Journals
2025 EN
McMurray Josephine · Levy AnneMarie · Rasheed Sabah
+6 more
Abstract Background The global workforce is aging 1 , increasing the prevalence of Mild Cognitive Impairment (MCI) and Young‐Onset Dementia (YOD) 2 , and driving organizations to adopt more comprehensive approaches to inclusion 3 . These conditions pose unique challenges for employers balancing inclusivity with operational efficiency. Traditional accommodation approaches often prove inadequate, relying on outdated practices unsuited to the evolving needs of employees with cognitive impairments. This study examines the intersection of empathetic organizational practices, technology integration, and resilience‐building strategies to support workers with cognitive disabilities. Method Using a multi‐level comparative case study design, we conducted 97 semi‐structured interviews in two diverse Canadian organizations—one in the public sector and one in healthcare. Drawing on a socio‐technical systems framework and the Job Demands‐Resources (JD‐R) model, we explored how these organizations manage job demands and resources for employees with MCI and YOD. Interviews addressed workplace culture, accommodation practices, managerial support, and technology's role in creating inclusive environments. Result Effective accommodations combined empathetic leadership, flexible management, and the strategic deployment of both digital and non‐digital technologies. Organizations enabling adaptive decision‐making and iterative feedback loops demonstrated greater resilience. However, technology alone was insufficient; a person‐centered, adaptive approach aligned with organizational workflows was vital to reduce strain and enhance job performance. Conclusion Findings underscore the need for empathetic, flexible workplaces where managerial and technological systems respond to employees’ evolving cognitive needs. A conceptual model of “strain and resilience cycles” highlights how organizational structures and technology must continuously adapt for sustained support. The results emphasize fostering an inclusive culture, reducing stigma, and leveraging technology in ways that enhance—rather than hinder—employees’ experiences. By integrating empathetic leadership, personalized accommodations, and adaptive feedback systems, organizations can improve both operational efficiency and the well‐being of employees with cognitive impairments.
Journals
2025 EN
Butt Maayra I · Chow Carolyn · Rosa Paola
+11 more
Abstract Background Persons living with dementia (PWD) and their family care partners may have different priorities when considering new dementia treatments. We sought to determine the relative importance of several different outcome domains when considering choosing a hypothetical dementia treatment. Method We conducted a discrete choice experiment (DCE) among PWD and family care partners administered online and facilitated by a trained research coordinator. Participants were recruited from memory centers in Pennsylvania, Wisconsin, and Michigan. In each DCE task, participants were asked to choose one of two hypothetical dementia treatments that would produce variable benefits across multiple outcome domains. The full DCE, conducted with care partners, consisted of eight forced‐choice tasks assessing respondent preferences within six attributes: brain function, distressing symptoms, physical function, home time, family caregiver stress, and socialization and engagement. Participating PWD were shown an abbreviated version of the DCE consisting of six tasks with a random subset of four of the six attributes. Data were analyzed using mixed effects logistic regression models to assess how each attribute influenced likelihood of selecting a treatment option. Participant comprehension, reasoning, and reactions to the DCE were solicited throughout and documented in field notes. Field notes were subsequently analyzed using constant comparison techniques to identify relevant themes. Result We surveyed 201 participants (154 care partners; 47 PWD; Table 1). Across all participants, the highest priority outcomes were relief in distressing symptoms and increasing home time (OR=0.66, 95% CI=0.61‐0.71 and OR=0.66, 95% CI=0.61‐0.71). When comparing utilities across PWD and care partners, PWD more highly valued increasing home time, improving physical function, reducing family caregiver stress, and increasing patient socialization and engagement compared to family care partners (Figure). Qualitative analysis revealed key themes regarding participant decision making processes and attitudes towards the DCE experience (Table 2). Conclusion Increasing home time is an important treatment outcome for PWD and family care partners. Prioritization of other treatment outcomes vary across these key stakeholder subgroups. Participation in a DCE assessing treatment outcomes as a communication process was valued by patients and care partners, suggesting its potential utility as a communication aid or values elicitation tool.
Journals
2025 EN
Ornish Dean · Madison Catherine · Kivipelto Miia
+18 more
Abstract Background We report the 40‐week follow‐up of a RCT to examine whether comprehensive lifestyle changes affect the progression of MCI or early dementia due to AD. Earlier results after 20 weeks showed significant improvement in cognition and function. [Ref: Alzheimers Res Ther . 2024 Jun 7;16(1):122. doi: 10.1186/s13195‐024‐01482‐z. PMID: 38849944; PMCID: PMC11157928.] Methods A 1:1 multicenter randomized controlled phase 2 trial, ages 45‐90 with MCI or early dementia due to AD and MoCA score of 18 or higher. After the first 20 weeks, the intervention group continued to receive the lifestyle intervention for a total of 40 weeks. The intervention group was compared to the usual‐care randomized control group after 20 weeks since the control group crossed over and received the lifestyle intervention after 20 weeks. Results Fifty‐one participants with MCI/AD enrolled, mean age 73.5. Active intervention and comparison groups did not differ in any baseline measures. After 40 weeks, there was significant improvement in the intervention group compared to the randomized nonintervention control group in the Clinical Global Impression of Change (CGIC) ( p = 0.000, Figs 1 & 2), Clinical Dementia Rating–Sum of Boxes ( p = 0.036), and Clinical Dementia Rating Global ( p = 0.045). Improvement in Alzheimer's Disease Assessment Scale (ADAS‐Cog) after 20 weeks ( p = 0.053) was not statistically significant after 40 weeks ( p = 0.258). When comparing changes in the intervention group from 20 weeks to 40 weeks, there were significant additional improvements in the CGIC ( p = 0.0000) and CDR‐SB ( p = 0.0082) and no significant differences (i.e., changes were maintained) from 20 to 40 weeks in CDR Global ( p = 0.1596) and ADAS‐Cog ( p = 0.3892). After 20 weeks, the nonintervention control group crossed over and received the lifestyle intervention for 40 weeks. CGIC values are shown in Figure 3. The plasma Aβ42/40 ratio increased in the intervention group from baseline to 40 weeks when compared to the randomized control group ( p = 0.0001). No significant between‐group changes in p ‐tau 217 occurred. Conclusions Comprehensive lifestyle changes may significantly improve cognition and function after 20 weeks in early dementia due to AD. After 40 weeks, these improvements were maintained in two measures and showed further improvement after 40 weeks in two measures.
Journals
2025 EN
Chan U Hang · Li Fengling · Bashore Frances M.
+5 more
Abstract Background To diversify Alzheimer’s Disease (AD) drug targets, a bioinformatics core is established to provide an unbiased ranking of AD risk‐associated genes by integrating multiple lines of genetic and multi‐omic evidence. From which, several RNA helicases, including RIG‐I‐like receptor 3 (LGP2), melanoma differentiation‐associated protein 5 (MDA5) and Dead Box 1 (DDX1) have been identified as high priority targets differentially expressed in AD brains. All three helicases play a role in the innate immune response pathway against viral RNA. Given the previous link between viral infection and AD pathology, this prompted the development of small molecule chemical probe against these targets to further elucidate their roles in AD. Method Purified proteins were used for ATPase assay development and compound screening. The ATPase assay was performed in the presence of annealed 24mer RNA, double‐stranded RNA (dsRNA) with a 25‐nt 3ʹ overhang, or single‐stranded DNA (ssDNA). We employed DNA‐encoded chemical library (DEL) and computational methods for small molecule hit discovery. Hit confirmation was carried out by ATPase assay, Surface Plasmon Resonance (SPR), Differential Scanning Fluorimetry (DSF) and 19Fluorine‐ Nuclear Magnetic Resonance (19F‐NMR). Hit expansion was carried out for the most promising hits to increase potency and selectivity. Result We describe the development and optimization of a bioluminescence assay to kinetically characterize the activity of three human RNA helicases involved in innate immune response pathway, including MDA5, LGP2, and DDX1. Through DEL‐ML screening, we identified a selective hit for MDA5, and characterized its activity by ATPase assay with IC50 of 8 µM, and orthogonally confirmed by F‐NMR. Ongoing studies aim to elucidate the ligand binding site using X‐ray crystallography. Conclusion We present a robust high‐throughput in vitro assay designed for small molecule screening in a 384‐well format, enabling hit optimization and facilitating the discovery of inhibitors for MDA5, LGP2, and DDX1. Through DEL‐ML screen, we identified a selective MDA5 inhibitor that can be used to further interrogate its role in AD pathogenesis, and serve as a chemical starting point for future drug discovery efforts. This ligand represents first‐in‐class small molecule inhibitor for MDA5, a target that has been underexplored in the context of its role in AD.
Journals
2025 EN
Cohen Sharon · Ducharme Simon · Brosch Jared R.
+9 more
Abstract Background Single doses of mivelsiran, an investigational RNA interference (RNAi) therapeutic, have demonstrated robust amyloid‐beta precursor protein (APP) lowering in the CNS. We report additional interim safety and pharmacodynamic data in patients with early‐onset Alzheimer’s disease (EOAD) who received single ascending doses (SAD) and, for the first time, multiple doses of mivelsiran in the ongoing Phase 1 study (NCT05231785). Methods Patients with EOAD (symptom onset <65 years of age, Clinical Dementia Rating global score 0.5 or 1.0, Mini‐Mental State Examination score >20) were randomized to a single intrathecal dose of mivelsiran 25–100mg or placebo for 6 months (plus up to 6 months follow‐up if needed for washout). After washout, patients could enter a separate multiple ascending dose (MAD) portion and receive open‐label mivelsiran. Presented here are data from a SAD cohort of mivelsiran 100mg and a MAD cohort of mivelsiran 50mg every 6 months (Q6M). Frequency of adverse events (AEs) and pharmacodynamics were primary and secondary endpoints, respectively. Results Forty‐five patients were enrolled in SAD cohorts (as of 11/20/2024). Of those, 9 patients were randomized to mivelsiran 100mg or placebo (mean [SD] age, 64.1 [3.7] years; 33.3% male; 100% white). Most AEs were mild or moderate. Peak mean (SE) change from baseline in cerebrospinal fluid (CSF) soluble APP beta (sAPPβ) at Month 1 (─84.5% [1.3]) was largely sustained through Month 10 (─61.1% [2.8]). After meeting washout criteria, 10 patients from SAD cohorts received mivelsiran 50mg Q6M (mean [SD] age, 59.9 [4.4] years; 70.0% male; 70.0% white). No serious or severe AEs were reported. At Day 15 after the first dose, mean (SE) change from baseline in CSF sAPPβ was ─63.7% (5.0); at Month 1 after the second dose, change was ─83.8% (2.3). Additional data will be presented. Conclusions In this first report of multiple‐dose clinical data for a CNS‐targeting RNAi therapeutic, single and multiple doses of mivelsiran were generally well tolerated and continued to demonstrate robust, durable, dose‐dependent CSF sAPPβ reductions. Further sAPPβ lowering was observed after a second dose of mivelsiran 50mg. These results support further evaluation of mivelsiran in patients with Alzheimer’s disease or cerebral amyloid angiopathy.
Journals
2025 EN
Iqbal Sabahat · Olivares Cristina Bonet · Rizzo Laura
+18 more
Abstract Background Despite recent developments in amyloid‐clearing therapies for Alzheimer's Disease (AD), there remains a need for more effective, safe treatments. Funded by the UK National Institute of Health and Care Research, our aim was to establish a robust, systematic, and unbiased drug prioritisation pipeline to identify repurposed drugs with the greatest potential for sustained clinical effect in clinical 'real‐world' AD (MMSE >17). These would then be considered for inclusion in a planned multi‐arm UK platform trial. Method We invited the wider AD community to propose compounds by summarising their rationale and evidence in a prespecified drug proposal form. Fourteen proposals were received, and the drug proposers were invited to the first panel meeting. They presented a pre‐clinical data focused rationale for each compound to an international expert panel comprised of AD clinicians, scientists, industry professionals, as well as both charity and patient/public representatives. In the context of a platform trial using prespecified primary outcome of cognition (ADAS‐Cog, with neuropsychiatric symptoms and everyday activities as secondary outcomes), the panel ranked their top three compounds based on efficacy, biological plausibility, and safety in AD. Ten compounds were taken forward with two subsequently excluded due to lack of data in humans. We compiled extended drug curriculum vitae (CV) for the eight shortlisted compounds. This incorporated practical clinically relevant information and was supplemented by systematic clinical literature review using Repurposing Living Systematic Review (ReLiSyR), a machine learning tool that searches databases and screens studies to identify relevant publications. Result Drug CVs were reviewed in a second panel meeting. Compound rankings were repeated with previous considerations and also practical clinical factors. The highest ranked compounds were atomoxetine (1 st ), metformin (2 nd ), isosorbide mononitrate and levetiracetam (joint 3 rd ). The pivotal determining factors across the top ranked compounds included scientific evidence of plausible mechanistic pathways in AD as well as evidence of substantial clinical data on safety and tolerability. Conclusion We present a practical approach to prioritising repurposed drugs to evaluate in the context of clinical AD. We would like to thank our patient and public contributors and the wider investigator team.
Journals
2025 EN
Mummery Catherine J. · Villaseñor Roberto · Niewoehner Jens
+2 more
Abstract Background The positive study results and approvals for first‐generation anti‐amyloid‐beta (Aβ)‐targeting therapies are an important advancement in the treatment of Alzheimer’s disease (AD), offering new hope for people living with AD and important learnings for the field. We know from existing anti‐amyloid therapy data that rapid and efficient removal of amyloid is needed to achieve significant clinical effects. In addition, the range of targets and modes of action of biologics being explored in AD is increasing. However, delivering large molecules across the blood–brain barrier (BBB) is challenging. The objective of this presentation is to provide an overview of emerging biologic therapeutics and innovative drug delivery methods to actively transport drugs across the BBB. Method We will focus on active transport mechanisms in development, which consist of an antibody fragment that binds to the transferrin receptor and harnesses a process called receptor‐mediated transcytosis. Result These novel active transport mechanisms have been applied to different modalities, including monoclonal antibodies and antisense oligonucleotides, and have shown clear improvements in the distribution of drugs in preclinical models, such as the Brainshuttle™ and TransportVehicle™ technology described here. In humans, trontinemab is the first amyloid‐directed Brainshuttle™ antibody fusion to show proof of concept in people living with AD; demonstrating increased brain penetration and amyloid plaque removal with improved safety to date. Latest results from the Phase Ib/IIa Brainshuttle™ M AD study in people with mild cognitive impairment due to AD or mild‐to‐moderate AD (NCT04639050) will be presented at this conference. Conclusion Utilizing active transport mechanisms, such as the Brainshuttle™ technology, to achieve rapid and efficient amyloid clearance may unlock the full potential of disease modification with Aβ‐targeting monoclonal antibodies in AD. Active transport mechanisms could also be used in other large molecule delivery systems to improve distribution of drugs as well as efficacy and safety profiles.
Journals
2025 EN
Smith Janice · Mummery Catherine J. · Cummings Jeffrey L.
+13 more
Abstract Background Developing potent therapies that reduce amyloid plaques has been shown as one means of producing clinical benefit in the early stages of symptomatic Alzheimer’s disease (AD). Trontinemab is a novel amyloid‐targeting Brainshuttle™ antibody specifically engineered for efficient transferrin receptor 1‐mediated transport across the blood–brain barrier. Trontinemab has demonstrated robust and rapid mean amyloid plaque removal of 107 centiloids after 28 weeks of 3.6 mg/kg treatment in the Phase Ib/IIa Brainshuttle AD study (n=12; NCT04639050), coupled with a low incidence of amyloid‐related imaging abnormalities (ARIA). Based on the results from the Brainshuttle AD study, to be presented at AAIC 2025 by Kulic et al., a pivotal program with trontinemab in early AD will be discussed. Method TRONTIER 1 and 2 are two identically designed global, randomized, double‐blind, placebo‐controlled, parallel‐group Phase III studies designed to investigate the efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of trontinemab following intravenous infusion in participants with early AD who have confirmed amyloid pathology. A pre‐screener study, Traveller, based on a brief clinical assessment and a plasma biomarker will also be initiated to enable broader community outreach and extend access to these trials to more diverse populations. Result The primary endpoint is the change from baseline on the Clinical Dementia Rating – Sum of Boxes at 18 months’ treatment duration. Secondary outcome measures include assessments of cognition, function, behavioral symptoms, and quality of life. PD effects of trontinemab will be evaluated using amyloid and tau positron emission tomography, magnetic resonance imaging, and fluid biomarkers. Additional important objectives include assessment of safety, PK, and immunogenicity. Conclusion The recent Phase Ib/IIa interim results suggest that rapid and robust amyloid plaque clearance and fluid biomarker changes may be achieved with low ARIA incidence. The overall favorable safety and interim biomarker results to date support the rationale for moving into the pivotal Phase III studies TRONTIER 1 and TRONTIER 2. These studies will provide the opportunity to assess whether treatment with trontinemab slows disease progression in people living with early symptomatic AD.
Journals
2025 EN
Conti Catherine C. · Amaza Hannatu · Miller Melanie J.
+13 more
Abstract Background The Alzheimer's Disease Neuroimaging Initiative (ADNI4) aims to increase participation of individuals from different communities so results are more generalizable. ADNI uses digital marketing to recruit and enroll older adults into a Digital cohort for screening into In‐Clinic. This abstract presents ad engagement data by ad theme and modality, and enrollment data. Method We employed a demographic community‐focused marketing approach developed in partnership with ADNI's Community Scientific Partnership Board and marketing firm. Digital ads were run in geographic areas near ADNI sites based on site readiness to enroll participants and informed by the older adult population's demographic composition in those areas, estimated using American Community Survey (ACS) data for adults age 65+. Digital campaigns (Meta ads, landing pages, emails) used themes (solo, family, community; educational content, aspirational messaging) designed to resonate with different communities in static image or video format (Figure 1). Varying ads were run simultaneously to compare effectiveness. Ads directed potential participants to study websites for Digital cohort enrollment. Select Digital participants were referred for site screening into the In‐Clinic cohort. Ad engagement was estimated as the ratio of clicks (clicks on ad) to impressions (ad views). Result Digital campaigns enrolled 5,931 participants between 9/18/2023 and 1/21/2025 into the Digital cohort. Most campaigns enrolled the desired community group at a higher percentage than the associated metropolitan area's population. Overall, we enrolled 22% from one community and 32% from another, compared to ACS estimates of 13.39% and 11.09% (Table 1), helping improve generalizability of our study. Ad themes and format types performed similarly across different community campaigns. In both, “solo” messaging‐themed ads yielded highest engagement. Ads with educational content yielded higher engagement compared to aspirational ads; and a higher percentage of those shown image ads clicked than those shown video (Table 2). ADNI sites screened 18 participants traced from ad campaigns into the In‐Clinic cohort. Conclusion Successful recruitment of adults from different communities demonstrates the feasibility of community‐focused, site‐specific digital marketing for the ADNI Digital study cohort. High engagement with ads of solo themes, educational content, and static imagery demonstrates these ad configurations are most effective for both communities.
Journals
2025 EN
Landau Susan M. · Miller Melanie J. · Conti Catherine C.
+8 more
Abstract Background A major limitation of the Alzheimer's Disease Neuroimaging Initiative (ADNI) and most ADRD clinical research is lack of generalizability due to under‐inclusion of low socioeconomic status (LSES) participants. ADNI is planning a sub‐study to explore methods and determine feasibility of engaging and enrolling LSES participants. Method ADNI plans to use two approaches to identify, engage, enroll LSES participants: (1) Several organizations have large databases with health care and SES indicators (e.g. education, occupation, income) on millions of individuals. These databases can identify LSES individuals in various geographic areas and provide contact information for informational marketing and recruitment efforts. (2) Thousands of Federally Qualified Health Clinics (FQHCs) across the USA provide primary care to LSES communities. Although several networks of FQHCs have enrolled LSES participants in clinical research, to our knowledge such individuals have not been previously included in AD biomarker research. ADNI plans to use these approaches to enroll 100‐200 LSES participants in a sub‐study. ADNI leadership and staff will extensively interact with relevant organizations and members of the FQHC community to understand the needs of clients and clinic staff, and to optimize the engagement and enrollment approach. To enroll LSES participants from diverse geographical regions, including rural areas, participants may be assessed at existing ADNI sites or new assessment sites using remote assessment. Result Participants will be assessed with a simplified ADNI battery: clinical measures (Clinical Dementia Rating, brief tests of memory and executive function), routine blood screening (HbA1C, cholesterol) and AD plasma biomarkers. A subset will undergo neuroimaging (MRI, amyloid PET, tau PET). Critically, acquisition and analysis of all measurements will be harmonized with existing ADNI procedures to enable direct comparison with decades of legacy ADNI measurements. The first participants are expected to be enrolled in late 2025. Conclusion This sub‐study will identify the most effective methods to engage and enroll LSES participants into ADRD biomarker research. These methods will also evaluate feasibility for ADNI5, which aims to establish a national cohort of participants over age 55 who approximate the US census for gender, race, ethnicity, socioeconomic status and geographic distribution.