios (OR), hazard ratios (HR) and 95% confidence intervals (CI) were calculated using a random-effects, generic inverse variance method. Meta-analysis of the included studies was performed using Review Manager 5.4. Results: A total of 10 studies on the association between sugary beverages and cognitive dysfunction in middle-aged and older adults were included, of which 3 were cross-sectional studies and the rest were cohort studies. Eight of the ten studies had results suggestive of a negative association. However, Meta-analysis results showed that the association between the intake of sugar-sweetened beverages and the risk of cognitive impairment was not statistically significant (OR=1.59, 95% CI: 0.93-2.74, P=0.08); but from two studies, the hazard ratios of all-cause dementia in middle-aged and older people consuming sugar-sweetened beverages was 2.77 (95%CI: 2.24-3.43, P<0.00001); the hazard ratios of Alzheimer’s disease in middle-aged and older people consuming sugar-sweetened beverages was 2.63 (95%CI: 1.70-4.05, P<0.0001). Conclusion: There is insufficient evidence to state conclusively that sugar-sweetened beverages intake causes cognitive dysfunction in middle-aged and older adults.

CITATION:
Q. Sun ; Y. Yang ; X. Wang ; R. Yang ; X. Li (2021): The Association between Sugar-Sweetened Beverages and Cognitive Function in Middle-Aged and Older People: A Meta-Analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.71

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PLASMA MMP-9 LEVELS AS THE FUTURE RISK OF CONVERSION TO DEMENTIA IN APOE4-POSITIVE MCI PATIENTS: INVESTIGATION BASED ON THE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE DATABASE

K. Abe, Y. Chiba, K. Ide, A. Yoshimi, T. Asami, A. Suda, T. Odawara, A. Hishimoto

J Prev Alz Dis 2022;2(9):331-337

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Background: Matrix metalloproteinase 9 (MMP-9) has been reported to be correlated with declines in hippocampal volume and cognitive function in ApoE4-positive MCI patients. Objectives: The present study was aimed to investigate the effects of plasma matrix MMP-9 on the conversion risk between mild cognitive impairment (MCI) patients with and without ApoE4. Design and setting: Retrospective observational study using the data extracted from the Alzheimer’s Disease Neuroimaging Initiative database. Participants: We included 211 ApoE4-positive MCI subjects (ApoE4+ MCI) and 184 ApoE4-negative MCI subjects (ApoE4- MCI). Measurements: We obtained demographic and data including plasma MMP-9 levels at baseline and longitudinal changes in Clinical Dementia Rating (CDR) up to 15 years. We compared conversion rates between ApoE4+ MCI and ApoE4- MCI by the Log-rank test and calculated the hazard ratio (HR) for covariates including age, sex, educational attainment, drinking and smoking histories, medications, and plasma MMP-9 levels using a multiple Cox regression analysis of ApoE4+ MCI and ApoE4- MCI. Results: No significant differences were observed in baseline plasma MMP-9 levels between ApoE4+ MCI and ApoE4- MCI. High plasma MMP-9 levels increased the conversion risk significantly more than low plasma MMP-9 levels (HR, 2.46 [95% CI, 1.31-4.48]) and middle plasma MMP-9 levels (HR, 1.67 [95% CI, 1.04-2.65]) in ApoE4+ MCI, but not in ApoE4- MCI. Conclusion: Plasma MMP-9 would be the risk of the future conversion to dementia in ApoE4+ MCI.

CITATION:
K. Abe ; Y. Chiba ; K. Ide ; A. Yoshimi ; T. Asami ; A. Suda ; T. Odawara ; A. Hishimoto (2022): Plasma MMP-9 Levels as the Future Risk of Conversion to Dementia in ApoE4-Positive MCI Patients: Investigation Based on the Alzheimer’s Disease Neuroimaging Initiative Database. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.19

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EVALUATION OF MEMANTINE IN AAV-AD RAT: A MODEL OF LATEONSET ALZHEIMER’S DISEASE PREDEMENTIA

B. Souchet, M. Audrain, S. Alves, R. Fol, S. Tada, N.S Orefice, B. Potier, P. Dutar, J.-M. Billard, N. Cartier, J. Braudeau

J Prev Alz Dis 2022;2(9):338-347

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Background: Though our understanding of Alzheimer’s disease (AD) remains elusive, it is well known that the disease starts long before the first signs of dementia. This is supported by the large number of symptomatic drug failures in clinical trials and the increased trend to enroll patients at predementia stages with either mild or no cognitive symptoms. However, the design of pre-clinical studies does not follow this attitude, in particular regarding the choice of animal models, often irrelevant to mimic predementia Late Onset Alzheimer’s Disease (LOAD). OBJECTIVES: We aimed to pharmacologically validate the AAV-AD rat model to evaluate preventive treatment of AD. METHODS: We evaluated an N-methyl-D-aspartate receptor antagonist, named memantine, in AAV-AD rats, an age-dependent amyloid rat model which closely mimics Alzheimer’s pathology including asymptomatic and prodromal stages. Memantine was used at a clinically relevant dose (20 mg daily oral administration) from 4 (asymptomatic phase) to 10 (mild cognitive impairment phase) months of age. RESULTS: A 6-month treatment with memantine promoted a non-amyloidogenic cleavage of APP followed by a decrease in soluble Aβ42. Consequently, both long-term potentiation and cognitive impairments were prevented. By contrast, the levels of hyperphosphorylated endogenous tau remained unchanged, indicating that a long-term memantine treatment is ineffective to restrain the APP processing-induced tauopathy. CONCLUSIONS: Together, our data confirm that relevant models to LOAD, such as the AAV-AD rat, can provide a framework for a better understanding of the disease and accurate assessment of preventive treatments.

CITATION:
B. Souchet ; M. Audrain ; S. Alves ; R. Fol ; S. Tada ; N.S Orefice ; B. Potier ; P. Dutar ; J.-M. Billard ; N. Cartier ; J. Braudeau ; (2021): Evaluation of Memantine in AAV-AD Rat: A Model of Late-Onset Alzheimer’s Disease Predementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.67

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THE SCOTTISH BRAIN HEALTH SERVICE MODEL: RATIONALE AND SCIENTIFIC BASIS FOR A NATIONAL CARE PATHWAY OF BRAIN HEALTH SERVICES IN SCOTLAND

C.W. Ritchie, J.M.J. Waymont, C. Pennington, K. Draper, A. Borthwick, N. Fullerton, M. Chantler, M.E. Porteous, S.O. Danso, A. Green, L. McWhirter, G. Muniz Terrera, S. Simpson, G. Thompson, D. Trépel, T.J. Quinn, A. Kilgour

J Prev Alz Dis 2022;2(9):348-358

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In order to address the oft-cited societal, economic, and health and social care impacts of neurodegenerative diseases, such as Alzheimer’s disease, we must move decisively from reactive to proactive clinical practice and to embed evidence-based brain health education throughout society. Most disease processes can be at least partially prevented, slowed, or reversed. We have long neglected to intervene in neurodegenerative disease processes, largely due to a misconception that their predominant symptom – cognitive decline – is a normal, age-related process, but also due to a lack of multi-disciplinary collaboration. We now understand that there are modifiable risk factors for neurodegenerative diseases, that successful management of common comorbidities (such as diabetes and hypertension) can reduce the incidence of neurodegenerative disease, and that disease processes begin (and, crucially, can be detected, reduced, and delayed, prevented, or treated) decades earlier in life than had previously been appreciated. Brain Health Scotland, established by Scottish Government and working in partnership with Alzheimer Scotland, propose far-reaching public health and clinical practice approaches to reduce neurodegenerative disease incidence. Focusing here on Brain Health Scotland’s clinical offerings, we present the Scottish Model for Brain Health Services. To our knowledge, the Scottish Model for Brain Health, built on foundations of personalised risk profiling, targeted risk reduction and prevention, early disease detection, equity of access, and harnessing comprehensive data to assist in clinical decision-making, marks the first example of a nationwide approach to overhauling clinical, societal, and political approaches to the prevention, assessment, and treatment of neurodegenerative disease.

CITATION:
C.W. Ritchie ; J.M.J. Waymont ; C. Pennington ; K. Draper ; A. Borthwick ; N. Fullerton ; M. Chantler ; M.E. Porteous ; S.O. Danso ; A. Green ; L. McWhirter ; G. Muniz Terrera ; S. Simpson ; G. Thompson ; D. Trépel ; T.J. Quinn ; A. Kilgour ; (2021): The Scottish Brain Health Service Model: Rationale and Scientific Basis for a National Care Pathway of Brain Health Services in Scotland. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2021.63

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THE EFFECTS OF DUAL-TASK TRAINING ON COGNITIVE AND PHYSICAL FUNCTIONS IN OLDER ADULTS WITH COGNITIVE IMPAIRMENT; A SYSTEMATIC REVIEW AND META-ANALYSIS

N. Ali, H. Tian, L. Thabane, J. Ma, H. Wu, Q. Zhong, Y. Gao, C. Sun, Y. Zhu, T. Wang

J Prev Alz Dis 2022;2(9):359-370

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Background and objective: Individuals with Alzheimer disease and dementia experience cognitive decline and reduction in physical capabilities. Engaging in cognitive challenges and physical exercises is effective in reducing age-related cognitive and physical decline. It is believed that physical activity in the context of cognitive challenges might enhance the process of neurogenesis in the adult brain, but how effective are such interventions? Is there enough evidence to support that dual-task training is more effective than cognitive or physical training alone? To what extent can such training improve cognitive and physical functions in patients at various stages of cognitive decline? Methodology: This systematic review with meta-analysis summarizes the emerging evidence of dual-task training for enhancing cognitive and physical functions in older individuals with cognitive impairment, dementia or Alzheimer’s disease. A systematic search was carried out in MEDLINE, PubMed, EMBASE, and Cochrane Library with the following search terms: randomized control trials, dual-task training, SCD, MCI, dementia, and Alzheimer’s disease. Results: A total of 21 studies with 2,221 participants were identified. The results of dual-task tanning intervention are summarized as change in global cognitive function; SMD = 0.24, (P= 0.002), memory; SMD = 0.28, (P = 0.000), executive function; SMD = 0.35, (P = 0.000), attention; SMD = −0.19, (P = 0.1), gait speed; SMD = 0.26, (P = 0.007), dual-task cost; SMD 0.56, (P = 0.000), and balance; SMD 0.36, (P = 0.004). Conclusion: Primary analysis showed a small-to-medium positive effect of dual-task training interventions on cognitive functions and medium-to-large positive effect on gait functions and balance.

CITATION:
N. Ali ; H. Tian ; L. Thabane ; J. Ma ; H. Wu ; Q. Zhong ; Y. Gao ; C. Sun ; Y. Zhu ; T. Wang (2022): The Effects of Dual-Task Training on Cognitive and Physical Functions in Older Adults with Cognitive Impairment; A Systematic Review and Meta-Analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.16

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IDENTIFYING DEMENTIA RISK IN OLDER VETERANS USING A MAILING SURVEY

A. Shah, O. Ysea-Hill, A. Torres-Morales, C.J. Gomez, A. Castellanos, J.G. Ruiz

J Prev Alz Dis 2022;2(9):371-375

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Evidence suggests that dementia can be prevented. Patients with frailty may be particularly at risk for cognitive impairment (CI). The aim of this study was to determine dementia risk in older Veterans and whether the risk varies according to frailty status. We also evaluated the feasibility of mailed dementia risk screening. Participants were mailed a questionnaire and the Self-Administered Gerocognitive Examination (SAGE). High dementia risk was defined as having mild cognitive impairment (MCI) on SAGE or a CAIDE score ≥6. Out of 5,432 mailed surveys, we obtained a response rate of 19.75%. Most responders completed the questionnaire items. We identified a total of 689 (75.9%) subjects to be at high risk for dementia. Individuals with frailty were at a greater risk for dementia when compared to robust individuals OR:1.921 (95%CI:1.259-2.930), p=.002. The mailed screening represents a convenient, alternative and scalable approach to screen for dementia risk.

CITATION:
A. Shah ; O. Ysea-Hill ; A. Torres-Morales ; C.J. Gomez ; A. Castellanos ; J.G. Ruiz ; (2022): Identifying Dementia Risk in Older Veterans Using A Mailing Survey. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.14

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STUDY PROTOCOL OF A COMPREHENSIVE ACTIVITY PROMOTION

H. Shimada, S. Lee, K. Harada, S. Bae, K. Makino, I. Chiba, O. Katayama, H. Arai

J Prev Alz Dis 2022;2(9):376-384

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BACKGROUND: Several technical devices are available to monitor and promote changes in behavior toward higher activity. In particular, smartphones are becoming the primary platform for recognizing human activity. However, the effects of behavior change techniques that promote physical, cognitive, and social activities on incident dementia in older adults remain unknown. Objectives: This randomized controlled trial aims to examine the effects of behavior change techniques on the prevention of dementia among community-dwelling older adults using a smartphone as a behavior change tool. Design: A randomized controlled trial. Setting: Community in Japan. Participants: The study cohort comprises 3,498 individuals, aged ≥60 years, randomized into two groups: the smartphone group (n = 1,749) and the control group (n = 1,749). Intervention. The smartphone group will be asked to use smartphone applications for at least 30 minutes daily to self-manage and improve their physical, cognitive, and social activities. The smartphone group will perform 60-minute group walking sessions using application-linked Nordic walking poles with cognitive stimulation twice a week during the intervention period. The walking poles are a dual-task exercise tool that works with a smartphone to perform cognitive tasks while walking, and the poles are equipped with switches to answer questions for simple calculation and memory tasks. The smartphone and control groups will receive lectures about general health that will be provided during the baseline and follow-up assessments. Measurements: Incident dementia will be detected using cognitive tests (at baseline, after 15 months, and after 30 months) and by preparing diagnostic monthly reports based on data from the Japanese Health Insurance System. Participants without dementia at baseline who will be diagnosed with dementia over the 30-month follow-up period will be considered to have incident dementia. Conclusions: This study has the potential to provide the first evidence of the effectiveness of information communication technology and Internet of Things in incident dementia. If our trial results show a delayed dementia onset for self-determination interventions, the study protocol will provide a cost-effective and safe method for maintaining healthy cognitive aging.

CITATION:
H. Shimada ; S. Lee ; K. Harada ; S. Bae ; K. Makino ; I. Chiba ; O. Katayama ; H. Arai ; (2022): Study Protocol of a Comprehensive Activity Promotion. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.12

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