David S. Geldmacher

Background: Alzheimer's disease (AD) is a leading cause of death worldwide, with growing prevalence as life expectancy increases. An important neurological hallmark of AD is the deposition of extracellular neuritic amyloid-β (Aβ) plaques that can disrupt synaptic transmission and cause neuronal death. More recent studies suggest that targeting Aβ species can slow the progression of cognitive decline in AD. Review Summary: This narrative review examines the efficacy of monoclonal antibodies targeting the amyloid-β (Aβ) protein in the treatment of AD. It discusses the mechanisms by which these antibodies aim to mitigate amyloid pathology and explores their clinical outcomes in various trials. The review highlights the importance of amyloid plaque reduction to less than 25 Centiloids observed through amyloid positron emission tomography (PET) scans as a predictor of slowing cognitive decline. The findings suggest that targeting insoluble amyloid plaques is crucial for achieving clinical benefits in AD treatment. This review also discusses the phenomenon of amyloid-related imaging abnormalities (ARIA) that may be associated with monoclonal antibody therapy. Conclusion: Monoclonal antibodies that target Aβ monomers, soluble oligomers and protofibrils, and insoluble fibrils/plaques were developed, and not all have provided clinical benefit. Emerging evidence suggests that it is important to reduce amyloid plaque burden to less than 25 Centiloids, consistent with a visually negative amyloid PET scan, in order to slow cognitive decline in early symptomatic AD.

Background: There are numerous communication barriers between family caregivers and providers of people living with dementia, which can pose challenges to caregiving and clinical decision-making. To address these barriers, a new web and mobile-enabled app, called CareHeroes, was developed, which promotes the collection and secured sharing of clinical information between caregivers and providers. It also provides caregiver support and education. Objective: The primary study objective was to examine whether dementia caregivers would use CareHeroes as an adjunct to care and gather psychosocial data from those who used the app. Methods: This paper presents the implementation process used to integrate CareHeroes into clinical care at 2 memory clinics and preliminary outcome evaluation. Family caregivers receiving services at clinics were asked to use the app for a 12-month period to collect, track, and share clinical information with the care recipient’s provider. They also used it to assess their own mental health symptoms. Psychosocial outcomes were assessed through telephone interviews and user data were collected by the app. Results: A total of 21 caregivers enrolled in the pilot study across the 2 memory clinics. Usage data indicated that caregivers used many of the features in the CareHeroes app, though the chatbot was the most frequently used feature. Outcome data indicated that caregivers’ depression was lower at 3-month follow-up ( t ₁₁ =2.03, P =.03). Conclusions: Recruitment and retention of the pilot study were impacted by COVID-19 restrictions, and therefore more testing is needed with a larger sample to determine the potential impact of CareHeroes on caregivers’ mental health. Despite this limitation, the pilot study demonstrated that integrating a new supportive app for caregivers as an adjunct to clinical dementia care is feasible. Implications for future technology intervention development, implementation planning, and testing for caregivers of people living with dementia are discussed.

PMENT Amyloid-lowering monoclonal antibody therapies entered clinical use in 2021. In July 2023, lecanemab became the first of these to gain full US Food and Drug Administration (FDA) approval and limited Medicare payment coverage. Donanemab gained similar approval status in July 2024. The approved agents remove amyloid plaque from the brain and appear to slow clinical disease progression but can produce significant adverse events known as amyloid-related imaging abnormalities with cerebral edema or effusion and with cerebral hemorrhages. Extensive safety monitoring is therefore required, including scheduled MRI scans. Also in 2023, brexpiprazole became the first agent specifically approved by the FDA for agitation associated with AD. Suvorexant, an orexin receptor antagonist, previously was approved for the treatment of insomnia in people with mild and moderate AD. ESSENTIAL POINTS There is robust evidence for the use of acetylcholinesterase inhibitors for patients with mild, moderate, and severe dementia due to AD, including outcomes beyond changes in cognitive screening test scores. More limited studies support the use of memantine in moderate and severe stages. These agents have a primary effect of delaying decline in cognition and function and postponing the emergence of adverse behaviors. Pharmacotherapy for behavioral and psychological symptoms is less predictable, and most clinical trials have had negative results. Anti-amyloid therapies provide the first FDA-approved option to alter AD pathology, but an understanding of overall utility and value to patients remains in its infancy....

Background: Workface projections indicate an increasing shortfall in neurologists and other medical specialists to treat persons with Alzheimer’s disease and other causes of dementia (Dall et al. Neurology 2013). This problem will be further magnified by available disease modifying therapies aimed at earlier stages of illness, markedly expanding the patient pool (Anderson et al. J Prev Alzheimers 2022; Hlavka et al. Rand 2019). With the Alzheimer’s disease treatment landscape approaching these turning points the University of Alabama at Birmingham Brain Aging and Memory (BAM) Clinic undertook a multidisciplinary expansion to improve access and increase the role of nonphysician professionals to optimize care. Onboarding this interdisciplinary team was complicated by separation of staff members mandated by the COVID‐19 pandemic. These factors, along with emerging use of “team‐based learning” educational models led to the creation of the BAM Learning Club (BAM LC).Methods: BAM LC is a weekly synchronous online series of didactics, lectures, case discussions, journal reviews, and team‐building wellness activities. Participants include Neurologists, Psychiatrists, Psychologists, RN Case managers, RN Clinical Care Coordinators, Social Workers, Nurse Practitioners, Pharmacists, Caregiver Counselors, Research Scientists, Clinical Trial Coordinators, Postdoctoral Fellows, Residents, and Medical Students. Sessions are recorded for future onboarding and educational needs. Content is generated by the BAM LC members with support from its director.Results: BAM LC began in June 2021 and has continued weekly with increasing interest and attendance. Shared learning has led to practice improvements, a collaborative environment, and a cohesive multidisciplinary team. Recorded sessions have been used to provide education outside of our cohort and will be maintained for future use.Conclusion: Team‐based learning has resulted in better academic, clinical, and communication outcomes among health care professionals (Joshi et al. Cureus 2022). Multidisciplinary team‐led learning opportunities focused on dementia care could serve as a tool to promote further practice improvement, collaboration, and cohesion within healthcare organizations. Normalization of synchronous remote learning during the pandemic facilitated acceptance, uptake, and participation across disciplines. This process also has the potential to provide further system‐wide education in health systems to diversify the workforce and improve readiness to treat a rapidly expanding patient population.

Background: Recent studies comparing non‐Hispanic Whites (NHW) to non‐Hispanic Blacks (NHB) with cognitive impairment found differences in associations between neuropsychological performance and ratings of daily function. Evaluating differences in these relationships by race and ethnicity may be important to interpreting disparities in clinical research outcomes for people with Alzheimer’s disease and related disorders.Method: We compared demographic and performance variables across consensus diagnostic groups (CN, impaired‐not‐MCI, MCI, or dementia) at baseline in NHB (N = 1,609; 15.62%), Hispanic (N = 706, 6.86%) and NHW (N = 7,984,77.52%) adults in the NACC cohort, using data from Version 3.0 of the UDS, collected at the 37 NIA‐ADRCs from March 2015 to June 2022 (alz.washington.edu). Spearman’s rank correlation examined the associations between CDR‐GS, MoCA, and FAS scores by race and ethnicity within consensus diagnostic groups.Result: Among 10,299 participants, 5,964 (57.91%) were women, mean age at baseline was 69.34 (±9.80), and mean education was 16.02 (±2.81) years. Significant differences in gender proportions between race and ethnic groups were observed. NHB had a higher proportion of female participants (χ2 = 233.39 <.0001); and reported the lowest FAS scores (Z = 200.67, P < .001). Hispanic participants had completed fewer years of education (Z = 3999.92, p = <.0001); and reported higher depressive symptoms (Z = 39.81, p = <.0001). Significant correlations were observed between all assessments by race and ethnic groups. When stratified by consensus group, in the NHW and NHB subsamples, CDR and MoCA scores associations were significant except in the “Impaired not MCI” groups. In the Hispanic subsample, significant correlations were only observed in the dementia group. After adjusting for the effects of GDS scores, correlations retained significance except in the NHB MCI group. Significant correlations between CDR and FAS scores were observed except in the “Impaired not MCI” group in the Hispanic subsample. These associations were retained after controlling for depressive symptoms except in the Hispanic MCI group.Conclusion: Associations between cognitive and functional performance measures varied by racial and ethnic group when stratified by consensus groups in the NACC dataset. Specific ethnic, racial and socio‐cultural factors, as well as implicit/explicit examiner bias that may drive differences in performance warrant further study.

Background: Family caregivers are often inexperienced and require information from clinic visits to effectively provide care for patients. Despite reported deficiencies, 68% of health systems facilitate sharing information with family caregivers through the patient portal. The patient portal is especially critical in the context of serious illnesses, like advanced cancer and dementia, where caregiving is intense and informational needs change over the trajectory of disease progression. Objective: The objective of our study was to analyze a large, nationally representative sample of family caregivers from the National Study of Caregiving (NSOC) to determine individual characteristics and demographic factors associated with patient portal use among family caregivers of persons living with dementia and those living with cancer. Methods: We conducted a secondary data analysis using data from the 2020 NSOC sample of family caregivers linked to National Health and Aging Trends Study. Weighted regression analysis by condition (ie, dementia or cancer) was used to examine associations between family caregiver use of the patient portal and demographic variables, including age, race or ethnicity, gender, employment status, caregiver health, education, and religiosity. Results: A total of 462 participants (representing 4,589,844 weighted responses) were included in our analysis. In the fully adjusted regression model for caregivers of persons living with dementia, Hispanic ethnicity was associated with higher odds of patient portal use (OR: 2.81, 95% CI 1.05-7.57; P=.04), whereas qualification lower than a college degree was associated with lower odds of patient portal use by family caregiver (OR 0.36, 95% CI 0.18-0.71; P<.001. In the fully adjusted regression model for caregivers of persons living with cancer, no variables were found to be statistically significantly associated with patient portal use at the .05 level. Conclusions: In our analysis of NSOC survey data, we found differences between how dementia and cancer caregivers access the patient portal. As the patient portal is a common method of connecting caregivers with information from clinic visits, future research should focus on understanding how the portal is used by the groups we have identified, and why.

We collected and analyzed genomic sequencing data from individuals with clinician-diagnosed early-onset or atypical dementia. Thirty-two patients were previously described, with 68 newly described in this report. Of those 68, 62 patients self-reported white, non-Hispanic ethnicity and 6 reported as African–American, non-Hispanic. Fifty-three percent of patients had a returnable variant. Five patients harbored a pathogenic variant as defined by the American College of Medical Genetics criteria for pathogenicity. A polygenic risk score (PRS) was calculated for Alzheimer's patients in the total cohort and compared to the scores of a late-onset Alzheimer's cohort and a control set. Patients with early-onset Alzheimer's had higher non-APOEPRSs than patients with late-onset Alzheimer's, supporting the conclusion that both rare and common genetic variation associate with early-onset neurodegenerative disease risk.

Episodic memory is widely recognized as a critically important aspect of cognition that is often impacted by cognitive and brain aging. Prior work has shown that episodic memory is related to the presence of teeth-like folds on the dentate gyrus, called dentation. We hypothesized that episodic memory performance relates to overall hippocampal structure (i.e., dentation and volume) in an oldest-old cohort. We used data from the McKnight Brain Aging Registry, which consisted of cognitively healthy 85+-year-old adults. We conducted a canonical correlation analysis on 111 participants between a set of episodic memory tests and a set of characterizations of hippocampal structure. The analysis yielded a strong canonical correlation between episodic memory and hippocampal structure (r = 0.491, p = Highlights We characterized hippocampal dentation in a healthy oldest-old sample. Hippocampal structure is related to episodic memory in healthy oldest-old adults. Memory functioning is related to both hippocampal volume and dentation.

Background: The Alzheimer's Clinical Trials Consortium (ACTC) aims to provide an optimal infrastructure, utilizing centralized resources and shared expertise, to accelerate the development of effective interventions for Alzheimer’s disease and related disorders (ADRD). Metrics help clinical research sites understand where they stand relative to other sites and share best practices. For ACTC and study leaders, metrics aid in tracking the progress towards established goals, assessing performance of the sites and of the coordinating center in supporting site efforts, and may identify areas where additional development is needed.Method: This initiative is led by an ACTC committee, comprised of member site PIs, research staff, and ACTC’s coordinating center. Proposed metrics were approved by the ACTC Steering Committee, and include those typically used to assess performance of a clinical trial (i.e., screening and randomization totals) as well as information not typically quantified (e.g. PI oversight and responsiveness). Reports are generated by extracting data from the ACTC data system, which ensures accuracy and minimizes site burden. A key element of this initiative is feedback from sites, obtained ad hoc and semiannually. Surveys were also used to understand the impact of COVID‐19 pandemic and other barriers to study startup. Interactive reports are distributed quarterly, facilitating both high level and detailed review. Site‐specific anonymized reports allow sites to see how they are performing relative to other sites.Result: 5 surveys were distributed with response rates between 50% and 82%. Quarterly reports, including summaries of site activation and screening performance, were distributed to 75 sites. Results obtained will be in our presentation.Conclusion: We established procedures to collect, report and disseminate metrics, providing the foundation for a strong connection between sites and study teams. Our next steps are to develop additional summaries, maximize survey responses, improve the efficiency of report dissemination, as well as to explore the utility of metrics in measuring efficiency of trial conduct. This initiative will inform the development and implementation of additional ACTC trials, as well as tracking ACTC progress in building a consortium responsive to a changing landscape of clinical trials.

Background: The growing Alzheimer’s disease (AD) population, the continued emergence of AD biomarkers, and the potential approval of therapies that target the underlying pathophysiology of AD have the potential to transform the diagnosis, treatment, and monitoring of AD within health systems. Transformation of the AD patient care pathway will present significant challenges, and resources are needed to help health systems prepare to integrate potential new AD therapies into patient care.Methods: Premier Applied Sciences developed a “Site Readiness Framework” for a new paradigm of AD care, with input from key medical experts in AD and select U.S. health systems, as well as financial support and input from Biogen. The development process involved interprofessional contributions from neurology, geriatrics, neuropsychology, psychiatry, radiology, infusion, memory disorders program coordination, and formulary management. Stakeholder interviews were conducted to illuminate the myriad challenges that potential new AD therapies may pose for health systems and guide the development of resources aimed to address those challenges.Results: Key components of the Site Readiness Framework for AD include a program self‐assessment to help health systems identify gaps in preparedness for new AD therapies, and tools for mapping key considerations, such as purposeful referral of patients from primary care to a specialist, biomarker assessment, preparing for infusion therapy, and care coordination. An overview of the resources available within the Site Readiness Framework for AD, as well as a description of their potential application within a large academic health system, will be reported.Conclusions: The approval of a disease‐modifying therapy for AD will require a transformation of the AD patient care pathway. The Site Readiness Framework for AD may help health systems prepare to integrate potential new therapies.