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Despite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public‐health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public‐domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements. To further understand the current gaps, we also conducted interviews with leading experts in regulatory/governmental agencies, LBD advocacy, academic research, and biopharmaceutical research, as well as with funding sources. We identified wide gaps across the entire landscape, the most critical being in research. Many of the experts participated in a workshop to discuss the prioritization of research areas with a view to accelerating therapeutic development and improving patient care. This white paper outlines the opportunities for bridging the major LBD gaps and creates the framework for collaboration in that endeavor. Highlights A group representing academia, government, industry, and consulting expertise was convened to discuss current progress in Dementia with Lewy Body care and research. Consideration of expert opinion,natural language processing of the literature as well as publicly available data bases, and Delphi inspired discussion led to a proposed consensus document of priorities for the field.

Lecanemab is a humanized IgG1 monoclonal antibody binding with high affinity to protofibrils of amyloid‐beta (Aβ) protein. In clinical studies, lecanemab has been shown to reduce amyloid markers in early symptomatic Alzheimer's disease and slow decline on clinical endpoints of cognition and function. Nonlinear mixed‐effects modeling assessed the correlation between amyloid PET and change in CDR‐SB using data from lecanemab phase 2 study (Study 201) and phase 3 study (Study 301; Clarity AD). Data from placebo‐treated subjects were used to establish a disease‐progression model; the effect of amyloid reduction on disease progression was defined using data from lecanemab‐treated subjects. CDR‐SB scores were used with beta regression to fit a Richard's function parameterized in terms of baseline CDR‐SB, intrinsic rate of disease progression, shape, and precision of the beta distribution. Simulations were conducted to evaluate the impact of lecanemab treatment over 4 years. Baseline CDR‐SB was predicted by diagnosis and baseline mini‐mental state examination (BMMSE) score. Intrinsic rate of disease progression was predicted by amyloid PET and BMMSE. Amyloid PET was a better predictor of drug effect than lecanemab exposure, demonstrating amyloid reduction as a surrogate marker of efficacy. Simulations projected the difference in CDR‐SB between lecanemab and placebo treated subjects continued increasing over 4 years. Patients with low baseline amyloid and less severe disease were projected to have slower disease progression and better outcomes with lecanemab treatment. Study Highlights What is the current knowledge on the topic? ○Lecanemab is a humanized IgG1 monoclonal antibody that targets protofibrils and plaques, reduces amyloid markers and slows cognitive decline in early Alzheimer's disease. What question did this study address? ○This analysis integrates lecanemab exposure effect on amyloid lowering and correlates amyloid lowering to non‐linear progression of CDR‐SB. This is a robust pharmacokinetic/pharmacodynamic model‐based approach, significantly improved over crude correlations between amyloid PET and clinical outcomes, which are highly confounded by correlations between (a) baseline amyloid level, cognitive decline and extent of amyloid clearance and (b) baseline cognition and rate of cognitive decline. What does this study add to our knowledge? ○The analyses provide insights into factors affecting disease progression (Clinical Disease Rating—Sum of Boxes; CDR‐SB) in early Alzheimer's disease, how amyloid load as measured by amyloid PET affects CDR‐SB, and show benefits of long‐term lecanemab treatment on CDR‐SB. How might this change drug discovery, development, and/or therapeutics? ○The analyses provide evidence of the beneficial effect of early and continuous treatment of lecanemab and show that a less intense monthly maintenance regimen after 18 months of biweekly treatment would maintain efficacy.

Background In Alzheimer’s disease (AD), pathological changes may arise up to 20 years before the onset of dementia. This pre-dementia window provides a unique opportunity for secondary prevention. However, exposing non-demented subjects to putative therapies requires reliable biomarkers for subject selection, stratification, and monitoring of treatment. Neuroimaging allows the detection of early pathological changes, and longitudinal imaging can assess the effect of interventions on markers of molecular pathology and rates of neurodegeneration. This is of particular importance in pre-dementia AD trials, where clinical outcomes have a limited ability to detect treatment effects within the typical time frame of a clinical trial. We review available evidence for the use of neuroimaging in clinical trials in pre-dementia AD. We appraise currently available imaging markers for subject selection, stratification, outcome measures, and safety in the context of such populations. Main body Amyloid positron emission tomography (PET) is a validated in-vivo marker of fibrillar amyloid plaques. It is appropriate for inclusion in trials targeting the amyloid pathway, as well as to monitor treatment target engagement. Amyloid PET, however, has limited ability to stage the disease and does not perform well as a prognostic marker within the time frame of a pre-dementia AD trial. Structural magnetic resonance imaging (MRI), providing markers of neurodegeneration, can improve the identification of subjects at risk of imminent decline and hence play a role in subject inclusion. Atrophy rates (either hippocampal or whole brain), which can be reliably derived from structural MRI, are useful in tracking disease progression and have the potential to serve as outcome measures. MRI can also be used to assess comorbid vascular pathology and define homogeneous groups for inclusion or for subject stratification. Finally, MRI also plays an important role in trial safety monitoring, particularly the identification of amyloid-related imaging abnormalities (ARIA). Tau PET to measure neurofibrillary tangle burden is currently under development. Evidence to support the use of advanced MRI markers such as resting-state functional MRI, arterial spin labelling, and diffusion tensor imaging in pre-dementia AD is preliminary and requires further validation. Conclusion We propose a strategy for longitudinal imaging to track early signs of AD including quantitative amyloid PET and yearly multiparametric MRI.

The Alzheimer's disease (AD) research field has entered a new era, where our fundamental understanding of the pathophysiology of AD and advances in biomarkers have not only allowed for earlier, timely, and accurate detection and diagnosis of the disease, but that amyloid removal has been shown to be associated with signals of slowing cognitive and functional decline. Although recent FDA‐approved amyloid plaque‐lowering monoclonal antibody therapies have shifted the trajectory of AD, additional treatment options will be key to further slowing clinical decline or stopping disease progression. Thus, new and emerging therapies for AD have created an evolving therapeutic landscape. The Alzheimer's Association Research Roundtable (AARR) Spring meeting held on May 23–34, 2023, brought together a broad array of scientific leaders from the AARR membership, academia, industry, and government and regulatory agencies to discuss the future of clinical trials in an era of regulator‐approved amyloid‐targeting therapies. Participants discussed lessons learned from other neurological diseases where disease‐modifying treatments were first approved and key considerations for future clinical trials, for example, trial population real‐world representativeness, duration, biomarker screening, efficacy endpoints, combination therapy, as well as overall trial design and the ethical and equity concerns that clinicians, patients, and their families face when considering clinical trial participation. Highlights The Alzheimer's Association Research Roundtable (AARR) convened leaders from industry and academia, as well as patients, clinicians, and government and regulatory agency scientists to discuss the topic, “Alzheimer's Disease Drug Development in an Evolving Therapeutic Landscape.” While recently approved amyloid‐targeting therapies show great promise in providing clinically meaningful outcomes for patients and families, additional treatments, and a better understanding of dosing and administration of these approved treatments, are needed to further slow and eventually prevent clinical decline in AD. Approved therapies will impact many aspects of clinical trial design including the use of placebo‐controls, participant re‐enrollment, safety monitoring, as well as biomarker selection. This exciting new era in AD research represents a hopeful future for clinicians, patients, and their care partners.

It has been proposed that the signal distribution on tau positron emission tomography (PET) images could be used to define pathologic stages similar to those seen in neuropathology. Three topographic staging schemes for tau PET, two sampling the temporal and occipital subregions only and one sampling cortical gray matter across the major brain lobes, were evaluated on flortaucipir F 18 PET images in a test-retest scenario and from Alzheimer's Disease Neuroimaging Initiative 2. All three schemes estimated stages that were significantly associated with amyloid status and when dichotomized to tau positive or negative were 90% to 94% concordant in the populations identified. However, the schemes with fewer regions and simpler decision rules yielded more robust performance in terms of fewer unclassified scans and increased test-retest reproducibility of assigned stage. Tau PET staging schemes could be useful tools to concisely index the regional involvement of tau pathology in living subjects. Simpler schemes may be more robust.

Dementia takes decades to develop, and effective prevention will likely require early intervention. Thus, it is critical to identify biomarkers of preclinical disease, allowing targeting of high-risk subjects for preventive efforts. Since telomeres shorten with age and oxidative stress, both of which are important contributors to the onset of dementia, telomere length might be a valuable biomarker. Among 62 participants of the Nurses' Health Study, we conducted neurologic evaluations, including patient and caregiver interviews, physical exam, neurologic exam, and neuropsychologic testing. We also conducted magnetic resonance imaging (MRI) in a sample of 29 of these women. In these preliminary data, after adjustment for numerous health and lifestyle factors, we found that truncated telomeres in peripheral blood leukocytes segregate with preclinical dementia states, including mild cognitive impairment (MCI); the odds of MCI were 12-fold higher (odds ratio = 12.00, 95% confidence interval 1.24-116.5) for those with shorter telomere length compared to longer telomere length. In addition, decreasing telomere length was strongly related to decreasing hippocampal volume (p = 0.038). These preliminary data suggest that telomere length may be a possible early marker of dementia risk, and merits further study in large, prospective investigations.

Background Single analyte blood‐based biomarkers such as p‐tau181 and p‐tau217 are promising biomarkers for identifying Alzheimer's disease (AD) pathology. However, multi‐analyte blood‐based biomarker panels are needed to further improve the detection, differential diagnosis, and screening of AD and to predict disease progression and assess response to therapy. The Alamar NULISASeq CNS Disease Panel (“NULISASeq”) simultaneously profiles 120 proteins associated with neurodegeneration, synaptic, and inflammatory pathways to support these goals. Multiplexed panels also maximize the potential of precious clinical trial biospecimens while also providing the sensitivity required to measure low abundant analytes. Methods Plasma samples were collected during screening from a Phase 3 program for elenbecestat (MissionAD) in early AD and analyzed using NULISASeq. Data normalization was performed using the vendor protocol to form NULISA Protein Quantification (NPQ) units, used for statistical analysis. Analysis of Variance (ANOVA) was used to determine statistical significance of the difference in each target protein level between amyloid+ and amyloid‐ subjects as determined by PET visual read. p‐values were adjusted for multiplicity. Cohen's D was calculated to show the effect size of difference in target protein levels. The correlation of overlapping target protein levels between NULISASeq and other assays was evaluated. Results A total of 124 subjects were included in the statistical analysis (74 amyloid+ and 50 amyloid‐). Statistical significance was observed in 7 plasma proteins (GFAP, MAPT, NEFH, SNAP25, pTau‐181, pTau‐217, pTau‐231) between amyloid+ and amyloid‐ subjects. pTau‐217 showed the largest effect size. In predicting amyloid status, using pTau‐217 alone also resulted in the highest AUC (0.87). Combining these proteins did not result in much improvement in prediction. NULISASeq protein levels of common ATN biomarkers showed high correlation with that of other assays in both plasma and CSF. Conclusion Targeted multiplexed panels such as NULISASeq quantifies multiple analytes in a single run thereby reducing the amount of precious input material and the time required for analysis. This offers advantage over fluid and neuroimaging‐based measurements tailored to singular targets. We have demonstrated the utility of a multiplexed panel for reliable detection of amyloid status as well as highlighted the potential of discovering novel biomarkers associated with AD.

Background Existing copathologies, such as Lewy body (LB) disease, can introduce heterogeneity to AD pathogenesis and presentation of symptoms and likely influence disease progression. A seed amplification assay (SAA) that detects aggregated, misfolded α‐synuclein (α‐syn) can detect LB. Incorporation of SAA can characterize disease heterogeneity in AD and potentially predict disease progression. Methods A validated SAA was used to characterize α‐syn SAA status (Amprion Clinical Laboratory) in baseline CSF samples collected from a Phase 3 program for elenbecestat in subjects with MCI or mild dementia due to AD (NCT02956486). Samples were selected by PET visual read status. The sample set was enriched using subjects considered to be progressors or non‐progressors based on change in cognition (CDR‐SB) at 18 months, before assessment of SAA status. Results of α‐syn status were reported as Detected, Not Detected, or Indeterminate. The proportion of samples defined as Detected and Not Detected were summarized by amyloid status. Cognition, at baseline and longitudinally, was summarized by amyloid and α‐syn status. Available baseline A/T/N biomarkers were also summarized and compared. Results Among the 201 samples that were included in the analyses, 15% of amyloid+ and 8% of amyloid‐ MCI/early AD subjects were determined to be SAA+ and hence determined to have LB copathology. In comparison, in ADNI, 17% of cognitively unimpaired (CU) subjects; 20% of MCI subjects and 39% of AD subjects had synuclein copathology (Tosun et al Alzheimer's Dement. 2024). In BioFinder2, synuclein copathology was detected in 8%, 17% and 23% of CU, MCI, and AD subjects, respectively (Palmqvist et al and Quadalti et al Nature Medicine 2023). The longitudinal trajectory of amyloid positive subjects with α‐syn copathology seemed to have faster cognitive decline in natural history studies. In the Phase 3 samples, the longitudinal cognitive trajectory showed trend towards faster decline over 18 months in the amyloid+ subjects with α‐syn copathology; however, this did not appear significant. Conclusion LB, a common copathology of AD, may be a source of heterogeneity. Incorporation of SAA, a specific biomarker of LB‐pathology, can help account for disease heterogeneity and potentially improve assessment of treatment response in amyloid and synuclein status confirmed AD target population.

Background Lecanemab is a novel, humanized immunoglobulin G (IgG) 1 monoclonal antibody, which has demonstrated the ability to substantially reduce markers of amyloid and slow clinical decline in early Alzheimer’s disease (AD). Subcutaneous administration using an autoinjector improves convenience and eliminates burden on patients, providers and healthcare systems necessitated by intravenous infusion, thereby broadening access. Herein, we share results from the human factors (HF) program implemented to support the lecanemab autoinjector clinical program. Methods The HF validation study evaluated whether the lecanemab autoinjector could be used safely and effectively – with and without training – under expected use environments. It characterized the type, frequency, and severity of potential use errors (including incomplete dosing) as well as labelling comprehension. The study participants (n=110; patients with self‐ or caregiver‐reported diagnosis of mild cognitive impairment or mild AD [n=63], caregivers [n=32], and healthcare providers [HCPs; n=15]) represented lecanemab autoinjector end users and included a mix of injection‐experienced and injection‐naïve. The patients were administered the Mini Mental State Examination (MMSE) and subsequently divided into low MMSE (22‐26) and high MMSE (27‐30) groups. Patients and caregivers were evaluated under trained and untrained conditions, while HCPs were always untrained. Results Overall, 94.5% (n=104/110) of participants were successful at delivering the first of 2 injections: untrained, low MMSE patients (93.3%, n=14/15); trained, low MMSE patients (100%, n=15/15); untrained, high MMSE patients (100%, n=16/16); trained, high MMSE patients (94.1%, n=16/17); untrained caregivers (100%, n=15/15); trained caregivers (100%, n=17/17); HCPs (100%, n=15/15). Furthermore, 82.7% (n=91/110) of participants were successful at delivering 2 consecutive injections: untrained, low MMSE patients (53.3%, n=8/15); trained, low MMSE patients (93.3%, n=14/15); untrained, high MMSE patients (93.8%, n=15/16); trained, high MMSE patients (88.2%, n=15/17); untrained caregivers (73.3%, n=11/15); trained caregivers (94.1%, n=16/17); HCPs (80%, n=12/15). Training increased injection success in caregivers and low MMSE patients. Critical information in the labelling was understood by 91.8% (n=101/110) of overall participants. No device malfunctions or harmful events occurred. Conclusions The HF validation study confirms that the lecanemab autoinjector is safe and effective for the intended users, uses, and use environments.

Single analyte blood-based biomarkers such as p-tau181 and p-tau217 are promising biomarkers for identifying Alzheimer's disease (AD) pathology. However, multi-analyte blood-based biomarker panels are needed to further improve the detection, differential diagnosis, and screening of AD and to predict disease progression and assess response to therapy. The Alamar NULISASeq CNS Disease Panel (\"NULISASeq\") simultaneously profiles 120 proteins associated with neurodegeneration, synaptic, and inflammatory pathways to support these goals. Multiplexed panels also maximize the potential of precious clinical trial biospecimens while also providing the sensitivity required to measure low abundant analytes. Plasma samples were collected during screening from a Phase 3 program for elenbecestat (MissionAD) in early AD and analyzed using NULISASeq. Data normalization was performed using the vendor protocol to form NULISA Protein Quantification (NPQ) units, used for statistical analysis. Analysis of Variance (ANOVA) was used to determine statistical significance of the difference in each target protein level between amyloid+ and amyloid- subjects as determined by PET visual read. p-values were adjusted for multiplicity. Cohen's D was calculated to show the effect size of difference in target protein levels. The correlation of overlapping target protein levels between NULISASeq and other assays was evaluated. A total of 124 subjects were included in the statistical analysis (74 amyloid+ and 50 amyloid-). Statistical significance was observed in 7 plasma proteins (GFAP, MAPT, NEFH, SNAP25, pTau-181, pTau-217, pTau-231) between amyloid+ and amyloid- subjects. pTau-217 showed the largest effect size. In predicting amyloid status, using pTau-217 alone also resulted in the highest AUC (0.87). Combining these proteins did not result in much improvement in prediction. NULISASeq protein levels of common ATN biomarkers showed high correlation with that of other assays in both plasma and CSF. Targeted multiplexed panels such as NULISASeq quantifies multiple analytes in a single run thereby reducing the amount of precious input material and the time required for analysis. This offers advantage over fluid and neuroimaging-based measurements tailored to singular targets. We have demonstrated the utility of a multiplexed panel for reliable detection of amyloid status as well as highlighted the potential of discovering novel biomarkers associated with AD.