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Objective: This systematic literature review (SLR) aimed to investigate the role of neuroinflammation in AD and explore the association of neuroinflammation with AD disease progression., Background: Several mediators of neuroinflammation can serve as therapeutic targets for Alzheimer's disease (AD) and as prognostic biomarkers., Design/methods: A SLR was conducted in 2023 using MEDLINE®, Embase®, and PsycInfo® databases to identify English-language articles from 2012 on AD including mild cognitive impairment (MCI). Two independent reviewers screened titles and examined full-text records for relevance., Results: The SLR identified 3669 articles, of which 114 were included, and detailed data were extracted from 56. Cerebrospinal fluid (CSF) inflammatory biomarkers - YKL-40, sTREM2, and GFAP were identified to have a key role in AD neuroinflammation. Significantly higher levels of CSF YKL-40, CSF sTREM2, and CSF GFAP were found in patients with dementia due to AD compared with cognitively unimpaired control subjects. CSF sTREM2 changes were found to be sensitive to preclinical stages of AD and showed prognostic value in predicting rate of cognitive decline in AD. CSF YKL-40 levels were higher in the dementia stage of AD and increased longitudinally in patients with all-cause MCI and AD patients with dementia; highest baseline levels of CSF YKL-40 in subjects with all-cause MCI predicted progression to dementia due to AD. In cognitively unimpaired/people with subjective cognitive decline, higher baseline levels of serum or plasma GFAP predicted steeper rate of cognitive decline and clinical progression to AD dementia. In AD patients with dementia, higher levels of plasma GFAP were associated with greater change in MMSE score and poor cognitive outcome during follow-up., Conclusions: Evidence from fluid biomarkers consolidates the role of neuroinflammation in pathophysiology of AD and supports clinical use of GFAP for prognostic purpose as recommended in the draft NIA-AA Revised Criteria for Diagnosis and Staging of Alzheimer's Disease 2023 guidelines. Disclosure: Prof. Heneka has nothing to disclose. Dr. Gauthier has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TauRx . Dr. Gauthier has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lilly Canada . Dr. Gauthier has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai . Dr. Gauthier has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ENIGMA USA. Dr. Gauthier has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AmyriAD. Dr. Gauthier has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Medesis. Dr. Gauthier has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Alzheon. Dr. Gauthier has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Karuna. Dr. Gauthier has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Otsuka . Dr. Gauthier has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NovoNordisk. Dr. Gauthier has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen Canada. Dr. Gauthier has received personal compensation in the range of $5,000-$9,999 for serving as an officer or member of the Board of Directors for Sharon Francis Foundation . Dr. Gauthier has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for JPAD. Dr. Gauthier has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Lundbeck Foundation . Dr. Gauthier has received publishing royalties from a publication relating to health care. Dr. Chandekar has received personal compensation for serving as an employee of Novo Nordisk A/S. Dr. Chandekar has stock in Novo Nordisk A/S. Mrs. Hviid Hahn-Pedersen has received personal compensation for serving as an employee of Novo Nordisk A/S. Mrs. Hviid Hahn-Pedersen has stock in Novo Nordisk. Dr. Bentsen has received personal compensation for serving as an employee of Novo Nordisk. An immediate family member of Dr. Bentsen has stock in Novo Nordisk. Henrik Zetterberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Henrik Zetterberg has received personal compensation in the range of $0-$499 for serving as a Consultant for Abbvie. Henrik Zetterberg has received personal compensation in the range of $0-$499 for serving as a Consultant for Acumen. Henrik Zetterberg has received personal compensation in the range of $0-$499 for serving as a Consultant for AlzPATH. Henrik Zetterberg has received personal compensation in the range of $0-$499 for serving as a Consultant for Annexon. Henrik Zetterberg has received personal compensation in the range of $0-$499 for serving as a Consultant for Apellis. Henrik Zetterberg has received personal compensation in the range of $0-$499 for serving as a Consultant for Fujirebio. Henrik Zetterberg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Siemens Healthineers. Henrik Zetterberg has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. Henrik Zetterberg has stock in Brain Biomarker Solutions.

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

Background: People with Alzheimer's disease (AD) have difficulties in performing activities of daily living (ADLs) as the disease progresses, commonly experience neuropsychiatric symptoms (NPS), and often have comorbidities such as cardiovascular disease. These factors all contribute to a requirement for care and considerable healthcare costs in AD. The Clinical Dementia Rating (CDR) scale is a widely used measure of dementia staging, but the correlations between scores on this scale and patient-/care partner-relevant outcomes have not been characterized fully. We conducted a systematic literature review to address this evidence gap., Methods: Embase, MEDLINE, and the Cochrane Library were searched September 13, 2022, to identify published studies (no restriction by date or country) in populations with mild cognitive impairment due to AD or AD dementia. Studies of interest reported data on the relationships between CDR Global or CDR-Sum of Boxes (CDR-SB) scores and outcomes including NPS, comorbidities, ADLs, nursing home placement, healthcare costs, and resource use., Results: Overall, 58 studies met the inclusion criteria (42 focusing on comorbidities, 14 on ADLs or dependence, five on nursing home placement, and six on economic outcomes). CDR/CDR-SB scores were correlated with the frequency of multiple NPS and with total scores on the Neuropsychiatric Inventory. For cardiovascular comorbidities, no single risk factor was consistently linked to AD progression. Increasing CDR/CDR-SB scores were correlated with decline in multiple different measures of ADLs and were also associated with nursing home placement and increasing costs of care., Conclusion: NPS, ADLs, and costs of care are clearly linked to AD progression, as measured using CDR Global or CDR-SB scores, from the earliest stages of disease. This indicates that scores derived from the CDR are a meaningful way to describe the severity and burden of AD for patients and care partners across disease stages., Competing Interests: KL has acted as an advisor/consultant for BioXcel Therapeutics, Bright Minds Biosciences, Cerevel Therapeutics, Eisai, GW Pharmaceuticals, IGCPharma, Kondor Pharma, Lundbeck, Merck, Novo Nordisk A/S, Praxis Precision Medicines, and Sumitomo Pharma. JH-P, AC, and LT are employed by Novo Nordisk A/S, which funded the systematic literature review. They contributed to design of the systematic literature review, data interpretation, review and revision of the manuscript, and approval for publication. CE and CF are employed by Oxford PharmaGenesis, which received funding for conducting the systematic literature review. JC has provided consultation to Acadia, Alkahest, AlphaCognition, AriBio, Biogen, Cassava, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, Karuna, Lilly, LSP, Merck, NervGen, Novo Nordisk A/S, Oligomerix, Ono, Otsuka, PRODEO, Prothena, ReMYND, Resverlogix, Roche, Signant Health, Suven, and United Neuroscience pharmaceutical, assessment, and investment companies. He is supported by US National Institute of General Medical Sciences (NIGMS) grant P20GM109025; National Institute of Neurological Disorders and Stroke (NINDS) grant U01NS093334; National Institute on Aging (NIA) grants R01AG053798, P20AG068053, P30AG072959, and R35AG71476; the Alzheimer’s Disease Drug Discovery Foundation (ADDF); the Ted and Maria Quirk Endowment; and the Joy Chambers-Grundy Endowment., (Copyright © 2023 Cummings, Hahn-Pedersen, Eichinger, Freeman, Clark, Tarazona and Lanctôt.)

Background: Caregiving in Alzheimer's disease (AD) is often provided by informal care partners, who spend more hours per week on average than care partners of individuals with conditions other than AD. However, the burden of care in partners of individuals with AD has not been systematically compared to that of other chronic diseases., Objective: The current study therefore aims to compare the care partner burden of AD to that of other chronic diseases through a systematic literature review., Methods: Data was collected from journal articles published in the last 10 years, using two unique search strings in PubMed and analysed using pre-defined patient-reported outcome measures (PROMs) including the EQ-5D-5L, GAD-7, GHQ-12, PHQ-9, WPAI and the ZBI. The data was grouped according to the included PROMs and the diseases studied. The number of participants in the studies reporting burden of caregiving in AD was adjusted to reflect the number of participants in studies reporting care partner burden in other chronic diseases., Results: All results in this study are reported as a mean value and standard deviation (SD). The ZBI measurement was the most frequently used PROM to collect care partner burden (15 studies) and showed a moderate burden (mean 36.80, SD 18.35) on care partners of individuals with AD, higher than most of the other included diseases except for those characterized by psychiatric symptoms (mean scores 55.92 and 59.11). Other PROMs such as PHQ-9 (six studies) and GHQ-12 (four studies) showed a greater burden on care partners of individuals with other chronic diseases such as heart failure, haematopoietic cell transplantations, cancer and depression compared to AD. Likewise, GAD-7 and EQ-5D-5L measurements showed a lesser burden on care partners of individuals with AD compared to care partners of individuals with anxiety, cancer, asthma and chronic obstructive pulmonary disease. The current study suggests that care partners of individuals with AD experience a moderate burden, but with some variations depending on the PROMs used., Conclusion: The results of this study were mixed with some PROMs indicating a greater burden for care partners of individuals with AD versus other chronic diseases, and other PROMs showing a greater burden for care partners of individuals with other chronic diseases. Psychiatric disorders imposed a greater burden on care partners compared to AD, while somatic diseases in the musculoskeletal system resulted in a significantly smaller burden on care partners compared to AD., (© 2023. The Author(s).)

Background: Many individuals with Alzheimer's disease (AD) are dependent on nonprofessional care partners. Providing informal care can result in emotional, physical, and financial burdens; however, there is a need for a better understanding of the impact of AD on care partners to support the clinical and economic assessment of potential new treatments., Objective: We conducted a literature review to evaluate the burden experienced by care partners of individuals with AD., Methods: Electronic screening and supplementary searches identified studies published from 2011 to 2022 describing the association between AD and the quality of life (QoL) and physical health of care partners, and the economic or financial burden of AD., Results: Following electronic screening, 62, 25, and 39 studies were included on care partner burden, cost, and healthcare resource use in AD, respectively. Supplementary searches identified an additional 32 studies, resulting in 149 unique studies. These studies showed that care partners of individuals with AD report moderate to severe burden. Higher burden and lower QoL were observed in those caring for individuals with more severe AD. Care partners of individuals with AD experience higher burden, lower QoL, and higher levels of stress, depression, and anxiety than those without caring responsibilities. Informal care costs increased with AD severity and accounted for the greatest proportion of overall societal cost., Conclusions: Care partners of individuals with AD experience emotional and economic burden, which increases with AD severity. These impacts should be quantified comprehensively in future studies and captured in economic evaluations of AD interventions.