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Objectives: Decision-analytic models assessing the value of emerging Alzheimer's disease (AD) treatments are challenged by limited evidence on short-term trial outcomes and uncertainty in extrapolating long-term patient-relevant outcomes. To improve understanding and foster transparency and credibility in modeling methods, we cross-compared AD decision models in a hypothetical context of disease-modifying treatment for mild cognitive impairment (MCI) due to AD., Methods: A benchmark scenario (US setting) was used with target population MCI due to AD and a set of synthetically generated hypothetical trial efficacy estimates. Treatment costs were excluded. Model predictions (10-year horizon) were assessed and discussed during a 2-day workshop., Results: Nine modeling groups provided model predictions. Implementation of treatment effectiveness varied across models based on trial efficacy outcome selection (CDR-SB, CDR-global, MMSE, FAQ) and analysis method (observed severity transitions, change from baseline, progression hazard ratio, or calibration to these). Predicted mean time in MCI ranged from 2.6-5.2 years for control strategy, and from 0.1-1.0 years for difference between intervention and control strategies. Predicted quality-adjusted life-year gains ranged from 0.0-0.6 and incremental costs (excluding treatment costs) from -US$66,897 to US$11,896., Conclusions: Trial data can be implemented in different ways across health-economic models leading to large variation in model predictions. We recommend 1) addressing the choice of outcome measure and treatment effectiveness assumptions in sensitivity analysis, 2) a standardized reporting table for model predictions, and 3) exploring the use of registries for future AD treatments measuring long-term disease progression to reduce uncertainty of extrapolating short-term trial results by health economic models., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: Reimbursement decisions for new Alzheimer's disease (AD) treatments are informed by economic evaluations. An open-source model with intuitive structure for model cross-validation can support the transparency and credibility of such evaluations. We describe the new International Pharmaco-Economic Collaboration on Alzheimer's Disease (IPECAD) open-source model framework (version 2) for the health-economic evaluation of early AD treatment and use it for cross-validation and addressing uncertainty., Methods: A cohort state-transition model using a categorized composite domain (cognition and function) was developed by replicating an existing reference model and testing it for internal validity. Then, features of existing Institute for Clinical and Economic Review (ICER) and Alzheimer's Disease Archimedes Condition-Event Simulator (AD-ACE) models assessing lecanemab treatment were implemented for model cross-validation. Additional uncertainty scenarios were performed on choice of efficacy outcome from trial, natural disease progression, treatment effect waning and stopping rules, and other methodological choices. The model is available open-source as R code, spreadsheet, and web-based version via https://github.com/ronhandels/IPECAD., Results: In the IPECAD model incremental life-years, quality-adjusted life-years (QALY) gains and cost savings were 21% to 31% smaller compared with the ICER model and 36% to 56% smaller compared with the AD-ACE model. IPECAD model results were particularly sensitive to assumptions on treatment effect waning and stopping rules and choice of efficacy outcome from trial., Conclusions: We demonstrated the ability of a new IPECAD open-source model framework for researchers and decision makers to cross-validate other (Health Technology Assessment submission) models and perform additional uncertainty analyses, setting an example for open science in AD decision modeling and supporting important reimbursement decisions., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Background: The expected increase of dementia prevalence in the coming decades will mainly be in low-income and middle-income countries and in people with low socioeconomic status in high-income countries. This study aims to reduce dementia risk factors in underserved populations at high-risk using a coach-supported mobile health (mHealth) intervention., Methods: This open-label, blinded endpoint, hybrid effectiveness-implementation randomised controlled trial (RCT) investigated whether a coach-supported mHealth intervention can reduce dementia risk in people aged 55-75 years of low socioeconomic status in the UK or from the general population in China with at least two dementia risk factors. The primary effectiveness outcome was change in cardiovascular risk factors, ageing, and incidence of dementia (CAIDE) risk score from baseline to after 12-18 months of intervention. Implementation outcomes were coverage, adoption, sustainability, appropriateness, acceptability, fidelity, feasibility, and costs assessed using a mixed-methods approach. All participants with complete data on the primary outcome, without imputation of missing outcomes were included in the analysis (intention-to-treat principle). This trial is registered with ISRCTN, ISRCTN15986016, and is completed., Findings: Between Jan 15, 2021, and April 18, 2023, 1488 people (601 male and 887 female) were randomly assigned (734 to intervention and 754 to control), with 1229 (83%) of 1488 available for analysis of the primary effectiveness outcome. After a mean follow-up of 16 months (SD 2·5), the mean CAIDE score improved 0·16 points in the intervention group versus 0·01 in the control group (mean difference -0·16, 95% CI -0·29 to -0·03). 1533 (10%) invited individuals responded; of the intervention participants, 593 (81%) of 734 adopted the intervention and 367 (50%) of 734 continued active participation throughout the study. Perceived appropriateness (85%), acceptability (81%), and fidelity (79%) were good, with fair overall feasibility (53% of intervention participants and 58% of coaches), at low cost. No differences in adverse events between study arms were found., Interpretation: A coach-supported mHealth intervention is modestly effective in reducing dementia risk factors in those with low socioeconomic status in the UK and any socioeconomic status in China. Implementation is challenging in these populations, but those reached actively participated. Whether this intervention will result in less cognitive decline and dementia requires a larger RCT with long follow-up., Funding: EU Horizon 2020 Research and Innovation Programme and the National Key R&D Programmes of China., Translation: For the Mandarin translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests AW received research grants from EU IMI2 (MOPEAD), JPND (ADDITION, EURO-FINGER, PMI-AD), IHI (PROMINENT), and the Swedish VINNOVA program (PREDEM)(all paid to institution) and is licence holder of RUD-instrument (in part); outside the submitted work. RH received research grants from JPND, ZonMW, IMI, H2020 (paid to institution); received consulting fees from Lilly Nederland, iMTA, Biogen Nederlands, Biogen MA, Eisai (paid to institution); is a member of ISPOR special interest group open-source models, IPECAD modelling group and Alzheimer Europe Expert Advisory Panel (unpaid); outside the submitted work. SA received grants from EU (Institutional grant [Horizon 2020 Research and Innovation Programme agreement 779238]); Region Occitanie/Pyrénées-Méditerranée (1901175); the European Regional Development Fund (MP0022856); MSD Avenir Inspire Chairs of Excellence (Alzheimer Prevention in Occitania and Catalonia, EDENIS, KORIAN, Pfizer, and Pierre-Fabre); AXA Personal (current); Biogen Personal (2022); Roche Personal (2021); Leventis foundation (2022); ADI (2022); and has a leadership role in the French Alzheimer association (Scientific Committee); outside the submitted work. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The clinical meaningfulness of the effects of recently approved disease-modifying treatments (DMT) in Alzheimer's disease is under debate. Available evidence is limited to short-term effects on clinical rating scales which may be difficult to interpret and have limited intrinsic meaning to patients. The main value of DMTs accrues over the long term as they are expected to cause a delay or slowing of disease progression. While awaiting such evidence, the translation of short-term effects to time delays or slowing of progression could offer a powerful and readily interpretable representation of clinical outcomes., Methods: We simulated disease progression trajectories representing two arms, active and placebo, of a hypothetical clinical trial of a DMT. The placebo arm was simulated based on estimated mean trajectories of clinical dementia rating scale-sum of boxes (CDR-SB) recordings from amyloid-positive subjects with mild cognitive impairment (MCI) from Alzheimer's Disease Neuroimaging Initiative (ADNI). The active arm was simulated to show an average slowing of disease progression versus placebo of 20% at each visit. The treatment effects in the simulated trials were estimated with a progression model for repeated measures (PMRM) and a mixed model for repeated measures (MMRM) for comparison. For PMRM, the treatment effect is expressed in units of time (e.g., days) and for MMRM in units of the outcome (e.g., CDR-SB points). PMRM results were implemented in a health economics Markov model extrapolating disease progression and death over 15 years., Results: The PMRM model estimated a 19% delay in disease progression at 18 months and 20% (~ 7 months delay) at 36 months, while the MMRM model estimated a 25% reduction in CDR-SB (~ 0.5 points) at 36 months. The PMRM model had slightly greater power compared to MMRM. The health economic model based on the estimated time delay suggested an increase in life expectancy (10 months) without extending time in severe stages of disease., Conclusion: PMRM methods can be used to estimate treatment effects in terms of slowing of progression which translates to time metrics that can be readily interpreted and appreciated as meaningful outcomes for patients, care partners, and health care practitioners., (© 2024. The Author(s).)

Background: Nursing home placement (NHP) can be the final step of patients with Alzheimer's disease., Objective: We aimed to identify NHP predictors among 508 people with dementia with a 3-year follow-up., Methods: We analyzed data from the international observational RECage study, involving 508 people with especially Alzheimer's disease and comparing a cohort enrolled by five centers with a Special Care Unit for BPSD (behavioral and psychological symptoms of dementia) and another one enrolled by six centers lacking this facility. The tertiary objective of the study was to assess the possible role of the SCU-B in delaying NHP. We assessed the relationship of the baseline characteristics with NHP by means of univariate analysis followed by Cox's multivariate model., Results: Patients' mean age was 78.1 years, 54.9% were women. Diagnosis mean age was 75.4 (±8.32) years; the main diagnosis was Alzheimer's disease (296; 58.4%). During follow-up, 96 (18.9%) patients died and 153 (30.1%) were institutionalized without a statistically significant difference between the two cohorts (p = 0.9626). The mean NHP time was 902 (95% CI: 870-934). The multivariable analysis without death as a competing risk retained four independent predictors of NHP: age increase (hazard ratio (HR) = 1.023, 95% CI: 1.000-1.046), patient education level increase (HR = 1.062, 95% CI: 1.024-1.101), Neuropsychiatric Inventory total increase (HR = 1.018; 95% CI: 1.011-1.026), and total Mini-Mental State Examination as a favorable factor (HR = 0.948, 95% CI: 0.925-0.971). Gender (females versus males: HR = 1.265, 95% CI: 0.899-1.781) was included in the final Cox's model for adjusting the estimates for., Conclusions: Our data partially agree with the predictors of NHP in literature including the effect of high education level. No caregivers' factors were statistically significant., Clinical Trial Registration: NCT03507504.

Background: Health-related quality of life (HR-QoL) is an important outcome for patients and crucial for demonstrating the value of new treatments. Health utility estimates in subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are limited, especially in biomarker-confirmed populations. Besides, little is known about the longitudinal HR-QoL trajectory. This study aims to provide health utility estimates for SCD and MCI and investigate the QoL trajectory along the disease continuum., Methods: Longitudinal data from 919 SCD and 1336 MCI patients from the MEMENTO cohort were included. SCD was defined as clinical dementia rating (CDR) = 0, and MCI as CDR = 0.5. HR-QoL was measured using the EQ-5D-3L patient-reported instrument. Linear mixed-effect models (LMM) were used to assess the longitudinal change in HR-QoL and identify predictors of these changes., Results: Baseline health utilities were 0.84 ± 0.16 and 0.81 ± 0.18, and visual analogue scale (VAS) were 75.8 ± 14.82 and 70.26 ± 15.77 in SCD and MCI. In amyloid-confirmed cases, health utilities were 0.85 ± 0.14 and 0.86 ± 0.12 in amyloid-negative and amyloid-positive SCD, and 0.83 ± 0.17 and 0.84 ± 0.16 in amyloid-negative and amyloid-positive MCI. LMM revealed an annual decline in health utility of - 0.015 (SE = 0.006) and - 0.09 (SE = 0.04) in moderate and severe dementia (P < 0.05). There was a negative association between clinical stage and VAS where individuals with MCI, mild, moderate, and severe dementia were on average 1.695 (SE = 0.274), 4.401 (SE = 0.676), 4.999 (SE = 0.8), and 15.386 (SE = 3.142) VAS points lower than individuals with SCD (P < 0.001). Older age, female sex, higher body mass index, diabetes, cardiovascular history, depression, and functional impairment were associated with poor HR-QoL. Amyloid positivity was associated with an annual decline of - 0.011 (SE = 0.004, P < 0.05) health utility over time., Conclusions: Health utility estimates from this study can be used in economic evaluations of interventions targeting SCD and MCI. Health utility declines over time in moderate and severe dementia, and VAS declines with advancing clinical stages. Amyloid-positive patients show a faster decline in health utility indicating the importance of considering biomarker status in HR-QoL assessments. Future research is needed to confirm the longitudinal relationship between amyloid status and HR-QoL and to examine the level at which depression and IADL contribute to HR-QoL decline in AD., (© 2023. The Author(s).)

Objectives: The aim of the current study was to investigate the health-related quality of life (HRQol) of the family caregiver in MCI, explore possible determinants and study possible differences with mild dementia., Methods: This secondary data analysis included 145 persons with MCI and 154 persons with dementia and their family caregivers from two Dutch cohort studies. HRQoL was measured with the VAS of the EuroQol-5D-3L version. Regressions analyses were conducted to examine potential demographic and clinical determinants of the caregiver's HRQoL., Results: The mean EQ5D-VAS in family caregivers of persons with MCI was 81.1 (SD 15.7), and did not significantly differ from family caregivers in mild dementia (81.9 (SD 13.0)). In MCI, patient measurements were not significantly associated with caregiver mean EQ5D-VAS. Concerning caregiver characteristics, being a spouse and a lower educational level were associated with a lower mean EQ5D-VAS (in a multiple linear regression model: unstandardized B -8.075, p  = 0.013 and unstandardized B -6.162, p  = 0.037 resp.). In mild dementia, the NPI item irritability showed an association with caregiver EQ5D-VAS in bivariate linear regression analyses., Conclusion: Results indicate that especially family caregiver characteristics seem to influence family caregiver HRQoL in MCI. Future research should include other potential determinants such as burden, coping strategies and relationship quality.

Objective: Behavioral and psychological symptoms of dementia (BPSD) profiles vary depending on etiology in patients with mild-to-moderate BPSD. It is not known if similar differences exist in patients with severe BPSD., Methods: We analyzed data collected at baseline in 398 patients with severe BPSD (NPI ≥ 32) and defined diagnosis of dementia (Alzheimer's disease [AD] 297; frontotemporal dementia [FTD] 39; Lewy body disease/Parkinsonian dementia [LBD/PD] 31; and vascular dementia [VD] 31) included in the European multicenter cohort RECAGE., Results: Mean total NPI was 52.11 (18.55). LBD/PD patients demonstrated more hallucinations, more anxiety and more delusions than patients with other dementia. FTD patients had less delusions and more disinhibition than patients with other neurodegenerative disorders. These profiles overlapped partially with those reported in the literature in patients with less severe symptoms., Conclusion: Patients with severe BPSD display different and specific profiles of neuropsychiatric symptoms depending on dementia etiology., (Copyright © 2023 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: Early health-technology assessment can support discussing scarce resource allocation among stakeholders. We explored the value of maintaining cognition in patients with mild cognitive impairment (MCI) by estimating: (1) the innovation headroom and (2) the potential cost effectiveness of roflumilast treatment in this population., Methods: The innovation headroom was operationalized by a fictive 100% efficacious treatment effect, and the roflumilast effect on memory word learning test was assumed to be associated with 7% relative risk reduction of dementia onset. Both were compared to Dutch setting usual care using the adapted International Pharmaco-Economic Collaboration on Alzheimer's Disease (IPECAD) open-source model., Results: The total innovation headroom expressed as net health benefit was 4.2 (95% bootstrap interval: 2.9-5.7) quality-adjusted life years (QALYs). The potential cost effectiveness of roflumilast was k€34 per QALY., Discussion: The innovation headroom in MCI is substantial. Although the potential cost effectiveness of roflumilast treatment is uncertain, further research on its effect on dementia onset is likely valuable., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Informal caregivers of people with dementia are crucial in dementia care. However, they are insufficiently supported and report caregiver burdens, which urges the need for cost-effective interventions aimed at supporting caregivers. This paper presents the design of a study evaluating the effectiveness, cost-effectiveness, and cost-utility of a blended self-management program for early-stage dementia caregivers., Methods/design: A pragmatic, cluster randomized controlled trial with a shared control group will be conducted. Participants will be informal caregivers of people with early-stage dementia and will be recruited by local care professionals. Randomization will be carried out at the level of the care professional level in a ratio of 35% to 65% (control arm vs. intervention arm). Participants in the control arm will receive care as usual and the intervention arm will receive the blended care self-management program "Partner in Balance" within a usual care setting in the Netherlands. Data will be collected at baseline and at 3-, 6-, 12-, and 24-month follow-ups. The primary outcome for effectiveness (part 1) is care management self-efficacy. For the health-economic evaluation (part 2) total care costs and the quality of life for individuals with dementia (cost-effectiveness) and quality-adjusted life years (cost-utility) will be the base case analysis. Secondary outcomes (parts 1 and 2) will include depression, anxiety, perceived informal caregiving stress, service-use self-efficacy, quality of life, caregivers' gain, and perseverance time. A process evaluation (part 3) will investigate the internal and external validity of the intervention., Discussion: In this trial, we plan to evaluate the effectiveness, cost-effectiveness, and cost-utility of "Partner in Balance" among informal caregivers of people with dementia. We expect to find a significant increase in care management self-efficacy, and the program to be cost-effective, and provide valuable insights to stakeholders of "Partner in Balance.", Trial Registration: ClinicalTrials.gov, NCT05450146. Registered on 4 November 2022., (© 2023. The Author(s).)

Lecanemab, an anti-amyloid antibody with effects on biomarker and clinical endpoints in early Alzheimer's Disease (AD), was granted accelerated approval by the FDA in 2023 and regulatory review in Europe is ongoing. We estimate the population potentially eligible for treatment with lecanemab in the 27 EU countries to 5.4 million individuals. Treatment costs would exceed 133 billion EUR per year if the drug is priced similarly as in the United States, amounting to over half of the total pharmaceutical expenditures in the EU. This pricing would be unsustainable; the ability to pay for high-priced therapies varies substantially across countries. Pricing similarly to what has been announced for the United States may place the drug out of reach for patients in some European countries. Disparities in access to novel amyloid-targeting agents may further deepen the inequalities across Europe in health outcomes. As representatives of the European Alzheimer's Disease Consortium Executive Committee, we call for pricing policies that allow eligible patients across Europe to access important innovations, but also continued investments in research and development. Infrastructure to follow up the usage of new therapies in routine care and new payment models may be needed to address affordability and inequalities in patient access., Competing Interests: No specific funding was received for the preparation of this manuscript. Authors have completed separate CoI forms. The authors declare the following Conflicts of Interest: LJ received research grants (paid to institution) by Vinnova, FORTE and Novo Nordisk, license fees for the RUD instrument paid to European Health Economics, advisory board honorarium from Laboratoires Servier, travel support from BioArctic AB. AW received grants from Vinnova and EU (PREDEM, MOPEAD, PRODEMOS, EURO-FINGER, PROMINENT, PMI-AD, ADDITION, paid to institution), and is a license holder of the RUD instrument. Member of MSAP for ADI (un-paid). RH received research grants from JPND, ZonMW, IMI, H2020 (paid to institution), consulting fees from Lilly Nederland, iMTA, Biogen Nederlands, Biogen MA Inc, Eisai Inc (paid to institution), member of ISPOR modeling SIG and IPECAD modeling group (un-paid). MB is Member of the Advisory Boards Grifols, Roche, Lilly, Araclon Biotech, Merck, Zambon, Biogen, Novo- Nordisk, Bioiberica, Eisai, Servier, Schwabe Pharma. SE received research grants from Interreg Vlaanderen-Nederland, Research Foundation Flanders (FWO), VLAIO, GSKE/FMRE (paid to institution), consulting fees from Icometrix, Novartis, Eisai (paid to institution), personal consulting fees from Roche and Biogen, personal honoraria from Eisai, Roche, travel support to institution from Biogen, Patent EP3452830B1 (institution), member of SMB/SAB for EU-H2020 project RECAGE. VP of Belgian Dementia Council (unpaid). LF received grants from EU (RADAR-AD, RECAGE, FRAILBRAIN, paid to institution), personal consulting fees from Biogen, Eisai, Grifols, Hummingbird, Infecto-Pharm, Janssen-Cilag, MSD, Neurimmune, Functional Neuromodulation, Noselab, NovoNordisk, Roche, TauRX, Schwabe, lecture honoraria from Hoffmann-LaRoche and Schwabe, personal advisory board honorarium from Avanir/Otsuka, Pharmatropix, FZ Jülich, Charité Berlin, Neuroscios, reMYND, Vivoryon. FJ received personal consulting fees and lecture honoraria from Eisai, Biogen, Lilly, and personal honoraria for participation in advisory board from AC Immune. PJO received grants from Alector, Alzheon, Araclon Biotech, Biogen, Avanir Pharmaceuticals, Cortexyme, Eisai, Eli Lilly, Green Valley Pharmaceutical, Hoffman-La Roche, Janssen, Novartis Pharmaceuticals, NovoNordisk, TauRx, UCB Biopharma (paid to institution). NS received grants from EU (EPAD) and NovoNordisk (paid to institution). Personal fee as member of SAB from Albert Einstein College of Medicine – NIH funded. PJV received grants from EU (AMYPAD, RADAR-AD, EPND), Zon-MW, Biogen, Amyloid biomarker study (paid to institution), honoraria from workshop grant writing by Stiftung Synapsis, Alzheimer Forschung Schweiz. Patent holder (PCT/NL2020/050216) on AD subtypes (all paid to institution). GW received research grant from Danish Ministry of Health (paid to institution). BW received personal honorarium for a 2 h meeting with BioArctic, member of SMB for Alzinova, member of SAB for Resverlogix, stocks in AlzeCure pharma. GJ, PK, MK and AM declare no conflicts of interest., (© 2023 The Author(s).)

Introduction: The aim of this study was to estimate the potential cost-effectiveness of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) program., Methods: A life-time Markov model with societal perspective, simulating a cohort of people at risk of dementia reflecting usual care and the FINGER program., Results: Costs were 1,653,275 and 1,635,346 SEK and quality-adjusted life years (QALYs) were 8.636 and 8.679 for usual care and the FINGER program, respectively, resulting in savings of 16,928 SEK (2023 US$) and 0.043 QALY gains per person, supporting extended dominance for the FINGER program. A total of 1623 dementia cases were avoided with 0.17 fewer person-years living with dementia. The sensitivity analysis confirmed the conclusions in most scenarios., Discussion: The model provides support that programs like FINGER have the potential to be cost-effective in preventing dementia. Results at the individual level are rather modest, but the societal benefits can be substantial because of the large potential target population., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Behavioral and psychological symptoms of dementia (BPSD) bring complexity in the clinical management of people with dementia; therefore, it is important to evaluate different models of care, such as Special Care Units (SCU-B).∥Objective:To evaluate the SCU-B effectiveness toward alleviating BPSD and improving the quality of life (QoL) of patients and their caregivers.∥Methods:ReCAGE was a multicenter, controlled, longitudinal study where 508 patients with BPSD were enrolled in two cohorts: 262 patients from centers endowed with a SCU-B, and 246 from centers without SCU-B. Statistical analyses included factorial ANCOVA for comparison among centers. The primary endpoint was effectiveness of the SCU-B, measured through the Neuropsychiatric Inventory (NPI) changes. Secondary endpoints were change in QoL of patients and caregivers, and the tertiary endpoint was time to nursing home admission.∥Results:The NPI scores decreased in both arms, with a statistically significant difference from baseline to 36 months (p < 0.0001) in both cohorts. Over time, NPI decreased more steeply during the first year in the SCU-B arm, but in the following two years the slope was clearly in favor of the control arm. This different pattern of the two cohorts reached statistical significance at the interaction "cohort by time" (p < 0.0001). Conflicting results were found regarding the outcomes of quality of life, while there were no differences in time to institutionalization in both cohorts.∥Conclusion:The RECage study did not confirm the long-term superiority of the pathway comprising a SCU-B. A post-hoc analysis revealed data supporting their acute effectiveness during behavioral crises.

The increasing global prevalence of dementia demands concrete actions that are aimed strategically at optimizing processes that drive clinical innovation. The first step in this direction requires outlining hurdles in the transition from research to practice. The different parties needed to support translational processes have communication mismatches; methodological gaps hamper evidence-based decision-making; and data are insufficient to provide reliable estimates of long-term health benefits and costs in decisional models. Pilot projects are tackling some of these gaps, but appropriate methods often still need to be devised or adapted to the dementia field. A consistent implementation perspective along the whole translational continuum, explicitly defined and shared among the relevant stakeholders, should overcome the "research-versus-adoption" dichotomy, and tackle the implementation cliff early on. Concrete next steps may consist of providing tools that support the effective participation of heterogeneous stakeholders and agreeing on a definition of clinical significance that facilitates the selection of proper outcome measures., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The successful development of an economic model for the evaluation of future Alzheimer's disease (AD) interventions is critical to accurately inform policy makers and payers. As our understanding of AD expands, this becomes an increasingly complex and challenging goal. Advances in diagnostic techniques for AD and the prospect of disease-modifying treatments raise an urgent need to define specifications for future economic models and to ensure that the necessary data to populate them are available. This Perspective article provides expert opinions from health economists and governmental agency representatives on how future economic models for AD might be structured, validated, and reported. We aim to stimulate much-needed discussion about the detailed specification of future health economic models for AD., Competing Interests: Filipa Landeiro has been funded by a grant from Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 116020 (ROADMAP). Jasmine Morton: none exist. Anders Gustavsson is a partner of Quantify Research, providing consultancy services to pharmaceutical companies and other private and public organizations and institutions. AG's contribution to ROADMAP was on behalf of Roche Pharmaceuticals. Michele Potashman is an employee of Biogen and owns stock in Biogen. She owns stock in a variety of companies that at times include other pharmaceutical and health care–related companies. Pascal Lecomte is employed by, owns stock in, and has stock options in Novartis Pharma AG. Mark Belger is a full‐time employee and shareholder of Eli Lilly and Company. Robin Thompson is an employee of Biogen and owns stock in Biogen. Emilse Roncancio‐Diaz is employed by GE Healthcare. Gurleen Jhuti is employed by F. Hoffmann‐La Roche Ltd. Christopher Butler: none exist. Linus Jönsson is employed by H. Lundbeck A/S. Ron Handels has received grants from ROADMAP (Innovative Medicines Initiative 2 Joint Undertaking 2016‐2018); consulting fees from Piramal, Roche, and Eisai; grants from Horizon 2020, JPND Joint Programming Neurodegenerative Disease Research, IMI Innovative Medicines Initiative, and national, European and patient charity funding organizations and private–public collaborations (ZonMw Netherlands; Alzheimer Netherlands; Dutch Flutemetamol Study; Alzheimer Research UK; Swedish National study on Aging and Care; European Brain Council). Alastair M. Gray has received a grant from Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 116020 (ROADMAP). A.M.G. is partially supported by the National Institute for Health Research Biomedical Research Centre at the University of Oxford (grant number NIHR‐BRC‐1215‐20008). Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Quality of life (QoL) is an important outcome from the perspective of patients and their caregivers, in both dementia and pre-dementia stages. Yet, little is known about the long-term changes in QoL over time. We aimed to compare the trajectories of QoL between amyloid-positive and amyloid-negative SCD or MCI patients and to evaluate QoL trajectories along the Alzheimer's disease (AD) continuum of cognitively normal to dementia., Methods: We included longitudinal data of 447 subjective cognitive decline (SCD), 276 mild cognitive impairment (MCI), and 417 AD dementia patients from the Amsterdam Dementia Cohort. We compared QoL trajectories (EQ-5D and visual analog scale (VAS)) between (1) amyloid-positive and amyloid-negative SCD or MCI patients and (2) amyloid-positive SCD, MCI, and dementia patients with linear mixed-effect models. The models were adjusted for age, sex, Charlson Comorbidity Index (CCI), education, and EQ-5D scale (3 or 5 level)., Results: In SCD, amyloid-positive participants had a higher VAS at baseline but showed a steeper decline over time in EQ-5D and VAS than amyloid-negative participants. Also, in MCI, amyloid-positive patients had higher QoL at baseline but subsequently showed a steeper decline in QoL over time compared to amyloid-negative patients. When we compared amyloid-positive patients along the Alzheimer continuum, we found no difference between SCD, MCI, or dementia in baseline QoL, but QoL decreased at a faster rate in the dementia stage compared with the of SCD and MCI stages., Conclusions: QoL decreased at a faster rate over time in amyloid-positive SCD or MCI patients than amyloid-negative patients. QoL decreases over time along the entire AD continuum of SCD, MCI and dementia, with the strongest decrease in dementia patients. Knowledge of QoL trajectories is essential for the future evaluation of treatments in AD., (© 2022. The Author(s).)

Importance: One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design., Objective: To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates., Design, Setting, and Participants: This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria., Exposures: Alzheimer disease biomarkers detected on PET or in CSF., Main Outcomes and Measures: Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations., Results: Among the 19 097 participants (mean [SD] age, 69.1 [9.8] years; 10 148 women [53.1%]) included, 10 139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P = .04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P = .004), subjective cognitive decline (9%; 95% CI, 3%-15%; P = .005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P = .004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P = .18)., Conclusions and Relevance: This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.

Background: Disease modifying treatments (DMTs) currently under development for Alzheimer's disease, have the potential to prevent or postpone institutionalization and more expensive care and might delay institutionalization of persons with dementia., Objective: The current study estimates costs of living in a nursing home for persons with dementia in the Netherlands to help inform economic evaluations of future DMTs., Methods: Data were collected during semi-structured interviews with healthcare professionals and from the financial administration of a healthcare organization with several nursing homes. Personnel costs were calculated using a bottom-up approach by valuing the time estimates. Non-personnel costs were calculated using information from the financial administration of the healthcare organization., Results: Total costs of a person with dementia per 24 hours, including both care staff and other healthcare providers, were € 151 for small-scale living wards and € 147 for independent living wards. Non-personnel costs were € 37 per day., Conclusion: This study provides Dutch estimates for total healthcare costs per day for institutionalized persons with dementia. These cost estimates can be used in cost-effectiveness analyses for future DMTs in dementia.

Introduction: Researchers, policy-makers and healthcare professionals often stress the importance of an early dementia diagnosis. Empirical evidence, however, is scarce leading to a lack of consensus on the necessity of diagnosing dementia early. We emphasise the need for a 'timely' diagnosis, that is, one that occurs at the right moment for a person with memory complaints and his/her significant other. As the optimal timing differs between individuals, the implementation of shared decision making (SDM), preferably by the general practitioner (GP), as the start of a diagnostic trajectory, could help to determine this timely moment. SDM, however, is rarely practised with respect to dementia diagnoses. Therefore, in the context of the Shared Decision-Making regarding Dementia Diagnosis project, a patient decision aid (PtDA) for 'timely' dementia diagnosis in general practice will be developed. This protocol will describe the planned before and after evaluation of its implementation., Methods and Analysis: In a mixed-methods pilot study, we will investigate decision-making processes and experiences regarding a diagnostic trajectory before and after the introduction of a PtDA for people with memory complaints, their significant others and their GPs. The 'before group' will receive diagnostics as usual from their GPs. The 'after group' will use the PtDA. We expect the PtDA to increase the level of SDM and to contribute to a timely and personalised diagnostic trajectory. Data will be collected using semistructured interviews, questionnaires and information retrieved from people with memory complaints' medical records., Ethics and Dissemination: This study protocol was approved by the Medical Review Ethics Committee of the Maastricht University Medical Centre. The findings will be published in peer-reviewed international journals and presented at conferences. This study was funded by the public funded Dutch Research Institute for Care and Medical Sciences (ZonMw)., Trial Registration Number: NCT04531956., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Profiles of high risk for future dementia are well understood and are likely to concern mostly those in low-income and middle-income countries and people at greater disadvantage in high-income countries. Approximately 30%-40% of dementia cases have been estimated to be attributed to modifiable risk factors, including hypertension, smoking and sedentary lifestyle. Tailored interventions targeting these risk factors can potentially prevent or delay the onset of dementia. Mobile health (mHealth) improves accessibility of such prevention strategies in hard-to-reach populations while at the same time tailoring such approaches. In the current study, we will investigate the effectiveness and implementation of a coach-supported mHealth intervention, targeting dementia risk factors, to reduce dementia risk., Methods and Analysis: The prevention of dementia using mobile phone applications (PRODEMOS) randomised controlled trial will follow an effectiveness-implementation hybrid design, taking place in the UK and China. People are eligible if they are 55-75 years old, of low socioeconomic status (UK) or from the general population (China); have ≥2 dementia risk factors; and own a smartphone. 2400 participants will be randomised to either a coach-supported, interactive mHealth platform, facilitating self-management of dementia risk factors, or a static control platform. The intervention and follow-up period will be 18 months. The primary effectiveness outcome is change in the previously validated Cardiovascular Risk Factors, Ageing and Incidence of Dementia dementia risk score. The main secondary outcomes include improvement of individual risk factors and cost-effectiveness. Implementation outcomes include acceptability, adoption, feasibility and sustainability of the intervention., Ethics and Dissemination: The PRODEMOS trial is sponsored in the UK by the University of Cambridge and is granted ethical approval by the London-Brighton and Sussex Research Ethics Committee (reference: 20/LO/01440). In China, the trial is approved by the medical ethics committees of Capital Medical University, Beijing Tiantan Hospital, Beijing Geriatric Hospital, Chinese People's Liberation Army General Hospital, Taishan Medical University and Xuanwu Hospital. Results will be published in a peer-reviewed journal., Trial Registration Number: ISRCTN15986016., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: The capability concept became a recognized approach to the measurement of quality of life. The ICECAP-O for older people aims to measure capabilities and has recently been used in people with dementia (self-rating) and informal carers (substituted judgement). However, linguistic validation studies have so far been lacking., Methods: A cross-sectional cognitive interview study with 15 people with dementia (PwD) and 23 informal carers (ICs) was conducted in Germany and Portugal. Respondents were asked to reveal their understanding of the ICECAP-O and the capability approach as well as the response process. A summarising content analysis was performed., Results: Despite the small sample, our linguistic validation of the German and Portuguese translations detected considerable difficulties or deviations in item comprehension when compared with the intended meaning. In some cases, the item interpretations did not reflect the entire scope of the associated capability dimension, though they were basically correct. Moreover, participants were not able to differentiate some items appropriately from one another, and some misinterpretations occurred. ICs relied mainly on observable behaviour, emotions, or verbal expressions of the PwD. Therefore, ICs found items that ask about the achievement of individual expectations or thoughts about the future difficult to assess. Only very few PwD clearly indicated that they understood the capability approach. ICs in Germany had more difficulties in understanding the capability concept than in ICs Portugal., Discussion: This linguistic validation study in Germany and Portugal indicates a need for some rephrasing and refinements of the ICECAP-O translated items in both countries to fully encompass some dimensions and avoid misinterpretations. Further studies with larger samples are necessary. Based on our findings, the current German version for ICs' substituted judgement cannot be recommended for this kind of respondents without further advancements., (Copyright © 2021. Published by Elsevier GmbH.)

Purpose: The Quality of Life Alzheimer's Disease Scale (QoL-AD) is commonly used to assess disease specific health-related quality of life (HRQoL) as rated by patients and their carers. For cost-effectiveness analyses, utilities based on the EQ-5D are often required. We report a new mapping algorithm to obtain EQ-5D indices when only QoL-AD data are available., Methods: Different statistical models to estimate utility directly, or responses to individual EQ-5D questions (response mapping) from QoL-AD, were trialled for patient-rated and proxy-rated questionnaires. Model performance was assessed by root mean square error and mean absolute error., Results: The response model using multinomial regression including age and sex, performed best in both the estimation dataset and an independent dataset., Conclusions: The recommended mapping algorithm allows researchers for the first time to estimate EQ-5D values from QoL-AD data, enabling cost-utility analyses using datasets where the QoL-AD but no utility measures were collected.

Objectives: To estimate (1) the duration of no formal care, home care, and institutional care after dementia diagnosis, and (2) the effect of age, sex, living situation, dementia medication, migration background, and income on this dementia care duration., Design: Longitudinal retrospective study using routinely recorded general practice electronic health records linked with population-based healthcare and mortality data., Setting and Participants: In total, 11,012 community-dwelling persons who received an incident dementia diagnosis and were listed in a Dutch general practitioner database from 448 general practices in the Netherlands., Methods: Using multistate modeling analyses, we estimated the mean duration of care types (no/home/institutional care) for different ages based on simulations of transition rates and examined the influence of demographic and clinical factors on these durations., Results: From dementia diagnosis onward in 85-year-old men, the mean duration without formal care was 0.7 years, of home care 1.7, and institutional care 1.1 years. In 85-year-old women, the duration without formal care was 0.8 years, of home care 2.3, and institutional care 2.3 years. Total care duration was 3.5 years in 85-year-old men and 5.4 years in 85-year-old women. In men, the duration of home care was longer compared with no formal care and institutional care. The duration of no formal care was longer in persons not living alone, without prescribed dementia medication, with a non‒Western migration background, or with a higher income. The duration of home or institutional care was longer in women, persons without polypharmacy, in those living alone, or those with a Western background., Conclusions and Implications: Our findings help to increase understanding of long-term dementia care trajectories and show that demographic and clinical factors determine the duration of care types. Our results can contribute to the organization of healthcare resource planning and monitoring of the effects of healthcare policy and interventions., (Copyright © 2020 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Loss to follow-up in dementia studies is common and related to cognition, which worsens over time. We aimed to (1) describe dropout and missing cognitive data in the Swedish dementia registry, SveDem; (2) identify factors associated with dropout; and (3) estimate propensity scores and use them to adjust for dropout., Methods: Longitudinal cognitive data were obtained from 53,880 persons from the SveDem national quality dementia registry. Inverse probability of censoring weights (IPCWs) were estimated using a logistic regression model on dropout., Results: The mean annualized rate of change in Mini-Mental State Examination (MMSE) in those with a low MMSE (0 to 10) was likely underestimated in the complete case analysis (+1.5 points/year) versus the IPCW analysis (-0.3 points/year)., Discussion: Handling dropout by IPCWs resulted in plausible estimates of cognitive decline. This method is likely of value to adjust for biased dropout in longitudinal cohorts of dementia., (© 2019 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Objectives: Previously developed dementia caregiver profiles defined by caregiver age and burden, have been associated with caregiver quality of life, depression and perseverance time. The current aim was to investigate whether these caregiver profiles could predict subsequent service use. In addition, non-personal (e.g. meals on wheels) and supportive services (e.g. Alzheimer café) in early dementia were investigated as predictors. Methods: A total of 451 dyads of people with dementia and their informal caregivers from eight European countries were followed for one year. People were included if they did not use formal (personal) care but were expected to do so within 1 year. Logistic regression analyses were used with four clusters of service use as dependent variables (home social care, home personal care, day care and admission). The independent variables were caregiver profiles, and non-personal and supportive services at baseline. Results: Caregiver profiles were significant predictors of service use; those experiencing high strain were more likely to use formal care. The use of low-intensity, less intrusive services at baseline significantly predicted the use of home personal care and admission at follow-up. The use of day care at follow-up was predicted by the baseline use of supportive services. Conclusion: Caregiver profiles are valuable predictors for service use: this knowledge can aid professionals in ensuring optimal access to services, which is important for maintaining independence at home. In addition, the use of supportive and less intrusive, non-personal services in the early stages of dementia is to be advised.

Background: A long-term horizon is necessary when the socioeconomic consequences and the potential effects of interventions in Alzheimer's disease (AD) are estimated., Objectives: To illustrate the potential societal costs of AD across the disease continuum and to illustrate the potential cost-effectiveness of a hypothetical intervention with disease modifying treatment (DMT)., Methods: Based on the Swedish dementia registry, a Markov model was used to simulate a virtual cohort of 100,000 people with mild cognitive impairment (MCI) due to AD (AD-MCI) in Sweden for 40 years starting at the age of 60. A simulated hypothetical intervention assumed a 25% reduction in progression rate during AD-MCI and mild AD-dementia. A comprehensive set of sensitivity analyses was included., Results: The cumulative risk to develop dementia was 96%. The mean simulated survival was 19.0 years. The net present value for a person year with dementia was 252,843 SEK (about 29,500 US$). The cost effectiveness model illustrated how the hypothetical scenario of a 25% reduction in progression to AD-dementia would require 41 AD-MCI patients to be treated to prevent one case of AD-dementia (2,447 avoided AD-dementia cases of 100,000 with AD-MCI). Most scenarios illustrated hypothetical cost effectiveness (based on a willingness to pay level of 600,000 SEK (70,000 US$) per gained QALY), but not cost savings., Discussion: Lifetime societal costs of AD are substantial. A future DMT may be potentially cost-effective given assumed treatment effects and costs, but cost savings are unlikely.

Objectives: In the current study, the Anderson model is used to determine equitable access to dementia care in Europe. Predisposing, enabling, and need variables were investigated to find out whether there is equitable access to dementia-specific formal care services. Results can identify which specific factors should be a target to improve access., Methods: A total of 451 People with middle-stage dementia and their informal carers from eight European countries were included. At baseline, there was no use of formal care yet, but people were expected to start using formal care within the next year. Logistic regressions were carried out with one of four clusters of service use as dependent variables (home social care, home personal care, day care, admission). The independent variables (predisposing, enabling, and need variables) were added to the regression in blocks., Results: The most significant predictors for the different care clusters are disease severity, a higher sum of (un)met needs, hours spent on informal care, living alone, age, region of residence, and gender., Conclusion: The Andersen model provided for this cohort the insight that (besides need factors) the predisposing variables region of residence, gender, and age do play a role in finding access to care. In addition, it showed us that the numbers of hours spent on informal care, living alone, needs, and disease severity are also important predictors within the model's framework. Health care professionals should pay attention to these predisposing factors to ensure that they do not become barriers for those in need for care., (© 2019 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Introduction: We develop a framework to model disease progression across Alzheimer's disease (AD) and to assess the cost-effectiveness of future disease-modifying therapies (DMTs) for people with mild cognitive impairment (MCI) due to AD., Methods: Using data from the US National Alzheimer's Coordinating Center, we apply survival analysis to estimate transition from predementia to AD dementia and ordered probit regression to estimate transitions across AD dementia stages. We investigate the cost-effectiveness of a hypothetical treatment scenario for people in MCI due to AD., Results: We present an open-access model-based decision-analytic framework. Assuming a modest DMT treatment effect in MCI, we predict extended life expectancy and a reduction in time with AD dementia., Discussion: Any future DMT for AD is expected to pose significant economic challenges across all health-care systems, and decision-analytic modeling will be required to assess costs and outcomes. Further developments are needed to inform these health policy considerations., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)