Clinical Characterization of Veterans With Alzheimer Disease by Disease Severity in the United States.

PURPOSE: We aimed to examine the clinical characteristics of US veterans who underwent neurocognitive test score-based assessments of Alzheimer disease (AD) stage in the Veterans Affairs Healthcare System (VAHS). METHODS: Test dates for specific stages of AD were referenced as index dates to study behavioral and psychological symptoms of dementia (BPSD) and other patient characteristics related to utilization/work-up and time to death. PATIENTS: We identified veterans with AD and neurocognitive evaluations using the VAHS Electronic Health Record (EHR). RESULTS: Anxiety and sleep disorders/disturbances were the most documented BPSDs across all AD severity stages. Magnetic resonance imaging, neurology and psychiatry consultations, and neuropsychiatric evaluations were slightly higher in veterans with mild AD than in those at later stages. The overall average time to death from the first AD severity record was 5 years for mild and 4 years for moderate/severe AD. CONCLUSION: We found differences in clinical symptoms, healthcare utilization, and survival among the mild, moderate, and severe stages of AD. These differences are limited by the low documentation of BPSDs among veterans with test score-based AD stages. These data support the hypothesis that our cohorts represent coherent subgroups of patients with AD based on disease severity.

Assessing Quality of Life, Economic Burden, and Independence Across the Alzheimer's Disease Continuum Using Patient-Caregiver Dyad Surveys.

Background: Alzheimer's disease (AD) and mild cognitive impairment (MCI) have negative quality of life (QoL) and economic impacts on patients and their caregivers and may increase along the disease continuum from MCI to mild, moderate, and severe AD. Objective: To assess how patient and caregiver QoL, indirect and intangible costs are associated with MCI and AD severity. Methods: An on-line survey of physician-identified patient-caregiver dyads living in the United States was conducted from June-October 2022 and included questions to both patients and their caregivers. Dementia Quality of Life Proxy, the Care-related Quality of Life, Work Productivity and Activity Impairment, and Dependence scale were incorporated into the survey. Regression analyses investigated the association between disease severity and QoL and cost outcomes with adjustment for baseline characteristics. Results: One-hundred patient-caregiver dyads were assessed with the survey (MCI, n = 27; mild AD, n = 27; moderate AD, n = 25; severe AD, n = 21). Decreased QoL was found with worsening severity in patients (p < 0.01) and in unpaid (informal) caregivers (n = 79; p = 0.02). Dependence increased with disease severity (p < 0.01). Advanced disease severity was associated with higher costs to employers (p = 0.04), but not with indirect costs to caregivers. Patient and unpaid caregiver intangible costs increased with disease severity (p < 0.01). A significant trend of higher summed costs (indirect costs to caregivers, costs to employers, intangible costs to patients and caregivers) in more severe AD was observed (p < 0.01). Conclusions: Patient QoL and functional independence and unpaid caregiver QoL decrease as AD severity increases. Intangible costs to patients and summed costs increase with disease severity and are highest in severe AD.

Alzheimer's Disease Stage Transitions Among United States Veterans.

BACKGROUND: Alzheimer's disease (AD) and related dementias are progressive neurological disorders with stage-specific clinical features and challenges. An important knowledge gap is the "window of time" within which patients transition from mild cognitive impairment or mild AD to moderate or severe AD. Better characterization/establishment of transition times would help clinicians initiating treatments, including anti-amyloid therapy. OBJECTIVE: To describe cognitive test score-based AD stage transitions in Veterans with AD in the US Veterans Affairs Healthcare System (VAHS). METHODS: This retrospective analysis (2010-2019) identified Veterans with AD from the VAHS Electronic Health Record (EHR) notes. AD stage was based on Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), or Saint Louis University Mental Status (SLUMS) Examination scores in the EHR. RESULTS: We identified 296,519 Veterans with cognitive test-based AD staging. Over the 10-year study, the proportion of veterans with MMSE scores declined from 24.9% to 9.5% while those with SLUMS rose from 9.0% to 17.8%; and MoCA rose from 5.0% to 25.4%. The average forward transition times between each stage were approximately 2-4 years, whether assessed by MMSE, MoCA, or SLUMS. CONCLUSION: The average transition time for cognitive test-based assessments of initial cognitive decline, early-stage AD, and moderate/severe AD in the VAHS is 2-4 years. In view of the short window for introducing disease-modifying therapy and the significant benefits of early treatment of AD, our data suggest a critical need for treatment guidelines in the management of AD.

The Role of Mental Health Conditions in Early Detection and Treatment of Veterans With Alzheimer's Dementia.

INTRODUCTION: The benefits of early detection of Alzheimer's disease (AD) have become increasingly recognized. Veterans with mental health conditions (MHCs) may be less likely to receive a specific AD diagnosis compared to veterans without MHCs. We investigated whether rates of MHCs differed between veterans diagnosed with unspecified dementia (UD) vs. AD to better understand the role MHCs might play in establishing a diagnosis of AD. MATERIALS AND METHODS: This retrospective analysis (2015-2022) identified UD and AD with diagnostic code-based criteria. We determined the proportion of veterans with MHCs in UD vs. AD cohorts. Secondarily, we assessed the distribution of UD/AD diagnoses in veterans with and without MHCs. RESULTS: We identified 145,309 veterans with UD and 33,996 with AD. The proportion of each MHC was consistently higher in UD vs. AD cohorts: 41.4% vs. 33.2% (depression), 26.9% vs. 20.3% (post-traumatic stress disorder), 23.4% vs. 18.2% (anxiety), 4.3% vs. 2.1% (bipolar disorder), and 3.9% vs. 1.5% (schizophrenia). The UD diagnostic code was used in 84% of veterans with MHCs vs. 78% without MHCs (P < .001). CONCLUSIONS: Mental health conditions were more likely in veterans with UD vs. AD diagnoses; comorbid MHC may contribute to delayed AD diagnosis.

Understanding Barriers Along the Patient Journey in Alzheimer's Disease Using Social Media Data.

INTRODUCTION: We speculated that social media data from Alzheimer's disease (AD) stakeholders (patients, caregivers, and clinicians) could identify barriers along the patient journey in AD, and that insights gained may help devise strategies to remove barriers, and ultimately improve the patient journey. METHODS: Our sample was drawn from a repository of social media posts extracted from 112 public sources between January 1998 and December 2021 using natural language processing text-mining algorithms. The patient journey was classified into three phases: (1) early signs/experiences (Early Signs); (2) screening/assessment/diagnosis (Screening); and (3) treatment/management (Treatment). In the Early Signs phase, issues/challenges derived from a conceptual AD identification framework (ADIF) were examined. In subsequent phases, behavioral/psychiatric challenges, access/barriers to health care, screening/diagnostic methods, and symptomatic treatments for AD were identified. Posts were classified by AD stakeholder type or disease stage, if possible. RESULTS: We identified 225,977 AD patient journey-related social media posts. Anxiety was a predominant issue/challenge in all patient journey phases. In the Screening and Treatment phases combined, access/barriers to care were described in 16% of posts; unwillingness/resistance to seeking care was a major barrier (≥ 75% of access-related posts across all stakeholders). Commonly identified structural barriers (e.g., affordability/cost, geography/transportation/distance) were more common in patient/caregiver posts than clinician posts. Among Screening-related posts, imaging/scans were commonly mentioned by all stakeholders; biomarkers were more commonly mentioned by patients than clinicians. Treatment-related concerns were identified in 17% of stakeholder-specified posts that named pharmacological agents/classes for the symptomatic management of AD. CONCLUSION: This descriptive analysis of out-of-clinic experiences reflected in AD social media posts found that unwillingness/resistance to seeking care was a key barrier, followed by structural barriers to health care, such as affordability/cost. Insights from the lived experiences of AD stakeholders are valuable and highlight the need to improve the patient journey in AD and ease patient and caregiver burden.

Estimating Transition Probabilities Across the Alzheimer's Disease Continuum Using a Nationally Representative Real-World Database in the United States.

INTRODUCTION: Clinical Alzheimer's disease (AD) begins with mild cognitive impairment (MCI) and progresses to mild, moderate, or severe dementia, constituting a disease continuum that eventually leads to death. This study aimed to estimate the probabilities of transitions across those disease states. METHODS: We developed a mixed-effects multi-state Markov model to estimate the transition probabilities, adjusted for 5 baseline covariates, using the Health and Retirement Study (HRS) database. HRS surveys older adults in the United States bi-annually. Alzheimer states were defined using the modified Telephone Interview of Cognitive Status (TICS-m). RESULTS: A total of 11,292 AD patients were analyzed. Patients were 70.8 ± 9.0 years old, 54.9% female, and with 12.0 ± 3.3 years of education. Within 1 year from the initial state, the model estimated a higher probability of transition to the next AD state in earlier disease: 12.8% from MCI to mild AD and 5.0% from mild to moderate AD, but < 1% from moderate to severe AD. After 10 years, the probability of transition to the next state was markedly higher for all states, but still higher in earlier disease: 29.8% from MCI to mild AD, 23.5% from mild to moderate AD, and 5.7% from moderate to severe AD. Across all AD states, the probability of transition to death was < 5% after 1 year and > 15% after 10 years. Older age, fewer years of education, unemployment, and nursing home stay were associated with a higher risk of disease progression (p < 0.01). CONCLUSIONS: This analysis shows that the risk of progression is greater in earlier AD states, increases over time, and is higher in patients who are older, with fewer years of education, unemployed, or in a nursing home at baseline. The estimated transition probabilities can provide guidance for future disease management and clinical trial design optimization, and can be used to refine existing cost-effectiveness frameworks.

Clinical and Scientific Challenges to Effectiveness Studies Under Coverage with Evidence Development in Alzheimer's Disease.

The Centers for Medicare and Medicaid Services (CMS) has recently issued a national coverage determination for US Food and Drug Administration (FDA)-approved anti-amyloid monoclonal antibodies (mAbs) for the treatment of Alzheimer's disease (AD) under coverage with evidence development (CED). CED schemes are complex, costly, and challenging, and often fail to achieve intended objectives because of administrative and implementation issues. AD is a heterogeneous, progressive neurodegenerative disorder with complex care pathway that additionally presents scientific challenges related to the choice of study design and methods used in evaluating CED schemes. These challenges are herein discussed. Clinical findings from the US Veterans Affairs healthcare system help inform our discussion of specific challenges to CED-required effectiveness studies in AD.

Estimated Societal Value of Lecanemab in Patients with Early Alzheimer's Disease Using Simulation Modeling.

INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with memory, cognitive, and behavioral deficits, and brings significant economic burden on caregivers and healthcare systems. This study aims to estimate the long-term societal value of lecanemab plus standard of care (SoC) versus SoC alone, corresponding to a range of willingness-to-pay (WTP) thresholds based on the phase III CLARITY AD trial readouts from both the US payer and societal perspectives. METHODS: An evidence-based model was developed to simulate the effects of lecanemab on disease progression in early AD using interconnected predictive equations based on longitudinal clinical and biomarker data derived from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The model was informed with the results of the phase III CLARITY AD trial and published literature. Key model outcomes included patient life-years (LYs), quality-adjusted life-years (QALYs), and total costs of both the direct and indirect costs of patients and caregivers over a lifetime horizon. RESULTS: Patients treated with lecanemab plus SoC gained an additional 0.62 years of life versus SoC alone (6.23 years vs. 5.61 years). The mean time on lecanemab was 3.91 years, and the treatment was associated with an increase in patient QALYs of 0.61 and an increase in total QALYs of 0.64 when both patient and caregiver utilities were considered. The model estimated that the annual value of lecanemab for the US payer perspective was US$18,709-35,678 ($19,710-37,351 for societal perspective) at the WTP threshold of $100,000-200,000 per QALY gained, respectively. Scenario analyses of patient subgroups, time horizon, input sources, treatment stopping rules, and treatment dosing were conducted to explore the impact of alternative assumptions on the model results. CONCLUSION: The economic study suggested that lecanemab plus SoC would improve health and humanistic (quality of life) outcomes and reduce economic burden for patients and caregivers in early AD.

A Path to Improved Alzheimer's Care: Simulating Long-Term Health Outcomes of Lecanemab in Early Alzheimer's Disease from the CLARITY AD Trial.

INTRODUCTION: Alzheimer's disease (AD), a progressive neurodegenerative disease, is the main cause of dementia and one of the leading causes of death for elderly people in the USA. Lecanemab is a humanized IgG1 monoclonal antibody targeting amyloid protofibrils for the treatment of early AD [i.e., mild cognitive impairment (MCI) or mild AD dementia]. In a recent 18-month phase III trial, using a double-blind, placebo-controlled design, lecanemab treatment led to reduced brain amyloid burden and significant improvements in cognitive and functional abilities in individuals with early AD. METHODS: An evidence-based patient-level disease simulation model was updated to estimate the long-term health outcomes of lecanemab plus standard of care (SoC) compared to SoC alone in patients with early AD and evidence of brain amyloid burden, using recent phase III trial data and published literature. The disease progression is described by changes in the underlying biomarkers of AD, including measures of amyloid and tau, and their connection to the clinical presentation of the disease assessed through various patient-level scales of cognition and function. RESULTS: Lecanemab treatment was estimated to slow the progression of AD to moderate and severe stages and reduce the time spent in these more advanced states. In individuals with early AD, lecanemab plus SoC was associated with a gain of 0.71 quality-adjusted life-years (QALYs), a 2.95-year delay in mean time to progression to AD dementia, a reduction of 0.11 years in institutional care, and an additional 1.07 years in community care as shown in the base-case study. Improved health outcomes were demonstrated with lecanemab treatment when initiated earlier based on age, disease severity, or tau pathology, resulting in estimated gains in QALYs ranging from 0.77 to 1.09 years, compared to 0.4 years in the mild AD dementia subset, as shown by the model. CONCLUSION: The study findings demonstrate the potential clinical value of lecanemab for individuals with early AD by slowing down disease progression and prolonging time in earlier stages of disease, which significantly benefits not only patients and caregivers but also society overall. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03887455.

Treatment Preference for Alzheimer's Disease: A Multicriteria Decision Analysis with Caregivers, Neurologists, and Payors.

INTRODUCTION: Alzheimer's disease (AD) is a chronic neurodegenerative disorder associated with a high burden of illness. New therapies under development include agents that target amyloid-beta (Aß), a key component in AD pathogenesis. Understanding the decision-making process for new AD drugs would help determine if such therapies should be adopted by society. Multicriteria decision analysis (MCDA) was applied to three key stakeholder groups to assess treatment alternatives for AD based on a multitude of decision trade-offs covering main components of care. METHODS: AD caregivers (n = 117), neurologists (n = 90), and payors (n = 90) from the USA received an online survey. The decision problem was broken down into four decision criterion and 12 subcriteria for two treatment scenarios: an Aß-targeted therapy vs. the standard of care (SOC). Respondents were asked to indicate how much they preferred one option over another on a scale from 1 (equal preference) to 9 (high preference) based on each criterion and subcriterion. The decision criteria and subcriteria were weighted and presented as partial utility scores (pUS), with higher scores suggesting an increased preference for that decision-making component. RESULTS: Caregivers and payors applied the highest value to need for intervention (mean pUS = 0.303 and 0.259) and clinical outcomes (mean pUS = 0.286 and 0.377). In contrast, neurologists placed the highest value on clinical outcomes and types of benefits (mean pUS = 0.436 and 0.248). When decision subcriteria were examined, efficacy (mean pUS = 0.115, 0.219, and 0.166) and the type of patient benefits (mean pUS = 0.135, 0.178, and 0.126) were among the most valued by caregivers, neurologists, and payors. CONCLUSION: All groups placed the highest value on drug efficacy and types of benefit derived by patients. In contrast, cost implications were among the least important aspects in their decision-making.

Predicting the Societal Value of Lecanemab in Early Alzheimer's Disease in Japan: A Patient-Level Simulation.

INTRODUCTION: Alzheimer's disease (AD), a neurodegenerative disorder that progresses from mild cognitive impairment (MCI) to dementia, is responsible for significant burden on caregivers and healthcare systems. In this study, data from the large phase III CLARITY AD trial were used to estimate the societal value of lecanemab plus standard of care (SoC) versus SoC alone against a range of willingness-to-pay (WTP) thresholds from a healthcare and societal perspective in Japan. METHODS: A disease simulation model was used to evaluate the impact of lecanemab on disease progression in early AD based on data from the phase III CLARITY AD trial and published literature. The model used a series of predictive risk equations based on clinical and biomarker data from the Alzheimer's Disease Neuroimaging Initiative and Assessment of Health Economics in Alzheimer's Disease II study. The model predicted key patient outcomes, including life years (LYs), quality-adjusted life years (QALYs), and total healthcare and informal costs of patients and caregivers. RESULTS: Over a lifetime horizon, patients treated with lecanemab plus SoC gained an additional 0.73 LYs compared with SoC alone (8.50 years vs. 7.77 years). Lecanemab, with an average treatment duration of 3.68 years, was found to be associated with a 0.91 increase in patient QALYs and a total increase of 0.96 when accounting for caregiver utility. The estimated value of lecanemab varied according to the WTP thresholds (JPY 5-15 million per QALY gained) and the perspective employed. From the narrow healthcare payer's perspective, it ranged from JPY 1,331,305 to JPY 3,939,399. From the broader healthcare payer's perspective, it ranged from JPY 1,636,827 to JPY 4,249,702, while from the societal perspective, it ranged from JPY 1,938,740 to JPY 4,675,818. CONCLUSION: The use of lecanemab plus SoC would improve health and humanistic outcomes with reduced economic burden for patients and caregivers with early AD in Japan.

A Systematic Review of Clinical Practice Guidelines for Alzheimer's Disease and Strategies for Future Advancements.

INTRODUCTION: Alzheimer's disease (AD) is a disease continuum from pathophysiologic, biomarker and clinical perspectives. With the advent of advanced technologies, diagnosing and managing patients is evolving. METHODS: A systematic literature review (SLR) of practice guidelines for mild cognitive impairment (MCI) and AD dementia was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). This systematic literature review (SLR) aimed to summarize current clinical practice guidelines for screening, testing, diagnosis, treatment and monitoring in the AD continuum. The results of this SLR were used to propose a way forward for practice guidelines given the possible introduction of biomarker-guided technology using blood- or plasma-based assays and disease-modifying treatments (DMTs) targeted for early disease. RESULTS: 53 clinical practice guidelines were identified, 15 of which were published since 2018. Screening for asymptomatic populations was not recommended. Biomarker testing was not included in routine diagnostic practice. There was no consensus on which neurocognitive tests to use to diagnose and monitor MCI or AD dementia. Pharmacologic therapies were not recommended for MCI, while cholinesterase inhibitors and memantine were recommended for AD treatment. DISCUSSION: The pre-2018 and post-2018 practice guidelines share similar recommendations for screening, diagnosis and treatment. However, once DMTs are approved, clinicians will require guidance on the appropriate use of DMTs in a clinical setting. This guidance should include strategies for identifying eligible patients and evaluating the DMT benefit-to-risk profile to facilitate shared decision-making among physicians, patients and care partners. CONCLUSION: Regular evidence-based updates of existing guidelines for the AD continuum are required over the coming decades to integrate rapidly evolving technologic and medical scientific advances and bring emerging approaches for management of early disease into clinical practice. This will pave the way toward biomarker-guided identification and targeted treatment and the realization of precision medicine for AD.

Staging Disease Severity Using the Alzheimer's Disease Composite Score (ADCOMS): A Retrospective Data Analysis.

INTRODUCTION: The Alzheimer's disease (AD) composite score (ADCOMS) has been shown to be a more sensitive measure of cognitive change in early AD (i.e., mild cognitive impairment [MCI] and mild AD) than commonly used measures. This study derived ADCOMS value ranges associated with different disease severity stages across the predementia and AD continuum. METHODS: Data from patients enrolled in the Alzheimer's Disease Neuroimaging Initiative were assessed at baseline and month 24. Data were randomly split into derivation and validation samples. Receiver-operating characteristic (ROC) curves of ADCOMS values were generated in the derivation sample to assess the sensitivity and specificity of ADCOMS cutoff values compared with existing disease severity cutoff scores using the Clinical Dementia Rating (CDR) global, CDR Sum of Boxes, Alzheimer's Disease Assessment Scale-Cognitive Subscale, and Mini-Mental State Examination. Optimal ADCOMS cutoff values for each disease stage were compared between the derivation and the validation samples using a χ2 test. The diagnostic accuracy of the derived ADCOMS cutoff values was then assessed. The analyses were repeated for the subset with positive amyloid ß confirmation (Aß +). RESULTS: The following ADCOMS value ranges for the total population and Aß + population were identified: < 0.29 indicative of normal cognition, 0.29 to < 0.45 indicative of MCI, 0.45-0.77 indicative of mild AD, and > 0.77 indicative of at least moderate AD. The reliability of these ADCOMS value ranges was supported by diagnostic accuracy tests and tests indicating no significant difference in the ROC curves between the derivation and validation samples. CONCLUSION: ADCOMS values ranges can be used to assess the severity of cognitive decline. The derived severity threshold score ranges for ADCOMS will enable its use as an endpoint in clinical trials assessing disease progression and clinical outcomes of disease-modifying therapies in persons with MCI or early AD, including patients with Aß + confirmation.

Assessing the Clinical Meaningfulness of the Alzheimer's Disease Composite Score (ADCOMS) Tool.

INTRODUCTION: The Alzheimer's Disease Composite Score (ADCOMS) is a tool developed to detect clinical progression and measure treatment effect in patients in early stages of Alzheimer's disease (AD). The psychometric properties of the ADCOMS have been established; however, the threshold for clinical meaningfulness has yet to be identified. METHODS: Anchor-based, distribution-based, and ROC curve analyses were used to estimate clinically meaningful thresholds for change in ADCOMS for patients with mild cognitive impairment (MCI) and AD dementia. This study included data from three sources: the Alzheimer's Disease Neuroimaging Initiative (ADNI), the National Alzheimer's Coordinating Center (NACC), and a legacy dataset that included data from four sources: the placebo group from three MCI trials and an earlier data cut from ADNI. Results were stratified by disease severity (MCI vs. dementia) and APOE ε4 carrier status. RESULTS: A total of 5355 participants were included in the analysis. The ADCOMS was able to detect change for MCI and dementia patients who experienced a meaningful decline in cognition (as defined by the Clinical Dementia Rating Scale Sum of Boxes [CDR-SOB]) between baseline and month 12. The following ADCOMS cut-offs were proposed: 0.05 for MCI and 0.10 for dementia. CONCLUSIONS: The ADCOMS was previously established as a valid and reliable tool for use in clinical trials for MCI due to AD and dementia populations. By defining thresholds for clinically meaningful change of ADCOMS, this work is an important step in interpreting clinical findings and estimates of treatment effects in early stage AD trials.

Long-Term Health Outcomes of Lecanemab in Patients with Early Alzheimer's Disease Using Simulation Modeling.

INTRODUCTION: Alzheimer's disease (AD) is a progressive, neurodegenerative disease and is the most common cause of dementia. Lecanemab is a humanized monoclonal antibody targeting amyloid protofibrils for the treatment of early AD. In the phase II BAN2401-G000-201 trial (NCT01767311), lecanemab reduced amyloid accumulated in the brain and slowed progression on key global and cognitive scales evaluating efficacy after 18 months of treatment. METHODS: A disease simulation model was used to predict the long-term clinical outcomes of lecanemab for patients with early AD [i.e., mild cognitive impairment (MCI) due to AD and mild AD dementia] on the basis of BAN2401-G000-201 trial data and published literature. The model captures the pathophysiology and management of AD, with a focus on simulating the effects of disease modification and early intervention on disease progression. The model compares lecanemab in addition to standard of care (SoC) versus SoC alone. RESULTS: Lecanemab treatment was estimated to slow the rate of disease progression, resulting in an extended duration of MCI due to AD and mild AD dementia and shortened duration in moderate and severe AD dementia. The mean time to mild, moderate, and severe AD dementia was longer for patients in the lecanemab + SoC group than for patients in the SoC group by 2.51, 3.13, and 2.34 years, respectively. On base-case analysis, lecanemab was associated with 0.73 incremental life years (LY) and 0.75 incremental quality-adjusted LYs (QALY), and the caregiver QALYs lost was reduced by 0.03 years. The model also predicted a lower lifetime probability of admission to institutional care in lecanemab + SoC versus SoC group (25% versus 31%). CONCLUSION: The model results demonstrate the potential clinical value of lecanemab for patients with early AD and how it can slow the rate of disease progression and reduce the lifetime probability for institutionalized care.

The Potential Economic Value of Lecanemab in Patients with Early Alzheimer's Disease Using Simulation Modeling.

INTRODUCTION: Alzheimer's disease (AD) is a progressive, neurodegenerative disease that affects memory, thinking, and behavior and places a substantial economic burden on caregivers and healthcare systems. This early-phase study aimed to model lecanemab, a humanized monoclonal antibody targeting amyloid protofibrils, for patients with early AD, and estimate the potential value-based price (VBP) of lecanemab + standard of care (SoC) compared to SoC alone given an expected product profile of lecanemab informed by data from a phase II trial from payer and societal perspectives using a broad range of willingness-to-pay (WTP) thresholds in the USA. METHODS: A disease simulation model was used to capture how key AD pathology components relate to the clinical and economic presentation of AD. The effects of disease modification and early intervention on disease progression were simulated on the basis of BAN2401-G000-201 trial data as well as published literature. Model outcomes included patient and caregiver quality-adjusted life years (QALYs), total life years, and total care costs including direct medical and non-medical costs for healthcare resource use and indirect costs for caregiving over a lifetime horizon. RESULTS: Lecanemab + SoC was predicted to result in a gain of 0.61 QALYs (societal, 0.64) and a $8707 decrease in total non-treatment costs (societal, $11,214) vs. SoC alone for patients with early AD. For a WTP threshold range of $50,000 to $200,000 per QALY gained, the potential annual VBP of lecanemab was estimated at $9249 (societal, $10,400) to $35,605 (societal, $38,053), respectively. Other patient subsets, treatment stopping rules, and dosing regimens were used to assess the sensitivity of the VBP estimates. CONCLUSION: The early model predicted that lecanemab would potentially improve long-term health outcomes and reduce formal and informal care costs, resulting in a range of VBPs that reflect the value of lecanemab to society.

The Humanistic and Economic Burden of Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of cognitive impairment and dementia in older individuals (aged ≥ 65 years) throughout the world. As a result of these progressive deficits in cognitive, emotional, and physical function, AD dementia can cause functional disability and loss of independence. To gain a deeper understanding of the recent literature on the burden of AD, including that of mild cognitive impairment (MCI) due to AD, we conducted a comprehensive targeted review of the PubMed-indexed literature (2014 to 2021) to examine the humanistic and economic burden of AD (including MCI) in North America, Europe, and Asia. Our literature review identified a range of factors associated with quality of life (QoL): some factors were positively associated with QoL, including caregiver relationship, religiosity, social engagement, and ability to engage in activities of daily living (ADL), whereas other factors such as neuropsychiatric symptoms were associated with poorer QoL. While patient- and proxy-rated QoL are highly correlated in patients with early AD dementia, proxy-rated QoL declines more substantially as severity worsens. The maintenance of self-reported QoL in patients with more severe AD dementia may be due to lack of awareness or to adaptation to circumstances. Compared to persons with normal cognition, MCI is associated with a greater cost burden, and individuals with MCI exhibit worse QoL. Key drivers of the societal economic burden of AD include disease severity, dependence level, institutionalization, and comorbidity burden. Evaluation of the impact of a hypothetical disease-modifying treatment delaying the progression from MCI to AD has suggested that such a treatment may result in cost savings.

Alzheimer's Disease: Epidemiology and Clinical Progression.

Alzheimer's disease (AD) is prevalent throughout the world and is the leading cause of dementia in older individuals (aged ≥ 65 years). To gain a deeper understanding of the recent literature on the epidemiology of AD and its progression, we conducted a review of the PubMed-indexed literature (2014-2021) in North America, Europe, and Asia. The worldwide toll of AD is evidenced by rising prevalence, incidence, and mortality due to AD-estimates which are low because of underdiagnosis of AD. Mild cognitive impairment (MCI) due to AD can ultimately progress to AD dementia; estimates of AD dementia etiology among patients with MCI range from 40% to 75% depending on the populations studied and whether the MCI diagnosis was made clinically or in combination with biomarkers. The risk of AD dementia increases with progression from normal cognition with no amyloid-beta (Aß) accumulation to early neurodegeneration and subsequently to MCI. For patients with Aß accumulation and neurodegeneration, lifetime risk of AD dementia has been estimated to be 41.9% among women and 33.6% among men. Data on progression from preclinical AD to MCI are sparse, but an analysis of progression across the three preclinical National Institute on Aging and Alzheimer's Association (NIA-AA) stages suggests that NIA-AA stage 3 (subtle cognitive decline with AD biomarker positivity) could be useful in combination with other tools for treatment decision-making. Factors shown to increase risk include lower Mini-Mental State Examination (MMSE) score, higher Alzheimer's Disease Assessment Scale (ADAS-cog) score, positive APOE4 status, white matter hyperintensities volume, entorhinal cortex atrophy, cerebrospinal fluid (CSF) total tau, CSF neurogranin levels, dependency in instrumental activities of daily living (IADL), and being female. Results suggest that use of biomarkers alongside neurocognitive tests will become an important part of clinical practice as new disease-modifying therapies are introduced.

Stakeholder Insights in Alzheimer's Disease: Natural Language Processing of Social Media Conversations.

BACKGROUND: Social media data may be especially effective for studying diseases associated with high stigma, such as Alzheimer's disease (AD). OBJECTIVE: We primarily aimed to identify issues/challenges experienced by patients with AD using natural language processing (NLP) of social media posts. METHODS: We searched 130 public social media sources between January 1998 and December 2021 for AD stakeholder social media posts using NLP to identify issues/challenges experienced by patients with AD. Issues/challenges identified by ≥10% of any AD stakeholder type were described. Illustrative posts were selected for qualitative review. Secondarily, issues/challenges were organized into a conceptual AD identification framework (ADIF) and representation of ADIF categories within clinical instruments was assessed. RESULTS: We analyzed 1,859,077 social media posts from 30,341 AD stakeholders (21,011 caregivers; 7,440 clinicians; 1,890 patients). The most common issues/challenges were Worry/anxiety (34.2%), Pain (33%), Malaise (28.7%), Confusional state (27.1%), and Falls (23.9%). Patients reported a markedly higher volume of issues/challenges than other stakeholders. Patient posts reflected the broader scope of patient burden, caregiver posts captured both patient and caregiver burden, and clinician posts tended to be targeted. Less than 5% of the high frequency issues/challenges were in the "function and independence" and "social and relational well-being" categories of the ADIF, suggesting these issues/challenges may be difficult to capture. No single clinical instrument covered all ADIF categories; "social and relational well-being" was least represented. CONCLUSION: NLP of AD stakeholder social media data revealed a broad spectrum of real-world insights regarding patient burden.

A Simulation Model to Evaluate the Potential Impact of Disease-Modifying Treatments on Burden of Illness in Alzheimer's Disease.

INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disease that places a substantial burden on patients, caregivers, and society. The advent of disease-modifying treatments (DMTs) would represent a major advancement in the management of AD, particularly in early AD. It is important to understand the potential value of these therapies to individuals and society. METHODS: A modeling framework was developed to estimate the potential clinical and economic burden of AD in the USA by simulating the impact, relative to that of usual care, of a DMT with hypothesized availability beginning from 2022. The model assessed AD epidemiology, disease progression, and burden of illness from 2020 to 2050. Model outcomes included the total number of Americans with mild cognitive impairment (MCI) due to AD and mild, moderate, or severe AD dementia in community or residential care settings and their associated care costs, including direct medical and non-medical costs for healthcare resource use and indirect costs for caregiving. RESULTS: A hypothetical DMT was compared to the usual care under different effect scenarios based on delay in onset of AD (1, 3, and 5 years) and DMT uptake (25%, 50%, and 100%). A delay in the onset of AD by 5 years would reduce the prevalence of AD in 2050 by 6%, 12%, and 25%, resulting in savings of $0.783, $1.566, and $3.132 trillion from 2022 to 2050 for the 25%, 50%, and 100% uptake scenarios, respectively. CONCLUSION: This analysis demonstrated that DMTs that provide even small delays in the onset of AD can lead to an increase in disease-free years and sizable savings in the cost of care, providing significant benefits to patients, caregivers, and society.