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Objectives: The implementation of disease-modifying treatments for Alzheimer's Disease (AD) will require cost-effective diagnostic processes. As part of The Precision Medicine In AD consortium (PMI-AD) project, the aim is to analyze the baseline costs of diagnosing early AD at memory clinics in Norway, Slovenia, and the Netherlands., Methods: The costs of cognitive testing and a clinical examination, apolipoprotein E, magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), positron emission tomography and blood-based biomarkers (BBM), which are used in different combinations in the three countries, were analyzed. Standardized unit costs, adjusted for GDP per capita and based on Swedish conditions were applied. The costs were expressed in euros (€) as of 2019. A diagnostic set comprising clinical examination, cognitive testing, MRI and CSF was defined as the gold standard, with MRI mainly used as an exclusion filter., Results: Cost data were available for 994 persons in Norway, 169 in Slovenia and 1015 in the Netherlands. The mean diagnostic costs were 1478 (95% confidence interval 1433-1523) € in Norway, 851 (731-970) € in Slovenia and 1184 (1135-1232) € in the Netherlands. Norway had the highest unit costs but also the greatest use of tests. With a uniform diagnostic test set applied, the diagnostic costs were 1264 (1238-1291) €, in Norway, 843 (771-914) € in Slovenia and 1184 (1156-1213) € in the Netherlands. There were no major cost differences between the final set of diagnoses., Conclusions: The total costs for setting a diagnosis of AD varied somewhat in the three countries, depending on unit costs and use of tests. These costs are relatively low in comparison to the societal costs of AD., (© 2024 The Author(s). International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Background: The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) showed cognitive benefits from a multidomain lifestyle intervention in at-risk older people. The LipiDiDiet trial highlighted benefits of medical food in prodromal Alzheimer's disease (AD). However, the feasibility and impact of multimodal interventions combining lifestyle with medical food in prodromal AD is unclear., Methods: MIND-AD mini was a 6-month multinational (Sweden, Finland, Germany, France) proof-of-concept randomized controlled trial (RCT). Participants were 60-85 years old, had prodromal AD (International Working Group-1 criteria), and vascular/lifestyle risk factors. The parallel-group RCT had three arms: multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management and social stimulation); multimodal lifestyle intervention + medical food (Fortasyn Connect); and regular health advice/care (control). Participants were randomized 1:1:1 (computer-generated allocation at each site). Outcome evaluators were blinded to randomization. Primary outcome was feasibility of the multimodal intervention, evaluated by recruitment rate during a 6-month recruitment phase, overall adherence in each intervention arm, and 6-month retention rate. Successful adherence was pre-specified as attending ≥ 40% of sessions/domain in ≥ 2/4 domains (lifestyle intervention), and consuming ≥ 60% of the medical food (lifestyle intervention + medical food). The secondary outcomes included adherence/participation to each intervention component and overall adherence to healthy lifestyle changes, measured using a composite score for healthy lifestyle. Cognitive assessments were included as exploratory outcomes, e.g. Clinical Dementia Rating scale., Results: During September 2017-May 2019, 93 individuals were randomized (32 lifestyle intervention, 31 lifestyle + medical food, and 30 control group). Overall recruitment rate was 76.2% (64.8% during the first 6 months). Overall 6-month retention rate was 91.4% (lifestyle intervention 87.5%; lifestyle + medical food 90.3%; control 96.7%). Domain-specific adherence in the lifestyle intervention group was 71.9% to cognitive training, 78.1% exercise, 68.8% nutritional guidance, and 81.3% vascular risk management; and in the lifestyle + medical food group, 90.3% to cognitive training, 87.1% exercise, 80.7% nutritional guidance, 87.1% vascular risk management, and 87.1% medical food. Compared with control, both intervention arms showed healthy diet improvements (β Lifestyle×Time  = 1.11, P = 0.038; β Lifestyle+medical food×Time  = 1.43, P = 0.007); the lifestyle + medical food group also showed vascular risk reduction (P = 0.043) and less cognitive-functional decline (P < 0.05, exploratory analysis). There were 5 serious adverse events (control group: 1; lifestyle intervention: 3; lifestyle + medical food: 1) unrelated to interventions., Conclusions: The multidomain lifestyle intervention, alone or combined with medical food, had good feasibility and adherence in prodromal AD. Longer-term cognitive and other health benefits should be further investigated in a larger-scale trial., Trial Registration: ClinicalTrials.gov NCT03249688., (© 2024. The Author(s).)

The development of disease-modifying therapies (DMTs) for Alzheimer's disease (AD) has progressed over the last decade, and the first-ever therapies with potential to slow the progression of disease are approved in the United States. AD DMTs could provide life-changing opportunities for people living with this disease, as well as for their caregivers. They could also ease some of the immense societal and economic burden of dementia. However, AD DMTs also come with major challenges due to the large unmet medical need, high prevalence of AD, new costs related to diagnosis, treatment and monitoring, and uncertainty in the therapies' actual clinical value. This perspective article discusses, from the broad perspective of various health systems and stakeholders, how we can overcome these challenges and improve society's readiness for AD DMTs. We propose that innovative payment models such as performance-based payments, in combination with learning healthcare systems, could be the way forward to enable timely patient access to treatments, improve accuracy of cost-effectiveness evaluations and overcome budgetary barriers. Other important considerations include the need for identification of key drivers of patient value, the relevance of different economic perspectives (i.e. healthcare vs. societal) and ethical questions in terms of treatment eligibility criteria., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Introduction: Inferring the timeline from mild cognitive impairment (MCI) to severe dementia is pivotal for patients, clinicians, and researchers. Literature is sparse and often contains few patients. We aim to determine the time spent in MCI, mild-, moderate-, severe dementia, and institutionalization until death., Methods: Multistate modeling with Cox regression was used to obtain the sojourn time. Covariates were age at baseline, sex, amyloid status, and Alzheimer's disease (AD) or other dementia diagnosis. The sample included a register (SveDem) and memory clinics (Amsterdam Dementia Cohort and Memento)., Results: Using 80,543 patients, the sojourn time from clinically identified MCI to death across all patient groups ranged from 6.20 (95% confidence interval [CI]: 5.57-6.98) to 10.08 (8.94-12.18) years., Discussion: Generally, sojourn time was inversely associated with older age at baseline, males, and AD diagnosis. The results provide key estimates for researchers and clinicians to estimate prognosis., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

β-amyloid-targeting antibodies represent the first generation of effective causal treatment of Alzheimer's disease (AD) and can be considered historical research milestones. Their effect sizes, side effects, implementation challenges and costs, however, have stimulated debates about their overall value. In this position statement academic clinicians of the European Alzheimer's Disease Consortium (EADC) discuss the critical relevance of introducing these new treatments in clinical care now. Given the complexity of AD it is unlikely that molecular single-target treatments will achieve substantially larger effects than those seen with current β-amyloid-targeting antibodies. Larger effects will most likely only be achieved incrementally by continuous optimization of molecular approaches, patient selection and combinations therapies. To be successful in this regard, drug development must be informed by the use of innovative treatments in real world practice, because full understanding of all facets of novel treatments requires experience and data of real-world care beyond those of clinical trials. Regarding the antibodies under discussion we consider their effects meaningful and potential side effects manageable. We assume that the number of eventually treated patient will only be a fraction of all early AD patients due to narrow eligibility criteria and barriers of access. We strongly endorse the use of these new compound in clinical practice in selected patients with treatment documentation in registries. We understand this as a critical step in advancing the field of AD treatment, and in shaping the health care systems for the new area of molecular-targeted treatment of neurodegenerative diseases., Competing Interests: D. Aarsland reports personal fees for advice and lectures from Eisai, Biogen, Eli Lilly, EIP Pharma, Roche Diagnostics, Sanofi, and Heptares, and grants from Roche Diagnostics, Sanofi and Evonik. D. Angioni reports being an investigator in clinical trials sponsored by Alector, Alzheon, Biogen, Eisai, Genentech, Green Valley, Hoffmann-La Roche, Janssen, Medesis Pharma, Nestle, Novo Nordisk, Otsuka, Regenlife, Toulouse University Hospital, and UCB Pharma. No direct personal benefit. M. Balasa reports no conflict of interest. M. Boban reports no conflict of interest. K. Bennys reports grants form Alzheon Inc, Araclon Biotech S.L., Biogen, Eisai, Roche Genentech. No personal fees. M. Boada reports fees for advice from Grifols, Araclon, Biotech, Roche, Biogen, Lilly, Merck, Zambon, Novo Nordisk, Bioiberica, Eisai, Servier, and Schwabe Pharma; fees for lectures from Roche, Biogen, Grifols, Nutricia, Araclon Biotech, Servier, and Novo Nordisk. A. Chincarini reports no conflict of interest. S. Engelborghs reports fees from Eisai, icometrix, Novartis, Roche all paid to institution, and personal fees from Roche and Biogen. L. Exalto received personal fees from Julius Clinical and Brain Research Center. A. Felbecker reports personal fees for advisory boards and lectures from Eisai, Eli Lilly, Schwabe Pharma AG, Ompharma, Roche Pharma, Specialty care Therapiezentren AG, and grants from Fujirebio. K. Fliessbach reports no conflict of interest. G.B. Frisoni reports funding through the Private Foundation of Geneva University Hospitals from: A.P.R.A. – Association Suisse pour la Recherche sur la Maladie d’Alzheimer, Genève; Fondation Segré, Genève; Ivan Pictet, Genève; Race Against Dementia Foundation, London, UK; Fondation Child Care, Genève; Fondation Edmond J. Safra, Genève; Fondation Minkoff, Genève; Fondazione Agusta, Lugano; McCall Macbain Foundation, Canada; Nicole et René Keller, Genève; Fondation AETAS, Genève. He has received funding through the University of Geneva or Geneva University Hospitals: for IISSs from ROCHE Pharmaceuticals OM Pharma EISAI Pharmaceuticals Biogen Pharmaceuticals and Novo Nordisk; for competitive research projects from: H2020, Innovative Medicines Initiative (IMI), IMI2, Swiss National Science Foundation, and VELUX Foundation as well as payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from: Biogen, Roche, Novo Nordisk, GE HealthCare, all through the institution. A.J. Garza-Martinez reports no conflict of interest. T. Grimmer reports consulting fees from AbbVie, Advantage Therapeutics Alector, Anavex, Biogen, BMS, Cogthera, Iqvia, Noselab, NuiCare, Orphanzyme Eisai, Eli Lilly, Functional Neuromodulation, Grifols, Janssen, Novo Nordisk, Roche Pharma, UCB, and Vivoryon, and lecture fees from Biogen, Eisai, Grifols, Medical Tribune, Schwabe, Synlab, Novo Nordisk, and Roche Pharma. Her served as Principal Investigator in drug trials by AbbVie, Advantage Therapeutics, Alector, Anavex, Biogen, Eli Lilly, Functional Neuromodulation, Roche Pharma, UCB, and Vivoryon; The Institution received payment for study performance. Further grants to his institution from: Biogen and Eisai and Roche Diagnostics. L. Froelich reports grants and personal fees for lectures and advice from Roche, and personal fees for lectures and advice from Eisai, Araclon/Grifols, Eli Lilly, Noselab, NovoNordisk, BioVie, Biogen, MerckSharpe and Dohme, Neurimmune, TauRX, Dr. Willmar Schwabe Otsuka/Avanir, Axon Neuroscience, Pharmatropix, Neuroscios, Vivoryon, Hummingbird, Anavex, and Boehringer Ingelheim. B. Hanseeuw reports personal fees for advice and lectures from Eisai, Roche, Biogen, and grants from Fonds National de la Recherche Scientifique, Fondation Stop Alzheimer, and WEL Research institute (WELBIO). J. Hort reports consulting and lecture fees from Schwabe, Eisai, and Eli Lilly and holds stock options in Alzheon. A. Ivanoiu reports no conflict of interest. F. Jessen has reports honoraria for advisory boards and presentations from Abbvie, AC immune, Biogen, Eli Lilly, Eisai, GE Healthcare, Grifols, Janssen-Cliag and Roche. L. Krajcovicova reports no conflict of interest. S. Klöppel reports fees for advice and lectures from Biogen, Eisai Switzerland, Lundbeck, and OM Pharma. M.G. Kramberger reports no conflict of interest. B. McGuinness reports personal fees from Eisai, Biogen, Eli Lilly, and Nutricia. P. Mecocci reports personal fees for advice and lectures from Lundbeck and Lilly, and non-financial support from Merck. A. de Mendonca reports no conflict of interest. A. Nous reports no conflict of interest. P.J. Dr. Ousset reports research grants from Acadia Pharmaceuticals, Alzheon Inc., Araclon Biotech S.L., AstraZeneca, Biogen, Avanir Pharmaceuticals, Eisai Inc., Eli Lilly, Genentech, Inc., Hoffmann-La Roche, Janssen Research and Development, Merck Sharp and Dohme, Novartis Pharmaceuticals, Shanghai Greenvalley Pharmaceutical Co., TauRx Therapeutics Ltd, UCB Biopharma without personal fee. He reports personal fees for advice from Lilly France. C. Paquet reports no conflict of interest. R. Perneczky reports personal fees for advice and lectures from Biogen, Eisai, Eli Lilly, Grifols, Novo Nordisk Roche, Schwabe, and GSK, and grants from Astra Zeneca, Roche, Janssen Cilag, Eli Lilly, and Takeda. O. Peters reports grants from Alector and Predemtec, grants and personal fees for advice and lectures from Biogen, Eisai, Roche, Noselab, and Novo Nordisk, personal fees for advice and lectures from Grifols, Lilly, Prinnovation, Medtrix, Neurolive, and Neurotransdata. F. Piazza reports consulting fees from Alector, Araclon, Alnylam, Biogen, Lilly, and Roche, and personal honoraria for advisory board membership from Roche, Araclon and Lilly. He holds a patent for the ultrasensitive quantification of anti-amyloid antibodies in human biological fluids. D. Platone reports no conflict of interest. M. Riverol reports personal fees for advice and lectures from Grifols, Nutricia and Esteve. A. Ruiz reports grants from the Instituto de Salud Carlos III (ISCIII), the European Comision-IMI program, the EU-JPND , VLAIO, Janssen, Grifols SA, Roche AG, and Araclon Biotech; and personal fees from Landstenier Genmed, Glenn Biggs Institute, UTHSA, Fundación ADEY, and Novo Nordisk. G. Sacco reports no conflict of interest. I. Santana reports grants from Biogen, and personal fees from Eisai. N. Scarmeas reports grants from NIH, and NovoNordisc. E. Solje reports personal fees from Novartis, Novo Nordisk, Eisai, and Roche and personal fees from Roche. E. Stefanova reports no conflict of interest. S. Sutovsky reports lecture fees from Eisai, Biogen, Schwabe and Krka. M. Tabuas-Pereira reports no conflict of interest. W. van der Flier reports grants from ZonMW, NWO, EU-JPND, EU-IHI, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health~Holland, Topsector Life Sciences and Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer and Neuropsychiatrie Foundation, Philips, Biogen MA Inc, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, Eisai, Combinostics. She holds the Pasman chair. She is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health~Holland, Topsector Life Sciences and Health (PPP-allowance; #LSHM20106). She is recipient of TAP-dementia (www.tap-dementia.nl), receiving funding from ZonMw (#10510032120003). TAP-dementia receives co-financing from Avid Radiopharmaceuticals and Amprion. All funding is paid to her institution. She reports fees to the institution for lectures from Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), Novo Nordisk, Springer Healthcare, and European Brain Council. She consulted the Oxford Health Policy Forum CIC, Roche, Biogen MA Inc, and Eisai. All funding is paid to her institution. WF participated in advisory boards of Biogen MA Inc, Roche, and Eli Lilly. WF is member of the steering committee of EVOKE/EVOKE+ (NovoNordisk). All funding is paid to her institution. WF is member of the steering committee of PAVE, and Think Brain Health. WF was associate editor of Alzheimer, Research and Therapy in 2020/2021. WF is associate editor at Brain. T. Welsh is Research and Medical Director of The Research Institute for the Care of Older People (RICE), Bath, UK, which runs a mixture of commercial and non-commercial research activity. Commercial research projects run in the Institute have been funded by: Lilly, Roche, Biogen, Eisai, Janssen, AC Immune, Novo Nordisk, Pfizer, Elan, Immunobrain, Actinogen, and Julius Clinical. A. Wimo report to be the License holder (part) of RUD instrument. B. Winblad reports no conflict of interest.

Background: The emergence of disease-modifying Alzheimer's (AD) treatments provides new hope to patients and families but concerns have been raised about the preparedness of healthcare systems to provide timely access to such treatments because of a combination of a complex diagnostic process and a large prevalent pool., Objectives: We assess the preparedness of Sweden, a high-income country known for its dementia-friendly policies, to diagnose AD patients eligible for treatment within a six-month window, given current capacity for specialist evaluations and biomarker testing. We calculate the investment requirements for Sweden to achieve this target over a timeframe of 20 years., Design: Desk research to identify data for population, mortality, disease burden, cost of services and current capacity, expert consultation to inform assumptions about patient journey, and use of a Markov model to predict waiting times. The model simulates the patients' journey through different evaluation stages: initial evaluation by a primary care specialist, neurocognitive testing by an AD specialist, and confirmatory biomarker testing with PET scanning or cerebrospinal fluid (CSF) testing. The model assumes specialist appointments and PET scans are capacity constrained, and patients progress from cognitively normal to MCI and from MCI to dementia in the resulting waiting times., Measurements: Projected waiting times for diagnosis of eligibility for disease-modifying Alzheimer's treatment from 2023 to 2042 assuming current capacity, assuming 20% of Swedish residents aged 60 years and above would seek an evaluation for cognitive decline. Investments required to scale capacity up to reach target of providing diagnosis within six months on average., Results: Initial average waiting times for AD specialist appointments would be around 21 months in 2023 and remain around 55 months through 2042, as demand would continue to outstrip supply throughout the 20-year model horizon. Waiting times for biomarker testing would be stable at less than four weeks, as patients would be held up in the queue for their first specialist consultations, and use of CSF testing is widely accepted in Sweden. An additional 25% of AD specialists would have to be added above the current growth trend to reduce waiting times to less than 6 months at an average annual cost of approximately 805 million SEK. The increased cost of volume of biomarker testing would amount to about 106 million SEK per year., Conclusions: At current capacity, the Swedish healthcare system is unable to provide timely diagnosis of patients eligible for disease-modifying AD treatment. Although future diagnostic technologies, such as digital cognitive assessments and blood tests for the AD pathology, might decrease demand for capacity-constrained services, substantial investments will be required to meet a target of less than six months of waiting time for a diagnosis., Competing Interests: Soeren Mattke serves on the board of directors of Senscio Systems, Inc., and the scientific advisory board of AiCure Technologies, Alzpath and Boston Millennia Partners. He has received consulting fees from Biogen, C2N, Eisai, Novartis, and Roche/Genentech. Anders Gustavsson is co-founder and partner of Quantify Research AB, providing consultancy services to pharmaceutical companies and other private and public organizations and institutions. He indirectly owns shares in and serves on the board of Mindmore AB. Lena Jacobs an employee of at Quantify Research AB. Anders Wimo reports funding by VINNOVA program: PREDEM, EU project IMI2 program: MOPEAD, EU project H2020 program: PRODEMOS, EU-project IHI:PROMINENT, EU-projects JPND: EURO-FINGER, PMI-AD, ADDITION, and is a license holder of the RUD-instrument. Bengt Winblad has taken part in one Scientific Advisory Board meeting for BioArctic where the lecanemab data were discussed. Linus Jönsson has received research funding to his institution from VINNOVA, FORTE, IHI, Novo Nordisk, serves on an advisory board for Servier, and receives license fees for the RUD instrument. Sebastian Palmqvist has received research funding to his institution from ki elements / ADDF, and consultancy/speaker fees from Bioartic, Biogen, Lilly, and Roche. Silke Kern has served on advisory boards and/or as consultant for Geras Solutions and Biogen. Maria Eriksdotter has served as consultant for Biogen and Roche. Ingmar Skoog reports no conflicts.

Slovenia, situated in Central Europe with a population of 2.1 million, has an estimated 44,278 individuals with mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's dementia, rendering them potential candidates for disease-modifying treatment (DMT), such as lecanemab. We identified 114 potential candidates whose real-life expenses for diagnostic process surmount to more than €80,000. Treating all potential candidates nationwide would amount to €1.06 billion, surpassing Slovenia's entire annual medication expenditure for 2022 (€743 million). The introduction of DMTs and the associated logistics, along with potential complications, will significantly change societal, professional, and patient approach to treatment of Alzheimer's disease.

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).)

Introduction: The credibility of model-based economic evaluations of Alzheimer's disease (AD) interventions is central to appropriate decision-making in a policy context. We report on the International PharmacoEconomic Collaboration on Alzheimer's Disease (IPECAD) Modeling Workshop Challenge., Methods: Two common benchmark scenarios, for the hypothetical treatment of AD mild cognitive impairment (MCI) and mild dementia, were developed jointly by 29 participants. Model outcomes were summarized, and cross-comparisons were discussed during a structured workshop., Results: A broad concordance was established among participants. Mean 10-year restricted survival and time in MCI in the control group ranged across 10 MCI models from 6.7 to 9.5 years and 3.4 to 5.6 years, respectively; and across 4 mild dementia models from 5.4 to 7.9 years (survival) and 1.5 to 4.2 years (mild dementia)., Discussion: The model comparison increased our understanding of methods, data used, and disease progression. We established a collaboration framework to assess cost-effectiveness outcomes, an important step toward transparent and credible AD models., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Competing Interests: Dr. Wimo reports license holder of the RUD instrument. Dr. Jönsson reports grants from Novo Nordisk, outside the submitted work; In addition, Dr. Jönsson has a patent RUD instrument licensed to European Health Economics AB.

Introduction: The Models of Patient Engagement for Alzheimer's Disease (MOPEAD) project was conceived to explore innovative complementary strategies to uncover hidden prodromal and mild Alzheimer's disease (AD) dementia cases and to raise awareness both in the general public and among health professionals about the importance of early diagnosis., Methods: Four different strategies or RUNs were used: (a) a web-based (WB) prescreening tool, (2) an open house initiative (OHI), (3) a primary care-based protocol for early detection of cognitive decline (PC), and (4) a tertiary care-based pre-screening at diabetologist clinics (DC)., Results: A total of 1129 patients at high risk of having prodromal AD or dementia were identified of 2847 pre-screened individuals (39.7%). The corresponding proportion for the different initiatives were 36.8% (WB), 35.6% (OHI), 44.4% (PC), and 58.3% (DC)., Conclusion: These four complementary pre-screening strategies were useful for identifying individuals at high risk of having prodromal or mild AD., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Interventions simultaneously targeting multiple risk factors and mechanisms are most likely to be effective in preventing cognitive impairment. This was indicated in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) testing a multidomain lifestyle intervention among at-risk individuals. The importance of medical food at the early symptomatic disease stage, prodromal Alzheimer's disease (AD), was emphasized in the LipiDiDiet trial. The feasibility and effects of multimodal interventions in prodromal AD are unclear., Objectives: To evaluate the feasibility of an adapted FINGER-based multimodal lifestyle intervention, with or without medical food, among individuals with prodromal AD., Methods: MIND-ADmini is a multinational proof-of-concept 6-month randomized controlled trial (RCT), with four trial sites (Sweden, Finland, Germany, France). The trial targeted individuals with prodromal AD defined using the International Working Group-1 criteria, and with vascular or lifestyle-related risk factors. The parallel-group RCT includes three arms: 1) multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management and social stimulation); 2) multimodal lifestyle intervention+medical food (Fortasyn Connect); and 3) regular health advice/care (control group). Primary outcomes are feasibility and adherence. Secondary outcomes are adherence to the individual intervention domains and healthy lifestyle changes., Results: Screening began on 28 September 2017 and was completed on 21 May 2019. Altogether 93 participants were randomized and enrolled. The intervention proceeded as planned., Conclusions: For the first time, this pilot trial tests the feasibility and adherence to a multimodal lifestyle intervention, alone or combined with medical food, among individuals with prodromal AD. It can serve as a model for combination therapy trials (non-pharma, nutrition-based and/or pharmacological interventions)., Competing Interests: Dr. Andrieu reports grants from EU – JPND program – MIND-AD project, during the conduct of the study; grants from EU – H2020 program – PRODEMOS project, grants from CNAV, personal fees and non-financial support from Nestlé SA, outside the submitted work. Dr. Broersen is employee of Danone Nutricia Research. Dr. Coley reports grants from Agence Nationale de la Recherche (ANR), during the conduct of the study. Dr. Wimo reports personal fees from Biogen, from Eisai, grants from Merck, outside the submitted work. Dr. Soininen reports grants from Academy of Finland for JNPD EU project, during the conduct of the study; personal fees from Consultation fee, outside the submitted work. Dr. Hartmann reports grants from BMBF-JPND, grants from EU FP7 LipiDiDiet, during the conduct of the study. Dr. Solomon reports grants from European Research Council grant 804371, grants from Alzheimerfonden, grants from Academy of Finland, during the conduct of the study. Dr. Kivipelto reports grants from The EU Joint Programme – Neurodegenerative Disease Research (JPND), Alzheimerfonden, Hjärnfonden, Center for Innovative Medicine (CIMED) at Karolinska Institutet South Campus, Knut and Alice Wallenberg Foundation, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, Joint Program of Neurodegenerative Disorders – prevention (EURO-FINGERS), Region Stockholm (ALF, NSV), Stiftelsen Stockholms sjukhem, Swedish Research Council for Health Working Life and Welfare (FORTE), during the conduct of the study; and was an invited speaker and received an honorarium at an industry-led symposium including Biogen, Nutricia and Nestlé, outside the submitted work.

Objective: To investigate whether cholinesterase inhibitors (ChEIs) are associated with slower cognitive decline in Alzheimer dementia and decreased risk of severe dementia or death., Methods: Patients with Alzheimer dementia from the Swedish Dementia Registry starting on ChEIs within 3 months of the dementia diagnosis were included and compared to nontreated patients with Alzheimer dementia. In a propensity score-matched cohort, the association between ChEI use and cognitive trajectories assessed by Mini-Mental State Examination (MMSE) scores was examined with a mixed model, and severe dementia (MMSE score <10) or death as an outcome was assessed with Cox proportional hazards models., Results: The matched cohort included 11,652 ChEI users and 5,826 nonusers. During an average of 5 years of follow-up, 255 cases developed severe dementia, and 6,055 (35%) died. ChEI use was associated with higher MMSE score at each visit (0.13 MMSE points per year; 95% confidence interval [CI] 0.06-0.20). ChEI users had a 27% lower risk of death (0.73, 95% CI 0.69-0.77) compared with nonusers. Galantamine was associated with lower risk of death (0.71, 95% CI 0.65-0.76) and lower risk of severe dementia (0.69, 95% CI 0.47-1.00) and had the strongest effect on cognitive decline of all the ChEIs (0.18 MMSE points per year, 95% CI 0.07-0.28)., Conclusions: ChEIs are associated with cognitive benefits that are modest but persist over time and with reduced mortality risk, which could be explained partly by their cognitive effects. Galantamine was the only ChEI demonstrating a significant reduction in the risk of developing severe dementia., Classification of Evidence: This study provides Class III evidence that for patients with Alzheimer dementia ChEIs decrease long-term cognitive decline and risk of death and that galantamine decreases the risk of severe dementia., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: For care planning and support, under-detection and late diagnosis of Alzheimer's disease (AD) is a great challenge. Models of Patient-Engagement for Alzheimer's Disease (MOPEAD) is an EU-funded project aiming at testing different strategies to improve this situation., Objective: To make a cost-consequence analysis of MOPEAD., Methods: Four screening strategies were tested in five countries (Germany, the Netherlands, Slovenia, Spain, and Sweden): 1) a web-approach; 2) Open-House initiative; 3) in primary care; and 4) by diabetes specialists. Persons-at-risk of AD in all strategies were offered referral to a hospital-based specialist. The primary health-economic outcome was the cost per true-positive case (TP) of AD from the screened population., Results: Of 2,847 screened persons, 1,121 screened positive (39%), 402 were evaluated at memory clinics (14%), and 236 got an AD diagnosis (8%). The cost per TP of those screened was €3,115 with the web-approach, €2,722 with the Open-House, €1,530 in primary care, and €1,190 by diabetes specialists. Sensitivity analyses that more likely reflect the real-world situation confirmed the results. The number-needed-to-screen was 30 with the web-approach, 8 with the Open-House and primary care, and 6 with the diabetes specialists.There were country differences in terms of screening rates, referrals to memory clinics, staff-types involved, and costs per TP., Conclusion: In primary care and by the diabetes specialist, the costs per TP/screened population were lowest, but the capacity of such settings to identify cases with AD-risk must be discussed. Hence new diagnostic strategies such as web-solutions and Open-House initiatives may be valuable after modifications.

Objective: To identify, in caregivers of patients with Alzheimer's disease (AD) dementia, factors associated with subjective (personal, physical, emotional, and social) and objective (informal caregiver time and costs) caregiver burden., Design: Prospective longitudinal European observational study: post-hoc analysis., Setting: Clinic., Participants: Community-dwelling patients in France and Germany aged ≥ 55 years (n = 969) with probable AD and their informal caregivers., Measurements: Mini-Mental State Examination (MMSE), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), 12-item Neuropsychiatric Inventory (NPI-12), Zarit Burden Interview (ZBI), informal caregiver basic and instrumental ADL hours (Resource Utilization in Dementia instrument), and informal caregiver costs. Mixed-effect models of repeated measures (MMRM) were run, including baseline and time-dependent covariates (change from baseline [CFB] to 18 months in MMSE, ADCS-ADL, and NPI-12 scores) associated with CFB in ZBI score/informal caregiver time over 36 months (analyzed using linear regression models) and informal caregiver costs over 36 months (analyzed using generalized linear models)., Results: Greater decline in patient function (ADCS-ADL) over 18 months was associated with increased subjective caregiver burden (ZBI), hours, and costs over 36 months. Increased behavioral problems (NPI-12) over 18 months also negatively impacted ZBI. Cognitive decline (MMSE) over 18 months did not affect change in caregiver burden., Conclusions: Long-term informal caregiver burden was driven by worsening functional abilities and behavioral symptoms but not cognitive decline, over 18 months in community-dwelling patients with AD dementia. Identifying the drivers of caregiver burden could highlight areas in which interventions may benefit both caregivers and patients.

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.

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.)

In most, if not all health systems, dementia is underdiagnosed, and when diagnosis occurs, it is typically at a relatively late stage in the disease process despite mounting evidence showing that a timely diagnosis would result in numerous benefits for patients, families, and society. Moving toward earlier diagnoses in Alzheimer's disease (AD) requires a conscientious and collective effort to implement a global strategy addressing the multiple causes hindering patient engagement at different levels of society. This article describes the design of the Models of Patient Engagement for Alzheimer's Disease project, an ongoing EU-funded public-private multinational initiative that will compare four innovative patient engagement strategies across five European countries regarding their ability to identify individuals with prodromal AD and mild AD dementia, which are "hidden" in their communities and traditionally not found in the typical memory clinic setting. The strategies include an online AD citizen science platform, an open house initiative at the memory clinics, and patient engagement at primary care and diabetologist clinics., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To examine the costs of caring for community-dwelling patients with Alzheimer's disease (AD) dementia in relation to the time to institutionalisation., Methods: GERAS was a prospective, non-interventional cohort study in community-dwelling patients with AD dementia and their caregivers in three European countries. Using identified factors associated with time to institutionalisation, models were developed to estimate the time to institutionalisation for all patients. Estimates of monthly total societal costs, patient healthcare costs and total patient costs (healthcare and social care together) prior to institutionalisation were developed as a function of the time to institutionalisation., Results: Of the 1495 patients assessed at baseline, 307 (20.5%) were institutionalised over 36 months. Disease severity at baseline [based on Mini-Mental State Examination (MMSE) scores] was associated with risk of being institutionalised during follow up (p < 0.001). Having a non-spousal informal caregiver was associated with a faster time to institutionalisation (944 fewer days versus having a spousal caregiver), as was each one-point worsening in baseline score of MMSE, instrumental activities of daily living and behavioural disturbance (67, 50 and 30 fewer days, respectively). Total societal costs, total patient costs and, to a lesser extent, patient healthcare-only costs were associated with time to institutionalisation. In the 5 years pre-institutionalisation, monthly total societal costs increased by more than £1000 (€1166 equivalent for 2010) from £1900 to £3160 and monthly total patient costs almost doubled from £770 to £1529., Conclusions: Total societal costs and total patient costs rise steeply as community-dwelling patients with AD dementia approach institutionalisation.

Introduction: The ε4 allele of the apolipoprotein E (APOE) gene is a prominent risk factor for Alzheimer's disease (AD), but its implication in other dementias is less well studied., Methods: We used a data set on 2858 subjects (1098 AD, 260 vascular dementia [VaD], 145 mixed AD and VaD, 90 other dementia diagnoses, and 1265 controls) to examine the association of APOE polymorphisms with clinical dementia diagnoses, biomarker profiles, and longevity., Results: The ε4 allele was associated with reduced longevity as ε4 versus ε3 homozygotes lived on average 2.6 years shorter (P = .006). In AD, ε4 carriers lived 1.0 years shorter than noncarriers (P = .028). The ε4 allele was more prevalent in AD, mixed AD and VaD, and VaD patients compared to controls, but not in other dementia disorders., Discussion: The APOE ε4 allele is influential in AD but might also be of importance in VaD and in mixed AD and VaD, diseases in which concomitant AD pathology is common., (Copyright © 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Although there have been so many failures in Alzheimer's disease (AD) modifying trials, there are still many compounds in the pipeline and the hope still remains that the entrance of disease-modifying treatment (DMT) for AD will positively and dramatically change the whole situation of AD treatment. However, if DMT does enter the market, it will be the beginning of a great number of challenges and problems. The current infrastructure for diagnostics of early (pre-dementia) AD does not have the capacity to meet the demands and expectations of the population. Neither is there capacity for treatment monitoring and follow-ups. If screening is considered, there will be a great risk for false positive cases and a great number of people who will have to undergo diagnostics. There will be high costs for diagnostics and treatment initially, while potential benefits will occur much later in other sectors than where the payers for treatment are. Although there are great hopes that prevention of cardiovascular risk factors and changes in lifestyle might impact the risk for dementia, there is still no consensus that this is the case. Finally, the relevance of different AD paradigms such as amyloid and tau is still a matter of discussion, particularly regarding the oldest old.

Available data and models for the health-economic evaluation of treatment in Alzheimer's disease (AD) have limitations causing uncertainty to decision makers. Forthcoming treatment strategies in preclinical or early AD warrant an update on the challenges associated with their economic evaluation. The perspectives of the co-authors were complemented with a targeted review of literature discussing methodological issues and data gaps in AD health-economic modelling. The methods and data available to translate treatment efficacy in early disease into long-term outcomes of relevance to policy makers and payers are limited. Current long-term large-scale data accurately representing the continuous, multifaceted, and heterogeneous disease process are missing. The potential effect of disease-modifying treatment on key long-term outcomes such as institutionalization and death is uncertain but may have great effect on cost-effectiveness. Future research should give priority to collaborative efforts to access better data on the natural progression of AD and its association with key long-term outcomes., (Copyright © 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background: The impact on informal caregivers of caring for people with Alzheimer's disease (AD) dementia can be substantial, but it remains unclear which measures(s) best assess such impact. Our objective was to use data from the GERAS study to assess the ability of the EuroQol 5-dimension questionnaire (EQ-5D) to measure the impact on caregivers of caring for people with AD dementia and to examine correlations between EQ-5D and caregiver burden., Methods: GERAS was a prospective, non-interventional cohort study in community-dwelling patients with AD dementia and their informal caregivers. The EQ-5D and Zarit Burden Interview (ZBI) were used to measure health-related quality of life and caregiver burden, respectively. Resource-use data collected included caregiver time spent with the patient on activities of daily living (ADL). Spearman correlations were computed between EQ-5D scores, ZBI scores, and time spent on instrumental ADL (T-IADL) at baseline, 18 months, and for 18-month change scores. T-IADL and ZBI change scores were summarized by EQ-5D domain change category (better/stable/worse)., Results: At baseline, 1495 caregivers had mean EQ-5D index scores of 0.86, 0.85, and 0.82, and ZBI total scores of 24.6, 29.4, and 34.1 for patients with mild, moderate, and moderately severe/severe AD dementia, respectively. Change in T-IADL showed a stronger correlation with change in ZBI (0.12; P < 0.001) than with change in EQ-5D index score (0.02; P = 0.546) although both correlations were very weak. Worsening within EQ-5D domains was associated with increases in ZBI scores, although 68%-90% of caregivers remained stable within each EQ-5D domain. There was no clear pattern for change in T-IADL by change in EQ-5D domain., Conclusions: EQ-5D may not be the optimum measure of the impact of caring for people with AD dementia due to its focus on physical health. Alternative measures need further investigation.

Background: Country differences in resource use and costs of Alzheimer's disease (AD) may be driven by differences in health care systems and resource availability., Objective: To compare country resource utilization drivers of societal costs for AD dementia over 18 months., Methods: GERAS is an observational study in France (n = 419), Germany (n = 550), and the UK (n = 526). Resource use of AD patients and caregivers contributing to >1% of total societal costs (year 2010) was assessed for country differences, adjusting for participant characteristics., Results: Mean 18-month societal costs per patient were France €33,339, Germany €38,197, and UK €37,899 (£32,501). Caregiver time spent on basic and instrumental activities of daily living (ADL) contributed the most to societal costs (54% France, 64% Germany, 65% UK). Caregivers in France spent less time on ADL than UK caregivers and missed fewer work days than in other countries. Compared with other countries, patients in France used more community care services overall and were more likely to use home aid. Patients in Germany were least likely to use temporary accommodation or to be institutionalized at 18 months. UK caregivers spent the most time on instrumental ADL, UK patients used fewest outpatient resources, and UK patients/caregivers were most likely to receive financial support., Conclusion: Caregiver time on ADL contributed the most to societal costs and differed across countries, possibly due to use of community care services and institutionalization. Other resources had different patterns of use across countries, reflecting country-specific health and social care systems.

Background: Diagnostic research criteria for Alzheimer's disease support the use of biomarkers in the cerebrospinal fluid (CSF) to improve the accuracy of the prognosis regarding progression to dementia for people with mild cognitive impairment (MCI)., Objective: The aim of this study was to estimate the potential incremental cost-effectiveness ratio of adding CSF biomarker testing to the standard diagnostic workup to determine the prognosis for patients with MCI., Methods: In an early technology assessment, a mathematical simulation model was built, using available evidence on added prognostic value as well as expert opinion to estimate the incremental costs and quality-adjusted life years (QALYs) of 20,000 virtual MCI patients with (intervention strategy) and without (control strategy) relying on CSF, from a health-care sector perspective and with a 5-year time horizon., Results: Adding the CSF test improved the accuracy of prognosis by 11%. This resulted in an average QALY gain of 0.046 and € 432 additional costs per patient, representing an incremental cost-effectiveness ratio of € 9,416., Conclusion: The results show the potential of CSF biomarkers in current practice from a health-economics perspective. This result was, however, marked by a high degree of uncertainty, and empirical research is required into the impact of a prognosis on worrying, false-positive/negative prognosis, and stigmatization.

Background: Missing data are a common problem in prospective studies with a long follow-up, and the volume, pattern and reasons for missing data may be relevant when estimating the cost of illness. We aimed to evaluate the effects of different methods for dealing with missing longitudinal cost data and for costing caregiver time on total societal costs in Alzheimer's disease (AD)., Methods: GERAS is an 18-month observational study of costs associated with AD. Total societal costs included patient health and social care costs, and caregiver health and informal care costs. Missing data were classified as missing completely at random (MCAR), missing at random (MAR) or missing not at random (MNAR). Simulation datasets were generated from baseline data with 10-40 % missing total cost data for each missing data mechanism. Datasets were also simulated to reflect the missing cost data pattern at 18 months using MAR and MNAR assumptions. Naïve and multiple imputation (MI) methods were applied to each dataset and results compared with complete GERAS 18-month cost data. Opportunity and replacement cost approaches were used for caregiver time, which was costed with and without supervision included and with time for working caregivers only being costed., Results: Total costs were available for 99.4 % of 1497 patients at baseline. For MCAR datasets, naïve methods performed as well as MI methods. For MAR, MI methods performed better than naïve methods. All imputation approaches were poor for MNAR data. For all approaches, percentage bias increased with missing data volume. For datasets reflecting 18-month patterns, a combination of imputation methods provided more accurate cost estimates (e.g. bias: -1 % vs -6 % for single MI method), although different approaches to costing caregiver time had a greater impact on estimated costs (29-43 % increase over base case estimate)., Conclusions: Methods used to impute missing cost data in AD will impact on accuracy of cost estimates although varying approaches to costing informal caregiver time has the greatest impact on total costs. Tailoring imputation methods to the reason for missing data will further our understanding of the best analytical approach for studies involving cost outcomes.

Background: We aimed to obtain a better understanding of how different aspects of patient functioning affect key cost and caregiver outcomes in Alzheimer's disease (AD)., Methods: Baseline data from a prospective observational study of community-living AD patients (GERAS) were used. Functioning was assessed using the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale. Generalized linear models were conducted to analyze the relationship between scores for total activities of daily living (ADL), basic ADL (BADL), instrumental ADL (IADL), ADL subdomains (confirmed through factor analysis) and individual ADL questions, and total societal costs, patient healthcare and social care costs, total and supervision caregiver time, and caregiver burden., Results: Four distinct ADL subdomains were confirmed: basic activities, domestic/household activities, communication, and outside activities. Higher total societal costs were associated with impairments in all aspects of ADL, including all subdomains; patient costs were associated with total ADL and BADL, and basic activities subdomain scores. Both total and supervision caregiver hours were associated with total ADL and IADL scores, and domestic/household and outside activities subdomain scores (greater hours associated with greater functional impairments). There was no association between caregiver burden and BADL or basic activities subdomain scores. The relationship between total ADL, IADL, and the outside activities subdomain and outcomes differed between patients with mild and moderate-to-severe AD., Conclusions: Identification of ADL subdomains may lead to a better understanding of the association between patient function and costs and caregiver outcomes at different stages of AD, in particular the outside activities subdomain within mild AD.

Introduction: New research guidelines for the diagnosis of Alzheimer's disease (AD) include biomarker evidence of amyloid-β (Aβ) and tau pathology. The aim of this study was to investigate what proportion of AD patients diagnosed in clinical routine in Sweden that had an AD-indicative cerebrospinal fluid (CSF) biomarker profile., Methods: By cross-referencing a laboratory database with the Swedish Dementia Registry (SveDem), 2357 patients with data on CSF Aβ and tau biomarkers and a clinical diagnosis of AD with dementia were acquired., Results: Altogether, 77.2% had pathologic Aβ42 and total tau or phosphorylated tau in CSF. These results were stable across age groups. Female sex and low mini-mental state examination score increased the likelihood of pathologic biomarkers., Discussion: About a quarter of clinically diagnosed AD patients did not have an AD-indicative CSF biomarker profile. This discrepancy may partly reflect incorrect (false positive) clinical diagnosis or a lack in sensitivity of the biomarker assays., (Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Introduction: The study aimed to determine the room for improvement of a perfect cerebrospinal fluid (CSF) biomarker and the societal incremental net monetary benefit of CSF in subjects with mild cognitive impairment (MCI) assuming a hypothetical disease-modifying Alzheimer's disease (AD) treatment., Methods: A decision model compared current practice to a perfect biomarker and to two strategies positioning CSF as add-on test when current practice concluded the presence or absence of AD., Results: The simulated MCI population was aged on average 68.3 and 49% had AD. The room for improvement by the perfect CSF test was 0.39 quality adjusted life years, €33,622 ($43,372) savings, 2.0 potential beneficial treatment years, and 1.3-year delay in dementia conversion., Discussion: The results indicated more potential benefit from a biomarker positioned to verify subjects who are not expected to have AD (i.e., to prevent undertreatment) rather than to verify subjects expected to have AD (prevent overtreatment). Sensitivity analyses explored different CSF positions., (Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background: To identify the main factors associated with societal costs of Alzheimer's disease (AD) in community-dwelling patients across three European countries., Methods: Baseline cost data from a prospective, observational study were used. Assessments included patients' cognition, activities of daily living (ADLs) and behavioral symptoms, and caregiver burden. Cost calculations (2010) from the societal perspective were based on patient/caregiver resource use. Generalized linear models estimated factors associated with costs., Results: Mean monthly costs per patient differed for France (€1881), Germany (€2349), and the UK (€2016), with informal care costs accounting for 50% to 61%. Independent factors associated with costs across all countries were ADL total score, patient living arrangements, caregiver working status, and caregiver burden (all P < .05). Additional factors were significant for the pooled cohort or individual countries., Conclusions: Several patient and caregiver factors, including factors associated with informal care, should be included when evaluating care options for patients with AD., (Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Health-care stakeholders increasingly recognize that the scientific and economic challenges associated with Alzheimer's disease (AD) are simply too great for individual stakeholder groups to address solely from within their own silos. In the necessary spirit of collaboration, we present in this perspective a set of multicountry multistakeholder recommendations to improve the organization of existing AD and dementia care and the development of new treatments. In brief, the five recommendations are (1) health-care systems must make choices regarding the patient populations to be diagnosed and treated, (2) health-care systems should use an evidence-based standard of care, (3) increased collaboration between public and private institutions is needed to enhance research, (4) reimbursement end points need to be agreed on and validated, and (5) innovative business models should be used to spur the introduction of new medicines., (Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to describe the baseline characteristics of informal carers of community-living Alzheimer's disease (AD) patients by AD severity group and to identify factors associated with two measures of caregiver burden., Design and Setting: GERAS is a prospective observational study in France, Germany, and the UK, designed to assess costs and resource use associated with AD, for patients and their caregivers, stratified by disease severity., Participants: 1497 community-dwelling AD patients and their primary caregivers., Measurements: Subjective caregiver burden assessed using the Zarit Burden Interview [ZBI] and time spent supervising patients (an objective measure of burden recorded using the Resource Utilization in Dementia instrument) during the month before the baseline visit were recorded. Separate multiple linear regression analyses using ZBI total score and caregiver supervision time as dependent variables were performed to identify patient and caregiver factors independently associated with caregiver burden., Results: Increasing AD severity was associated with both subjective caregiver burden (ZBI total score) and overall caregiver time, which includes supervision time (both p<0.001, ANOVA). Better patient functioning (on instrumental activities of daily living) was independently associated with both a lower ZBI total score and less supervision time, whereas higher levels of caregiver distress due to patient behavior were associated with greater caregiver burden. Other factors independently associated with an increased ZBI total score included younger caregiver age, caregiver self-reported depression, caring for a male patient, and longer time since AD diagnosis. Caregivers living with the patient, being a male caregiver, patient living in a rural location, higher patient behavioral problem subdomain scores for apathy and psychosis, more patient emergency room visits, not receiving food delivery and receiving financial support for caregiving were all associated with greater caregiver supervision time., Conclusion: Our results show that subjective caregiver burden and caregiver time are influenced by different factors, reinforcing the need to consider both aspects of caregiving when trying to minimize the burden of AD. However, interventions that minimize caregiver distress and improve patient functioning may impact on both subjective and objective burden.

Objective: To investigate the use of formal care during the first three years after diagnosis of mild dementia and identify cost-predicting factors., Design: Prospective longitudinal study over three years., Setting: An incidence-based bottom-up cost-of-illness study where information about formal health care services was drawn from the municipalities' registers during the first three years after the diagnosis of mild dementia., Participants: 109 patients with mild dementia at baseline, diagnosed according to consensus criteria based on standardized assessments., Measurement: The use of formal care as registered by the municipalities' registration systems. Costs were estimated by applying unit costs, including municipal expenses and out-of-pocket contributions. Clinical data were collected at baseline to identify cost-predicting factors., Results: Costs for formal care were increasing from € 535 per month of survival (MOS) at baseline to € 3,611 per MOS during the third year, with a mean of € 2,420 during the whole observation period. The major cost driver (74%) was institutional care. The costs for people with dementia with Lewy bodies (€ 3,247 per MOS) were significantly higher than for people with Alzheimer disease (€ 1,855 per MOS). The most important cost-predicting factors we identified were the living situation, a diagnosis of non-Alzheimer disease, comorbidity, and daily living functioning. The use of cholinesterase inhibitors was related to lower costs., Conclusion: Formal care costs increased significantly over time with institutional care being the heaviest cost driver. Studies with longer observation periods will be necessary to evaluate the complete socioeconomic impact of the course of dementia., (Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

The socio-economic impact of Alzheimer's disease (AD) and other dementias is enormous, and the potential economic challenges ahead are clear given the projected future numbers of individuals with these conditions. Because of the high prevalence and cost of dementia, it is very important to assess any intervention from a cost-effectiveness viewpoint. The diagnostic criteria for preclinical AD suggested by the National Institute on Aging and Alzheimer's Association workgroups in combination with the goal of effective disease-modifying treatment (DMT) are, however, a challenge for clinical practice and for the design of clinical trials. Key issues for future cost-effectiveness studies include the following: (i) the consequences for patients if diagnosis is shifted from AD-dementia to predementia states, (ii) bridging the gap between clinical trial populations and patients treated in clinical practice, (iii) translation of clinical trial end-points into measures that are meaningful to patients and policymakers/payers and (iv) how to measure long-term effects. To improve cost-effectiveness studies, long-term population-based data on disease progression, costs and outcomes in clinical practice are needed not only in dementia but also in predementia states. Reliable surrogate end-points in clinical trials that are sensitive to detect effects even in predementia states are also essential as well as robust and validated modelling methods from predementia states that also take into account comorbidities and age. Finally, the ethical consequences of early diagnosis should be considered., (© 2014 The Association for the Publication of the Journal of Internal Medicine.)

Aims: Cholinesterase inhibitors (ChEIs) are used for symptomatic treatment of Alzheimer's disease. These drugs have vagotonic and anti-inflammatory properties that could be of interest also with respect to cardiovascular disease. This study evaluated the use of ChEIs and the later risk of myocardial infarction and death., Methods and Results: The cohort consisted of 7073 subjects (mean age 79 years) from the Swedish Dementia Registry with the diagnoses of Alzheimer's dementia or Alzheimer's mixed dementia since 2007. Cholinesterase inhibitor use was linked to diagnosed myocardial infarctions (MIs) and death using national registers. During a mean follow-up period of 503 (range 0-2009) days, 831 subjects in the cohort suffered MI or died. After adjustment for confounders, subjects who used ChEIs had a 34% lower risk for this composite endpoint during the follow-up than those who did not [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.56-0.78]. Cholinesterase inhibitor use was also associated with a lower risk of death (HR: 0.64, 95% CI: 0.54-0.76) and MI (HR: 0.62, 95% CI: 0.40-0.95) when analysed separately. Subjects taking the highest recommended ChEI doses (donepezil 10 mg, rivastigmine >6 mg, galantamine 24 mg) had the lowest risk of MI (HR: 0.35, 95% CI: 0.19-0.64), or death (HR: 0.54, 95% CI: 0.43-0.67) compared with those who had never used ChEIs., Conclusion: Cholinesterase inhibitor use was associated with a reduced risk of MI and death in a nationwide cohort of subjects diagnosed with Alzheimer's dementia. These associations were stronger with increasing ChEI dose.

Background: The Resource Utilization in Dementia (RUD) questionnaire is the most widely used instrument for resource use data collection in dementia, enabling comparison of costs of care across countries with differing health care provisions. Recent feedback from payers questioned its face validity given that health care provisions have changed since the initial development of the RUD in 1998. The aim of this study was to update the RUD to improve its face validity in Alzheimer's disease (AD) clinical research and its utility for health care resource allocation., Methods: An extensive PubMed review was conducted of current relevant resource items in AD in 15 countries. The findings were complemented by interviews with local care providers and experts in dementia care and health economics. Their proposed revisions were discussed with five leading dementia experts in North and South America, northern and southern Europe, and Asia. A new version of the RUD was developed based on their recommendations., Results: RUD users identified a need for more information relevant to coverage decisions. Proposed revisions included changes to existing questions (e.g., to capture more accurately the number and type of health care visits) and the addition of new questions (e.g., on informal caregiver hours and the primary caregiver's hours of sleep)., Conclusion: Several minor changes were made to the RUD instrument to improve the accuracy and precision of the data while maintaining comparability with the original version and reflecting current medical practice. The RUD Complete Version 4.0 is now available for use in future AD clinical trials., (Copyright © 2013 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background: The societal costs of Alzheimer's Disease (AD) are enormous and pose a great challenge for the health and social care in any society. It is of vital importance to develop and identify cost effective treatment. The aim of the study was to present a hypothetical economic model of Disease Modifying Treatment (DMT) in AD., Methods: A 20 year Markov cohort model of DMT was constructed, based on Swedish care conditions. States and progression were defined according to the Mini Mental State Examination (MMSE). Epidemiological studies of incidence of dementia, prevalence and costs of Mild Cognitive Impairment (MCI) and AD as well as conversion studies of MCI and demographic statistics were used as inputs in the model., Results: Total costs were 113,797 million SEK for patients treated with DMT vs 88,562 million SEK for untreated patients. The corresponding gained QALYs were 529,945 and 450,307 respectively, giving an incremental cost effectiveness ratio of 293,002 SEK/QALY in the base option. Survival in the model was 8.72 years with DMT and 7.77 years for untreated. With an assumed Willingness to pay (WTP) of 600,000 SEK (about 86,200 US$ and 62,000 ) per gained QALY, the model indicated cost effectiveness with DMT. The sensitivity analysis implied no cost savings with DMT, but most options indicated cost effectiveness vs. the chosen WTP., Conclusion: The main reasons for the higher costs with DMT were the costs of DMT itself and the prolonged survival with DMT. Even if costs increase with DMT, the model indicates cost effectiveness.

Background: Empirical models of the natural history of Alzheimer's disease (AD) may help to evaluate new interventions for AD., Objective: We aimed to estimate AD-free survival time in people with mild cognitive impairment (MCI) and decline of cognitive and physical function in AD cases., Methods: Within the Kungsholmen project, 153 incident MCI and 323 incident AD cases (international criteria) were identified during 9 years of follow-up in a cognitively healthy cohort of elderly people aged ≥75 at baseline (n = 1,082). Global cognitive function was assessed with the Mini-Mental State Examination (MMSE), and daily life function was evaluated with the Katz index of activities of daily living (ADL) at each follow-up examination. Data were analyzed using parametric survival analysis and mixed effect models., Results: Median AD-free survival time of 153 participants with incident MCI was 3.5 years. Among 323 incident AD cases, the cognitive decline was 1.84 MMSE points per year, which was significantly associated with age. Physical functioning declined by 0.38 ADL points per year and was significantly associated with age, education, and MMSE, but not with gender., Conclusion: Elderly people with MCI may develop AD in approximately 3.5 years. Both cognitive and physical function may decline gradually after AD onset. The empirical models can be used to evaluate long-term disease progression of new interventions for AD.

To address socioeconomic challenges associated with its increasing prevalence, data are needed on country-level resource use and costs associated with Alzheimer's disease (AD). GERAS is an 18-month observational study being conducted in France, Germany, and the U.K. (with an 18-month extension in France and Germany), aimed at determining resource use and total costs associated with AD, stratified by AD severity at baseline. Resource use information and time spent on informal care by non-professional caregivers was obtained using the Resource Utilization in Dementia instrument. Total baseline societal costs were based on four cost components: patient health care costs, patient social care costs, caregiver health care costs, and caregiver informal care costs. Overall, 1,497 community-dwelling patients with AD were analyzed at baseline. Estimated mean monthly total societal costs per patient at baseline differed significantly between groups with mild, moderate, and moderately severe/severe AD (p < 0.001 in each country): euro $1,418, euro 1,737, and euro 2,453 in France; euro 1,312, euro $2,412, and euro 3,722 in Germany; and euro 1,621, euro 1,836, andeuro 2,784 in the U.K., respectively. All cost components except caregiver health care costs increased with AD severity. Informal caregiver costs were the largest cost component accounting for about half to just over 60% of total societal costs, depending on country and AD severity group. In conclusion, GERAS study baseline results showed that country-specific costs increase with AD severity. Informal care costs formed the greatest proportion of total societal costs, increasing with AD severity independent of costing method. Longitudinal data will provide information on cost trends with disease progression.

Objectives: Amyloid immunotherapy trials are central in Alzheimer disease (AD) drug development, with the potential to influence all future disease-modifying randomized controlled trials (RCTs). This study investigates practical experiences of staff and participants in immunotherapy RCTs., Setting and Methods: The Clinical Trial Research Unit of the Memory Clinic at Karolinska University Hospital, Sweden is an experienced centre specialized in Alzheimer RCTs, where four active and passive phase I/II immunotherapy trials are currently ongoing. Meetings were held with staff members, who were asked to describe their experiences and suggest necessary improvements. In addition, a pilot study was conducted to investigate motivations and expectations of participants in immunotherapy RCTs. A questionnaire was sent to 20 patients, and another similar questionnaire to their caregivers., Results: The main issues emphasized by staff members concerned the critical window of opportunity for recruiting RCTs participants, the much higher level of effort required of patients and caregivers in immunotherapy RCTs compared to classical cholinesterase inhibitor RCTs, problematic informed consent procedures, and confidentiality limitations in trials with different sponsors. For patients and caregivers, the main reason for participating in RCTs was the wish to help research and other people, followed by the need for information, continuity of care, safety and support. Compared to patients, caregivers' expectations of trial results were more realistic., Conclusions: More open debates of practical experiences from different trial centres and sponsors are essential for optimizing trial designs and improving conditions for participants.

Aims: We examine the dementia assessment with focus on age and gender differences., Methods: Data from the national quality database, Swedish Dementia Registry (SveDem), including 6,937 dementia patients diagnosed during 2007-2009 at memory clinics were used. We have studied the use of investigations for dementia diagnostics such as cognitive tests, blood and cerebrospinal fluid analyses, electroencephalography, radiological examinations and assessments of functions. Severity of cognitive impairment was assessed with the Mini Mental State Examination (MMSE)., Results: There was a significant decrease in the number of total tests used in the elderly group (>75 years) when compared with the middle-aged group (65-75 years) and younger patients (<65 years). The oldest group was examined with 4 of 11 possible tests, the middle-aged group had 5/11 tests performed and the youngest age group 6/11 tests. There was also a significant gender difference in the diagnostic workup, however, mostly attributable to age. The number of tests positively correlated with the level of cognition assessed by the MMSE., Conclusion: We show here for the first time the impact of age, gender and MMSE score on the dementia diagnostic workup in a large memory clinic patient population in one country., (Copyright © 2012 S. Karger AG, Basel.)

Background: The costs of care for patients with Alzheimer's disease are correlated with key measures of disease severity. This relationship is important in the economic evaluation of new treatments and is used to translate treatment efficacy into effects on costs through economic modeling. We aimed to identify what measures of disease severity are the most important predictors of societal costs of care and whether their relationship differs across countries., Methods: Interviews were conducted with 1222 patient and caregiver pairs residing in the community or in residential care settings in Spain, Sweden, United Kingdom, and the United States. Assessments included costs of care (Resource Utilization in Dementia) and key disease severity measures: cognitive function (Mini-Mental State Examination), ability to perform Activities of Daily Living (ADL-ability, Disability Assessment for Dementia [DAD]), and behavioral symptoms (Neuropsychiatry Inventory (NPI)-severity)., Results: ADL-ability was the most important predictor of societal costs of care of community-dwelling patients in all countries. A one-point decrease in DAD resulted in a 1.4% increase in costs of care in Spain, United Kingdom, and the United States on average, and a 2% increase in Sweden. This translated into a 45% increase from a standard deviation decrease in DAD on average. NPI-severity and Mini-Mental State Examination were also significant predictors but with lesser effect. Although mean costs of care differed across countries, the important predictors were the same., Conclusion: ADL-ability is the most important predictor of societal costs of care in community dwellings irrespective of country and should therefore be central in the economic evaluation of Alzheimer's disease therapies., (Copyright © 2011 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background: Cognition, abilities in activities of daily living (ADL), and behavioral disturbances in patients with Alzheimer's disease (AD) all influence the number of hours informal caregivers spend caring for their patients, and the burden caregivers experience. However, the direct effect and relative importance of each disease severity measure remains unclear., Methods: Cross-sectional interviews were conducted with 1,222 AD patients and primary caregivers in Spain, Sweden, the U.K. and the U.S.A. Assessments included informal care hours, caregiver burden (Zarit Burden Inventory; ZBI), cognition (Mini-mental State Examination; MMSE), ADL-abilities (Disability Assessment for Dementia scale; DAD), and behavioral symptoms (Neuropsychiatric Inventory Questionnaire; NPI-severity)., Results: Multivariate analyses of 866 community-dwelling patients revealed that ADL-ability was the strongest predictor of informal care hours (36% decrease in informal care hours per standard deviation (SD) increase in DAD scores). Severity of behavioral disturbances was the strongest predictor of caregiver burden (0.35 SD increase in ZBI score per SD increase in NPI-Q severity score). In addition, the effect of ADL-abilities was, although attenuated, not negligible (0.28 SD increase in ZBI score per SD increase in DAD score). Decreasing cognition (MMSE) was associated with more informal care hours and increased caregiver burden in univariate, but not in adjusted analyses., Conclusions: For patients residing in community dwellings, the direct influence of patients' cognition on caregiver burden is limited and rather mediated by other disease indicators. Instead, the patients' ADL-abilities are the main predictor of informal care hours, and both ADL-abilities and behavioral disturbances are important predictors of perceived caregiver burden, where the latter has the strongest effect. These results were consistent across Sweden, U.K. and the U.S.A.

Objective: To estimate the value of informal care in Alzheimer's disease using contingent valuation., Methods: A questionnaire was administered to 517 primary carers in four countries (UK, Spain, Sweden, and US). Dichotomous choice and bidding game methods were used to elicit their willingness to pay for a reduction in care burden by 1 h per day, or a total elimination of care needs. Further, the relationship between carer willingness to pay and carer and patient characteristics including disease severity and income was examined., Results: Carers spend on average about 7-9 h per day on giving care to their patient, of which 4-5 h constituted basic and instrumental ADL tasks. For a 1 h reduction in need for care per day, carers in the UK, Spain, Sweden, and US said that they were willing to pay pound105, pound121, pound59, and pound144 per month respectively. The willingness to pay was higher for carers with higher disposable income while the influence of other determinants varied across countries. About one-third of carers were not willing to pay anything for a reduction in care., Conclusions: Carers' stated willingness to pay for reductions in care giving time is substantial and comparable to the prices currently paid for treatments that achieve this benefit. Its determinants seem more directly related to carer status than directly to patient status and may vary by region and by cultural and sociologic factors.

Introduction: Alzheimer's disease (AD) is one of the most important causes of morbidity and functional decline among the elderly and gives rise to substantial costs for society. There is today limited data on resource utilization and quality of life in AD, in particular in the severe stage of disease., Aims & Methods: The objectives of this study were to estimate the relationship between costs, patient and caregiver quality of life, and disease severity. For 233 patients in Sweden and their caregivers cross-sectional data on cognitive function (MMSE), ADL ability, behavioral disturbances, formal and informal resource use and health related quality of life (HRQoL) were collected by questionnaires to caregivers and to the treating physician. Patients were stratified into the disease stages mild, moderate and severe AD based on MMSE-scores., Results: The mean annual total cost in 2007 USD was 23,400 in mild, 56,800 in moderate and 71,400 in severe AD. Special forms of accommodation accounted for the majority of costs. Costs were higher for patients with lower cognitive function, lower ADL ability and more behavioral disturbances, with ADL ability being the most consistent predictor of costs. There were significant differences in HRQoL between the disease stages: health utility scores were 0.64 in mild, 0.39 in moderate and 0.24 in severe AD., Conclusions: The societal costs of AD are very high, especially for patients with moderate and severe AD. This implies that treatments with the ability to delay progression of the disease into more severe stages have the potential to save large costs for society.