Geldmacher, David

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.

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

AbstractBackgroundWe developed the Institute on Methods and Protocols for Advancement of Clinical Trials in ADRD (IMPACT‐AD) to address the shortage of qualified investigators with adequate training and expertise to conduct Alzheimer’s Disease (AD) and AD Related Dementias (ADRD) clinical trials.MethodWe describe the experience of the first two years of funding of the IMPACT‐AD course, specifically the rates of applications to the course, descriptive summaries of the accepted trainees, and the measures of participant satisfaction and learning.ResultOver the first two years of the course, we received 195 eligible applications to the course. Most (n = 121, 62%) applicants were female and nearly half self‐reported as being African American/Black, Asian, or Pacific Islander race and/or Hispanic/Latino ethnicity. Forty‐one applicants (21%) indicated that they were the first in their family to attend collegeOf 69 total trainees accepted to the course (36% acceptance rate), a majority (n = 44, 64%) were female. Twenty‐eight (41%) self‐reported as being African American/Black, Asian, or Pacific Islander race and eleven (16%) were of Hispanic ethnicity. Fourteen trainees (20%) identified as being the first person in their family to attend college. Among trainees, 24 (35%) were MDs, 30 (43%) were PhDs, and 9 (13%) held master’s degrees.Course lecture topics were rated, on average, as “essential” or “valuable” by 98% of trainees. Across lecture topics, on average, 48% of trainees rated their prior knowledge of topics as “very strong” or “strong,” and 11% of trainees rated their prior knowledge as “weak.” Overall, 52% of trainees evaluated their change in knowledge based on the lectures as “very much increased,” 46% as “somewhat” or “slightly” increased, and 2% as “no change.” Results were similar for the two tracks. Based on pre‐ and post‐course assessments, trainees improved their knowledge of covered content (from 62% to 79% correct responses on knowledge assessments).ConclusionThe IMPACT‐AD course is achieving its mission of educating and diversifying the next generation of ADRD trialists.We thank Dr. Laurie Ryan and Dr. Kristina McLinden from the National Institute on Aging for their key contributions in leadership and scientific guidance of IMPACT‐AD.