People get ready! A new generation of Alzheimer's therapies may require new ways to deliver and pay for healthcare.

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.

Efficacy assessment of an active tau immunotherapy in Alzheimer's disease patients with amyloid and tau pathology: a post hoc analysis of the "ADAMANT" randomised, placebo-controlled, double-blind, multi-centre, phase 2 clinical trial.

BACKGROUND: Tau pathology correlates with and predicts clinical decline in Alzheimer's disease. Approved tau-targeted therapies are not available. METHODS: ADAMANT, a 24-month randomised, placebo-controlled, parallel-group, double-blinded, multicenter, Phase 2 clinical trial (EudraCT2015-000630-30, NCT02579252) enrolled 196 participants with Alzheimer's disease; 119 are included in this post-hoc subgroup analysis. AADvac1, active immunotherapy against pathological tau protein. A machine learning model predicted likely Amyloid+Tau+ participants from baseline MRI. STATISTICAL METHODS: MMRM for change from baseline in cognition, function, and neurodegeneration; linear regression for associations between antibody response and endpoints. RESULTS: The prediction model achieved PPV of 97.7% for amyloid, 96.2% for tau. 119 participants in the full analysis set (70 treatment and 49 placebo) were classified as A+T+. A trend for CDR-SB 104-week change (estimated marginal means [emm] = -0.99 points, 95% CI [-2.13, 0.13], p = 0.0825]) and ADCS-MCI-ADL (emm = 3.82 points, CI [-0.29, 7.92], p = 0.0679) in favour of the treatment group was seen. Reduction was seen in plasma NF-L (emm = -0.15 log pg/mL, CI [-0.27, -0.03], p = 0.0139). Higher antibody response to AADvac1 was related to slowing of decline on CDR-SB (rho = -0.10, CI [-0.21, 0.01], p = 0.0376) and ADL (rho = 0.15, CI [0.03, 0.27], p = 0.0201), and related to slower brain atrophy (rho = 0.18-0.35, p < 0.05 for temporal volume, whole cortex, and right and left hippocampus). CONCLUSIONS: In the subgroup of ML imputed or CSF identified A+T+, AADvac1 slowed AD-related decline in an antibody-dependent manner. Larger anti-tau trials are warranted. FUNDING: AXON Neuroscience SE.

Feasibility of a standard cognitive assessment in European academic memory clinics.

INTRODUCTION: Standardized cognitive assessment would enhance diagnostic reliability across memory clinics. An expert consensus adapted the Uniform Dataset (UDS)-3 for European centers, the clinician's UDS (cUDS). This study assessed its implementation acceptability and feasibility. METHODS: We developed a survey investigating barriers, facilitators, and willingness to implement the cUDS. With a mixed-methods design, we analyzed data from academic memory clinics. RESULTS: Seventy-eight percent of responding clinicians were experienced neuropsychologists/psychologists and 22% were medical specialists coming from 18 European countries. Sixty-five percent clinicians were willing to implement cUDS. General barriers related to implementation (43%) and clinical-methodological domains (21%). Favorable clinicians reported finances (15%) and digitalization (9%) as facilitating, but unavailability of local norms (23%) as hindering. Unfavorable clinicians reported logistical (23%) and time issues (18%). DISCUSSION: Despite challenges, data showed moderate clinicians' acceptability and requirements to improve feasibility. Nonetheless, these results come from academic clinicians. The next steps will require feasibility evaluation in non-academic contexts.

Cost-effectiveness models for Alzheimer's disease and related dementias: IPECAD modeling workshop cross-comparison challenge.

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.

Cost of Diagnosing and Treating Cognitive Complaints: One-year Cost-evaluation Study in a Patient Cohort from a Slovenian Memory Clinic.

Introduction: Dementias present a global health challenge and give rise to significant economic costs. This study aims to evaluate the economic impact of one-year outpatient healthcare, nursing home, and formal and informal home help costs for all patients referred to the Centre for Cognitive Impairments at the Department of Neurology, Ljubljana University Medical Centre, Slovenia. Methods: Data was acquired retrospectively from physicians' records and the costs for 2015 were calculated. Total costs were estimated by means of a bottom-up calculation of outpatient visits, diagnostic examinations and anti-dementia medication. In a subgroup of 120 patients with dementia, the Resource Utilization in Dementia questionnaire was used to estimate formal and informal care costs. Results: A total of 720 patients visited the memory clinic in 2015. Diagnosis at first visit was subjective cognitive or mild cognitive impairment (SCI/ MCI) for 322 patients, dementia for 258 patients, and psychiatric or other disorders for 140 patients. The average annual cost per patient was EUR 578. It was highest for patients with dementia (EUR 751), EUR 550 for patients with SCI/MCI, and lowest for patients with psychiatric and other disorders (EUR 324). Monthly informal and social care costs were between EUR 1,037 and EUR 3,369, depending on the methodology used. Conclusion: The cost of diagnosing a cognitive disorder depends on how extensive the diagnosis is. With an estimated prevalence of 34,137 persons with dementia in Slovenia, basic diagnostic investigations incur costs of approximately EUR 7 million. Direct medical costs represent a smaller portion of total dementia costs; this is because annual costs for formal and informal home help are estimated at EUR 265 million and nursing home placements at EUR 105 million.

Cognitive Effects of the BET Protein Inhibitor Apabetalone: A Prespecified Montreal Cognitive Assessment Analysis Nested in the BETonMACE Randomized Controlled Trial.

BACKGROUND: Epigenetic changes may contribute importantly to cognitive decline in late life including Alzheimer's disease (AD) and vascular dementia (VaD). Bromodomain and extra-terminal (BET) proteins are epigenetic "readers" that may distort normal gene expression and contribute to chronic disorders. OBJECTIVE: To assess the effects of apabetalone, a small molecule BET protein inhibitor, on cognitive performance of patients 70 years or older participating in a randomized trial of patients at high risk for major cardiovascular events (MACE). METHODS: The Montreal Cognitive Assessment (MoCA) was performed on all patients 70 years or older at the time of randomization. 464 participants were randomized to apabetalone or placebo in the cognition sub-study. In a prespecified analysis, participants were assigned to one of three groups: MoCA score≥26 (normal performance), MoCA score 25-22 (mild cognitive impairment), and MoCA score≤21 (dementia). Exposure to apabetalone was equivalent in the treatment groups in each MoCA-defined group. RESULTS: Apabetalone was associated with an increased total MoCA score in participants with baseline MoCA score of≤21 (p = 0.02). There was no significant difference in change from baseline in the treatment groups with higher MoCA scores. In the cognition study, more patients randomized to apabetalone discontinued study drug for adverse effects (11.3% versus 7.9%). CONCLUSION: In this randomized controlled study, apabetalone was associated with improved cognition as measured by MoCA scores in those with baseline scores of 21 or less. BET protein inhibitors warrant further investigation for late life cognitive disorders.

A Cost-Consequence Analysis of Different Screening Procedures in Alzheimer's Disease: Results from the MOPEAD Project.

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.

Quantifying and Describing the Natural History and Costs of Alzheimer's Disease and Effects of Hypothetical Interventions.

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.

The thriving of older people assessment scale: Psychometric evaluation and short-form development.

AIM: To evaluate the psychometric properties and performance of the 32-item Thriving of Older People Assessment Scale (TOPAS) and to explore reduction into a short-form. BACKGROUND: The 32-item TOPAS has been used in studies of place-related well-being as a positive measure in long-term care to assess nursing home resident thriving; however, item redundancy has not previously been explored. DESIGN: Cross-sectional study. METHOD: Staff members completed the 32-item TOPAS as proxy raters for a random sample of Swedish nursing home residents (N = 4,831) between November 2013 - September 2014. Reliability analysis, exploratory factor analysis and item response theory-based analysis were undertaken. Items were systematically identified for reduction using statistical and theoretical analysis. Correlation testing, means comparison and model fit evaluation confirmed scale equivalence. RESULTS: Psychometric properties of the 32-item TOPAS were satisfactory and several items were identified for scale reduction. The proposed short-form TOPAS exhibited a high level of internal consistency (α = 0.90) and strong correlation (r = 0.98) to the original scale, while also retaining diversity among items in terms of factor structure and item difficulties. CONCLUSION: The 32-item and short-form TOPAS' indicated sound validity and reliability to measure resident thriving in the nursing home context. IMPACT: There is a lack of positive life-world measures for use in nursing homes. The short-form TOPAS indicated sound validity and reliability to measure resident thriving, providing a feasible measure with enhanced functionality for use in aged care research, assessments and care planning for health-promoting purposes in nursing homes.

Assessing cost-effectiveness of early intervention in Alzheimer's disease: An open-source modeling framework.

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.

Residing in sheltered housing versus ageing in place - Population characteristics, health status and social participation.

Sheltered housing is a housing model that provides accessible apartments with elevated social possibilities for older people, which is expected to increase resident health and independence, reducing the need for care. As previous research on sheltered housing is scarce, the aim of this study was to explore the characteristics, health status and social participation of older people living in sheltered housing, compared to ageing in place. The study utilised baseline data from a matched cohort study survey on a nationally representative total population of residents in all sheltered housings in Sweden, and a matched control group (n = 3,805). The data collection took place between October 2016 and January 2017. The survey assessed functional capability using the Katz ADL and Lawton IADL scale, self-rated health using the EQ5D scale, and depressive mood using the GDS-4 scale. Descriptive statistics, frequencies, mean scores, independent t tests, p-values and effect sizes were utilised to compare the two groups. The results of the study show that older people living in sheltered housing, compared to ageing in place, had lower self-reported health (M = 64.68/70.08, p = <0.001), lower self-reported quality of life (M = 0.73/0.81, p = <0.001), lower functional status concerning activities of daily living (M = 5.19/5.40, p = <0.001), lower functional status concerning instrumental activities of daily living (M = 4.98/5.42 p = <0.001,), and higher probability of depressive mood (M = 0.80/0.58, p = <0.001). The results imply that residents in sheltered housing may have more care needs than those ageing in place. Further longitudinal comparative studies are needed to explore the impact residence in sheltered housing has on resident health and well-being.

Development of GMP-1 a molecular chaperone network modulator protecting mitochondrial function and its assessment in fly and mice models of Alzheimer's disease.

Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD) and may play an important role in the pathogenesis of disease. It has been shown that amyloid beta peptide (Aß) and amyloid precursor protein (APP) interact with mitochondria contributing to the mitochondrial dysfunction in AD. Prevention of abnormal protein targeting to mitochondria can protect normal mitochondrial function, increase neuronal survival and at the end, ameliorate symptoms of AD and other neurodegenerative disorders. First steps of mitochondrial protein import are coordinated by molecular chaperones Hsp70 and Hsp90 that bind to the newly synthesized mitochondria-destined proteins and deliver them to the protein import receptors on the surface of organelle. Here, we have described the development of a novel compound named GMP-1 that disrupts interactions between Hsp70/Hsp90 molecular chaperones and protein import receptor Tom70. GMP-1 treatment of SH-SY5Y cells results in decrease in mitochondria-associated APP and protects SH-SY5Y cells from toxic effect of Aß1-42 exposure. Experiments in drosophila and mice models of AD demonstrated neuroprotective effect of GMP-1 treatment, improvement in memory and behaviour tests as well as restoration of mitochondrial function.

Cost-Utility of Using Alzheimer's Disease Biomarkers in Cerebrospinal Fluid to Predict Progression from Mild Cognitive Impairment to Dementia.

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.

The worldwide costs of dementia 2015 and comparisons with 2010.

INTRODUCTION: In 2010, Alzheimer's Disease International presented estimates of the global cost of illness (COI) of dementia. Since then, new studies have been conducted, and the number of people with dementia has increased. Here, we present an update of the global cost estimates. METHODS: This is a societal, prevalence-based global COI study. RESULTS: The worldwide costs of dementia were estimated at United States (US) $818 billion in 2015, an increase of 35% since 2010; 86% of the costs occur in high-income countries. Costs of informal care and the direct costs of social care still contribute similar proportions of total costs, whereas the costs in the medical sector are much lower. The threshold of US $1 trillion will be crossed by 2018. DISCUSSION: Worldwide costs of dementia are enormous and still inequitably distributed. The increase in costs arises from increases in numbers of people with dementia and in increases in per person costs.

Assessment and Reporting of Driving Fitness in Patients with Dementia in Clinical Practice: Data from SveDem, the Swedish Dementia Registry.

BACKGROUND: Driving constitutes a very important aspect of daily life and is dependent on cognitive functions such as attention, visuo-spatial skills and memory, which are often compromised in dementia. Therefore, the driving fitness of patients with dementia needs to be addressed by physicians and those that are deemed unfit should not be allowed to continue driving. OBJECTIVE: We aimed at investigating to what extent physicians assess driving fitness in dementia patients and determinant factors for revoking of their licenses. METHODS: This study includes 15113 patients with newly diagnosed dementia and driver's license registered in the Swedish Dementia Registry (SveDem). The main outcomes were reporting to the licensing authority and making an agreement about driving eligibility with the patients. RESULTS: Physicians had not taken any action in 16% of dementia patients, whereas 9% were reported to the authority to have their licenses revoked. Males (OR = 3.04), those with an MMSE score between 20-24 (OR = 1.35) and 10-19 (OR = 1.50), patients with frontotemporal (OR = 3.09) and vascular dementia (OR = 1.26) were more likely to be reported to the authority. CONCLUSION: For the majority of patients with dementia, driving fitness was assessed. Nevertheless, physicians did not address the issue in a sizeable proportion of dementia patients. Type of dementia, cognitive status, age, sex and burden of comorbidities are independent factors associated with the assessment of driving fitness in patients with dementia. Increased knowledge on how these factors relate to road safety may pave the way for more specific guidelines addressing the issue of driving in patients with dementia.

Alzheimer disease. Donepezil and nursing home placement--benefits and costs.

The recent DOMINO-AD trial suggests that continued treatment with donepezil delays nursing home placement for patients with severe Alzheimer disease, but more work is needed to support strong conclusions about whether the benefits outweigh the costs.

Neuropathologic assessment of dementia markers in identical and fraternal twins.

Twin studies are an incomparable source of investigation to shed light on genetic and non-genetic components of neurodegenerative diseases, as Alzheimer's disease (AD). Detailed clinicopathologic correlations using twin longitudinal data and post-mortem examinations are mostly missing. We describe clinical and pathologic findings of seven monozygotic (MZ) and dizygotic (DZ) twin pairs. Our findings show good agreement between clinical and pathologic diagnoses in the majority of the twin pairs, with greater neuropathologic concordance in MZ than DZ twins. Greater neuropathologic concordance was found for ß-amyloid than tau pathology within the pairs. ApoE4 was associated with higher ß-amyloid and earlier dementia onset, and importantly, higher frequency of other co-occurring brain pathologies, regardless of the zygosity. Dementia onset, dementia duration, difference between twins in age at dementia onset and at death, did not correlate with AD pathology. These clinicopathologic correlations of older identical and fraternal twins support the relevance of genetic factors in AD, but not their sufficiency to determine the pathology, and consequently the disease, even in monozygotic twins. It is the interaction among genetic and non-genetic risks which plays a major role in influencing, or probably determining, the degeneration of those brain circuits associated with pathology and cognitive deficits in AD.

Costs of diagnosing dementia: results from SveDem, the Swedish Dementia Registry.

OBJECTIVE: Diagnostic of different dementia disorders is an important part of dementia care. So far, there is limited knowledge about how dementia is diagnosed in clinical routine, and there are few reports on the costs of the dementia work-up leading to a diagnosis. Here, we examine the costs of diagnostic dementia work-up in Sweden. METHODS: The analyses were made on the data from the Swedish Dementia Registry (SveDem) and included 11,561 dementia patients diagnosed during 2007-2010, mainly not only in specialist care (SC) (n = 53) but also some primary care centres (PC). We have studied differences in the use of investigations for dementia diagnostics such as cognitive tests, blood and cerebrospinal fluid analyses, radiological examinations and assessments of functions. Unit costs for each diagnostic investigation were combined with the use of these investigations for all cases in the database. Results are presented versus gender and stratified for age. RESULTS: The number of diagnostic tests performed was 2.8 in PC and 4.6 in SC. The average costs (€1 = SEK9 and US$1 = SEK7 in 2010) were SEK6777 in PC and SEK11,682 in SC. Age was the strongest cost predictor while there were no gender differences. There were also regional differences, ranging from SEK8231 to SEK14,734 in SC. CONCLUSIONS: The SveDem database offers valuable information on the diagnostic procedures for dementia in daily clinical practice. The differences between PC and SC in diagnostic costs reflect national guidelines. The age effect needs to be studied more.

The worldwide economic impact of dementia 2010.

OBJECTIVE: To acquire an understanding of the societal costs of dementia and how they affect families, health and social care services, and governments to improve the lives of people with dementia and their caregivers. METHODS: The basic design of this study was a societal, prevalence-based, gross cost-of-illness study in which costs were aggregated to World Health Organization regions and World Bank income groupings. RESULTS: The total estimated worldwide costs of dementia were US$604 billion in 2010. About 70% of the costs occurred in western Europe and North America. In such high-income regions, costs of informal care and the direct costs of social care contribute similar proportions of total costs, whereas the direct medical costs were much lower. In low- and middle-income countries, informal care accounts for the majority of total costs; direct social care costs are negligible. CONCLUSIONS: Worldwide costs of dementia are enormous and distributed inequitably. There is considerable potential for cost increases in coming years as the diagnosis and treatment gap is reduced. There is also likely to be a trend in low- and middle-income countries for social care costs to shift from the informal to the formal sector, with important implications for future aggregated costs and the financing of long-term care. Only by investing now in research and the development of cost-effective approaches to early diagnosis and care can future societal costs be anticipated and managed.