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BackgroundThe current clinical trial assessment methodology relies on a combination of self-report measures, cognitive and physical function tests, and biomarkers. This methodology is limited by recall bias and recency effects in self-reporting and by assessments that are brief, episodic, and clinic based. Continuous monitoring of ecologically valid measures of cognition and daily functioning in the community may provide a more sensitive method to detect subtle, progressive changes in patients with cognitive impairment and dementia. ObjectiveThis study aimed to present an alternative trial approach using a home-based sensing and computing system to detect changes related to common treatments employed in Alzheimer disease (AD). This paper introduces an ongoing study that aims to determine the feasibility of capturing sensor-based data at home and to compare the sensor-based outcomes with conventional outcomes. We describe the methodology used in the assessment protocol and present preliminary results of feasibility measures and examples of data related to medication-taking behavior, activity levels, and sleep. MethodsThe EVALUATE-AD (Ecologically Valid, Ambient, Longitudinal and Unbiased Assessment of Treatment Efficacy in Alzheimer’s Disease) trial is a longitudinal naturalistic observational cohort study recruiting 30 patients and 30 spouse coresident care partners. Participants are monitored continuously using a home-based sensing and computing system for up to 24 months. Outcome measures of the automated system are compared with conventional clinical outcome measures in AD. Acceptance of the home system and protocol are assessed by rates of dropout and protocol adherence. After completion of the study monitoring period, a composite model using multiple functional outcome measures will be created that represents a behavioral-activity signature of initiating or discontinuing AD-related medications, such as cholinesterase inhibitors, memantine, or antidepressants. ResultsThe home-based sensing and computing system has been well accepted by individuals with cognitive impairment and their care partners. Participants showed good adherence to the completion of a weekly web-based health survey. Daily activity, medication adherence, and total time in bed could be derived from algorithms using data from the sensing and computing system. The mean monitoring time for current participants was 14.6 months. Medication adherence, as measured with an electronic pillbox, was 77% for participants taking AD-related medications. ConclusionsContinuous, home-based assessment provides a novel approach to test the impact of new or existing dementia treatments generating objective, clinically meaningful measures related to cognition and everyday functioning. Combining this approach with the current clinical trial methodology may ultimately reduce trial durations, sample size needs, and reliance on a clinic-based assessment. International Registered Report Identifier (IRRID)DERR1-10.2196/17603

BackgroundConsensus guidance for the development and identification of high-quality Alzheimer's disease clinical trials is needed for protocol development and conduct of clinical trials.MethodsAn ad hoc consensus committee was convened in conjunction with the Alzheimer's Association to develop consensus recommendations.ResultsConsensus was readily reached for the need to provide scientific justification, registration of trials, institutional review board oversight, conflict of interest disclosure, funding source disclosure, defined trial population, recruitment resources, definition of the intervention, specification of trial duration, appropriate payment for participant engagement, risk-benefit disclosure as part of the consent process, and the requirement to disseminate and/or publish trial results even if the study is negative.ConclusionsThis consensus guidance should prove useful for the protocol development and conduct of clinical trials, and may further provide a platform for the development of education materials that may help guide appropriate clinical trial participation decisions for potential trial participants and the general public.

BackgroundConsensus guidance for the development and identification of high-quality Alzheimer's disease clinical trials is needed for protocol development and conduct of clinical trials.MethodsAn ad hoc consensus committee was convened in conjunction with the Alzheimer's Association to develop consensus recommendations.ResultsConsensus was readily reached for the need to provide scientific justification, registration of trials, institutional review board oversight, conflict of interest disclosure, funding source disclosure, defined trial population, recruitment resources, definition of the intervention, specification of trial duration, appropriate payment for participant engagement, risk-benefit disclosure as part of the consent process, and the requirement to disseminate and/or publish trial results even if the study is negative.ConclusionsThis consensus guidance should prove useful for the protocol development and conduct of clinical trials, and may further provide a platform for the development of education materials that may help guide appropriate clinical trial participation decisions for potential trial participants and the general public.

In the past decade a large body of evidence has accumulated on risk factors for dementia, primarily from Europe and North America. Drawing on recent integrative reviews and a consensus workshop, the International Research Network on Dementia Prevention developed a consensus statement on priorities for future research. Significant gaps in geographical location, representativeness, diversity, duration, mechanisms, and research on combinations of risk factors were identified. Future research to inform dementia risk reduction should fill gaps in the evidence base, take a life-course, multi-domain approach, and inform population health approaches that improve the brain-health of whole communities.

IntroductionFederally funded Alzheimer's Disease Centers in the United States have been using a standardized neuropsychological test battery as part of the National Alzheimer's Coordinating Center Uniform Data Set (UDS) since 2005. Version 3 (V3) of the UDS replaced the previous version (V2) in 2015. We compared V2 and V3 neuropsychological tests with respect to their ability to distinguish among the Clinical Dementia Rating (CDR) global scores of 0, 0.5, and 1.MethodsFirst, we matched participants receiving V2 tests (V2 cohort) and V3 tests (V3 cohort) in their cognitive functions using tests common to both versions. Then, we compared receiver-operating characteristic (ROC) area under the curve in differentiating CDRs for the remaining tests.ResultsSome V3 tests performed better than V2 tests in differentiating between CDR 0.5 and 0, but the improvement was limited to Caucasian participants.DiscussionFurther efforts to improve the ability for early identification of cognitive decline among diverse racial groups are required.

IntroductionConventional Z-scores are generated by subtracting the mean and dividing by the standard deviation. More recent methods linearly correct for age, sex, and education, so that these "adjusted" Z-scores better represent whether an individual's cognitive performance is abnormal. Extreme negative Z-scores for individuals relative to this normative distribution are considered indicative of cognitive deficiency.MethodsIn this article, we consider nonlinear shape constrained additive models accounting for age, sex, and education (correcting for nonlinearity). Additional shape constrained additive models account for varying standard deviation of the cognitive scores with age (correcting for heterogeneity of variance).ResultsCorrected Z-scores based on nonlinear shape constrained additive models provide improved adjustment for age, sex, and education, as indicated by higher adjusted-R2.DiscussionNonlinearly corrected Z-scores with respect to age, sex, and education with age-varying residual standard deviation allow for improved detection of non-normative extreme cognitive scores.

Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise "state-of-the-science" report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.

INTRODUCTION: Bumetanide, a loop diuretic, was identified as a candidate drug for repurposing for Alzheimer's disease (AD) based on its effects on transcriptomic apolipoprotein E signatures. Cross‐sectional analyses of electronic health records suggest that bumetanide is associated with decreased prevalence of AD; however, temporality between bumetanide exposure and AD development has not been established. METHODS: We evaluated Medicare claims data using Cox proportional hazards regression to evaluate the association between time‐dependent use of bumetanide and time to first AD diagnosis while controlling for patient characteristics. Multiple sensitivity analyses were conducted to test the robustness of the findings. RESULTS: We sampled 833,561 Medicare beneficiaries, 60.8% female, with mean (standard deviation) age of 70.4 (12). Bumetanide use was not significantly associated with AD risk (hazard ratio 1.05; 95% confidence interval, 0.99–1.10). DISCUSSION: Using a nationwide dataset and a retrospective cohort study design, we were not able to identify a time‐dependent effect of bumetanide lowering AD risk. Highlights: Bumetanide was identified as a candidate for repurposing for Alzheimer's disease (AD).We evaluated the association between bumetanide use and risk of AD.We used Medicare data and accounted for duration of bumetanide use.Bumetanide use was not significantly associated with risk of AD. [ABSTRACT FROM AUTHOR]

Introduction: Emotional functioning in older adults is influenced by normal aging and cognitive impairment, likely heterogeneous across positive versus negative aspects of emotional functioning. Little is known about positive emotional experiences at the early stages of cognitive impairment. Methods: We assessed different aspects of emotional functioning among 448 participants aged 65+ (Normal Control (NC) = 276, Mild Cognitive Impairment (MCI) = 103, and mild dementia of the Alzheimer type (mild DAT) = 69) and tested moderators. Results: Compared to NC, older adults with MCI and mild DAT have maintained many positive aspects of emotional functioning, despite higher levels of negative affect, sadness, and loneliness. Among the oldest-old, the mild DAT group experienced higher fear and lower self-efficacy. Discussion: Older adults at early stages of cognitive impairment can experience positive aspects of emotional functioning, such as positive affect, purpose, and life satisfaction, all of which are important buildable psychological resources for coping. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Recent growth in the functionality and use of technology has prompted an increased interest in the potential for remote or decentralized clinical trials in dementia. There are many potential benefits associated with decentralized medication trials, but we currently lack specific recommendations for their delivery in the dementia field. METHODS: A modified Delphi method engaged an expert panel to develop recommendations for the conduct of decentralized medication trials in dementia prevention. A working group of researchers and clinicians with expertise in dementia trials further refined the recommendations. RESULTS: Overall, the recommendations support the delivery of decentralized trials in dementia prevention provided adequate safety checks and balances are included. A total of 40 recommendations are presented, spanning aspects of decentralized clinical trials, including safety, dispensing, outcome assessment, and data collection. DISCUSSION: These recommendations provide an accessible, pragmatic guide for the design and conduct of remote medication trials for dementia prevention. Highlights: Clinical trials of medication have begun adopting decentralized approaches.Researchers in the field lack guidance on what would be appropriate circumstances and frameworks for what would be appropriate circumstances and frameworks for the use of decentralized trial methods in dementia prevention.The present report provides consensus‐based expert recommendations for decentralized clinical trials for dementia prevention. [ABSTRACT FROM AUTHOR]

Background: Policymakers advocate care integration models to enhance Medicare and Medicaid service coordination for dually eligible individuals. One rapidly expanding model is the fully integrated dual eligible (FIDE) plan, a sub‐type of the dual eligible special needs plan (D‐SNP) in which a parent insurer manages Medicare and Medicaid spending for dually eligible individuals. We examined healthcare utilization differences among dually eligible individuals aged 65 years or older enrolled in D‐SNPs by plan type (FIDE vs non‐FIDE). Methods: Using 2018 Medicare Advantage encounters and Medicaid claims of FIDE and non‐FIDE enrollees in six states (AZ, CA, FL, NY, TN, WI), we compared healthcare utilization between plan types, adjusting for enrollee characteristics and county indicators. We applied propensity score weighting to address differences between FIDE and non‐FIDE plan enrollees. Results: In our main analysis, which included all dually eligible individuals in our sample, we observed no significant difference in healthcare utilization between FIDE and non‐FIDE plan enrollees. However, we identified some differences in healthcare utilization between FIDE and non‐FIDE plan enrollees in subgroup analyses. For example, among home and community‐based service (HCBS) users, FIDE plan enrollees had 6.0 fewer hospitalizations per 1000 person‐months (95% CI: −7.9, −4.0) and were 7.0 percentage points more likely to be discharged to home (95% CI: 2.6, 11.5) after hospitalization, compared to non‐FIDE plan enrollees. Conclusion: While we found no differences in healthcare utilization between FIDE and non‐FIDE plan enrollees when considering all dually eligible individuals in our sample, some differences emerged when focusing on subgroups. For example, HCBS users with FIDE plans had fewer hospitalizations and were more likely to be discharged to their home following hospitalization, compared to HCBS users with non‐FIDE plans. These findings suggest that FIDE plans may improve care coordination for specific subsets of dually eligible individuals. See related article by Parsons et al. in this issue. [ABSTRACT FROM AUTHOR]

IntroductionThe neuropsychological battery of the Uniform Data Set (UDSNB) was implemented in 2005 by the National Institute on Aging (NIA) Alzheimer Disease Centers program to measure cognitive performance in dementia and mild cognitive impairment due to Alzheimer Disease. This paper describes a revision, the UDSNB 3.0.MethodsThe Neuropsychology Work Group of the NIA Clinical Task Force recommended revisions through a process of due diligence to address shortcomings of the original battery. The UDSNB 3.0 covers episodic memory, processing speed, executive function, language, and constructional ability. Data from 3602 cognitively normal participants in the National Alzheimer Coordinating Center database were analyzed.ResultsDescriptive statistics are presented. Multivariable linear regression analyses demonstrated score differences by age, sex, and education and were also used to create a normative calculator available online.DiscussionThe UDSNB 3.0 neuropsychological battery provides a valuable non proprietary resource for conducting research on cognitive aging and dementia.

Dementia is a neurodegenerative disorder with global impact, with the largest proportion of cases occurring in low- and middle-income countries. It is estimated that there are 46.8 million cases globally with approximately 10 million new cases each year or a new case occurring every 3 sec (Prince et al., 2015). For comparison there are 36.7 million HIV cases with an estimated 2 million new cases each year (WHO, 2017). The rise in dementia prevalence is largely due to population ageing, with the oldest being at highest risk. To date there are no diseases modifying medications for Alzheimer's disease or the other causes of dementia. Academics and research groups are increasingly focused on prevention or delay of dementia (Brayne and Miller, 2017) and a number of organizations now prioritize dementia, indicating a strong and coherent international effort to address this problem. Examples include the World Health Organisation (WHO), which has established a Global Dementia Observatory; the World Dementia Council; the Organisation for Economic Co-operation and Development (OECD); the U.S. National Alzheimer's Project Act (NAPA); and the Global Council on Brain Health.

IntroductionRacial and ethnic groups are under-represented among research subjects who assent to brain donation in Alzheimer disease research studies. There has been little research on this important topic. Although there are some studies that have investigated the barriers to brain donation among African American study volunteers, there is no known research on the factors that influence whether or not Asians or Latinos are willing to donate their brains for research.MethodsAfrican American, Caucasian, Asian, and Latino research volunteers were surveyed at 15 Alzheimer Disease Centers to identify predictors of willingness to assent to brain donation.ResultsPositive predictors included older age, Latino ethnicity, understanding of how the brain is used by researchers, and understanding of what participants need to do to ensure that their brain will be donated. Negative predictors included African/African American race, belief that the body should remain whole at burial, and concern that researchers might not be respectful of the body during autopsy.DiscussionThe predictive factors identified in this study may be useful for researchers seeking to increase participation of diverse ethnic groups in brain donation.

Home- and community-based services (HCBS) users, on average, experience hospitalizations more frequently than nursing facility residents. However, little is known about state-level variation in such adverse events among these groups. Using 2018 Medicare and Medicaid claims for dual-eligible beneficiaries with Alzheimer's disease and related dementias, we described hospitalization and emergency department (ED) visit rates among HCBS users and nursing facility residents and observed substantial state-level variation. In addition, consistent with prior evidence, we found more frequent hospitalizations and ED visits among HCBS users than nursing facility residents. The magnitude of this difference varied considerably across states, and the degree of variation was greatest among beneficiaries with six or more comorbid conditions. Our findings represent a crucial initial exploration of the state-level variation in adverse events among HCBS users and nursing facility residents, paving the way for further investigations into factors that contribute to this variability. [ABSTRACT FROM AUTHOR]

Background and Objectives Social isolation is a risk factor for cognitive decline and dementia. We conducted a randomized controlled clinical trial (RCT) of enhanced social interactions, hypothesizing that conversational interactions can stimulate brain functions among socially isolated older adults without dementia. We report topline results of this multisite RCT (Internet-based conversational engagement clinical trial [I-CONECT]; NCT02871921). Research Design and Methods The experimental group received cognitively stimulating semistructured conversations with trained interviewers via internet/webcam 4 times per week for 6 months (induction) and twice per week for an additional 6 months (maintenance). The experimental and control groups both received weekly 10 minutes telephone check-ins. Protocol modifications were required due to the coronavirus disease 2019 pandemic. Results A total of 186 participants were randomized. After the induction period, the experimental group had higher global cognitive test scores (Montreal Cognitive Assessment [primary outcome]; 1.75 points [ p  = .03]) compared with the control group. After induction, experimental group participants with normal cognition had higher language-based executive function (semantic fluency test [secondary outcome]; 2.56 points [ p  = .03]). At the end of the maintenance period, the experimental group of mild cognitive impairment subjects had higher encoding function (Craft Story immediate recall test [secondary outcome]; 2.19 points [ p  = .04]). Measure of emotional well-being improved in both control and experimental groups. Resting-state functional magnetic resonance imaging showed that the experimental group had increased connectivity within the dorsal attention network relative to the control group (p  = .02), but the sample size was limited. Discussion and Implications Providing frequent stimulating conversational interactions via the internet could be an effective home-based dementia risk-reduction strategy against social isolation and cognitive decline. Clinical Trials Registration Number NCT02871921 [ABSTRACT FROM AUTHOR]

IntroductionFour new nonproprietary tests were recommended for use in the National Alzheimer's Coordinating Center's Uniform Data Set Neuropsychological Battery. These tests are similar to previous tests but also allow for continuity of longitudinal data collection and wide dissemination among research collaborators.MethodsA Crosswalk Study was conducted in early 2014 to assess the correlation between each set of new and previous tests. Tests with good correlation were equated using equipercentile equating. The resulting conversion tables allow scores on the new tests to be converted to equivalent scores on the previous tests.ResultsAll pairs of tests had good correlation (ρ=0.68 to 0.78). Learning effects were detected for Logical Memory only. Confidence intervals were narrow at each point estimate, and prediction accuracy was high.DiscussionThe recommended new tests are well correlated with the previous tests. The equipercentile equating method produced conversion tables that provide a useful reference for clinicians and researchers.