Drug Development.

Background: Lecanemab is a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils. In two clinical studies (phase 2, NCT01767311 and phase 3 ClarityAD, NCT03887455) in early Alzheimer's disease, lecanemab substantially reduced amyloid PET and significantly slowed clinical decline on multiple measures of cognition and function, including CDR-SB at 18 months. Models describing the change in amyloid PET and CDR-SB in response to lecanemab treatment were used to explore the impact of changing from the initial dosage regimen (10 mg/kg every 2 weeks [Q2W]) to a less intensive maintenance dosing regimen (10 mg/kg every 4 weeks [Q4W]) on clinical efficacy, and to explore the optimal duration of the initial dosing regimen.

Drug Development.

Background: To help improve the Alzheimer's disease (AD) therapeutics research and development process, the Critical Path for Alzheimer's Disease (CPAD) Consortium at the Critical Path Institute (C-Path) provides a neutral framework for the drug development industry, regulatory agencies, academia, and patient advocacy organizations to collaborate. CPAD's extensive track record of developing regulatory-grade quantitative drug development tools motivates sponsors to share patient-level data and neuroimages from clinical trials. CPAD leverages these data and uses C-Path's core competencies in data management and standardization, quantitative modeling, and regulatory science to develop tools that help de-risk decision making in AD drug development.

Drug Development.

Background: SHIP1 is a phosphatidyl inositol phosphatase encoded by INPP5D, which has been identified as a risk gene for Alzheimer's disease (AD). SHIP1 is expressed in microglia, the resident macrophage in brain. It is a complex, multidomain protein that acts as a negative regulator downstream from TREM2.

Drug Development.

Background: Pivotal Alzheimer's Disease (AD) trials typically require thousands of participants, resulting in long enrollment timelines and substantial costs. We leverage deep learning predictive models to create prognostic scores (forecasted control outcome) of trial participants and in combination with a linear statistical model to increase statistical power in randomized clinical trials (RCT). This is a straightforward extension of the traditional RCT analysis, allowing for ease of use in any clinical program.

Drug Development.

Background: Recent anti-amyloid mAb trial results demonstrate slowing of Alzheimer's disease progression, but to date do not fully halt or reverse this progression. Optimization of anti-amyloid therapy (timing and duration of intervention, modality, combinations, biomarker guidance) is limited by incomplete understanding of the disease, such as relationship between amyloid and tau pathways. Mechanistic Alzheimer's progression modeling investigated how amyloid and tau pathologies are connected in driving progression.

Drug Development.

Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to amyloid-beta (Aβ) protofibrils, was formally evaluated as a treatment for early Alzheimer's disease in a phase 2 study (Study 201) and the phase 3 Clarity AD study. These trials both included an 18-month, randomized study (core) and an open-label extension (OLE) phase where eligible participants received open-label lecanemab for up to 30 months to date. Clinical (CDR-SB, ADAS-Cog14, and ADCS-MCI-ADL), biomarker (PET, Aβ42/40 ratio, and ptau181) and safety outcomes were evaluated.

Drug Development.

Background: 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 markers of amyloid in early symptomatic Alzheimer's disease (AD) and slow decline on clinical endpoints of cognition and function. Herein, a modeling approach was used to correlate amyloid reduction with change in rate of AD progression.

Drug Development.

Alzheimer's disease pathophysiology is believed to involve various abnormalities, including those of amyloid beta (Ab) peptide and tau processing, inflammation, oxidative stress, and vascular risk factors. Aβ peptides exist in a dynamic continuum of conformational states from monomeric Aβ, to soluble progressively larger Aβ assemblies that include a range of low molecular weight oligomers to higher molecular weight protofibrils, and finally to insoluble fibrils (plaques). Various lines of evidence support the "amyloid hypothesis" that Aβ plays a central role in the pathogenesis of AD, and several immunotherapies have been developed to interact with this cascade in various different places which may reduce the number of soluble aggregates and insoluble Aβ fibrils deposited in the brain.

Drug Development.

Background: Lecanemab is a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils. In two clinical study evaluations of lecanemab, Clarity AD (NCT03887455) and lecanemab phase 2 study (Study 201, NCT01767311), the drug showed statistically significant reduction in disease progression during 18 months of treatment relative to placebo. Anti-amyloid immunotherapy can result in higher rates of "pseudo-atrophy" (ie, whole brain volume loss or ventricular enlargement) relative to disease progression observed in placebo-treated subjects.

Drug Development.

Background: Lecanemab, a novel humanized immunoglobulin G1 monoclonal antibody targeting both neurotoxic Aβ protofibrils and Aβ plaques, has demonstrated the ability to substantially reduce markers of amyloid and significantly slow clinical decline on multiple measures of cognition and function in early AD in phase 2 (Study 201) and phase 3 (Clarity AD) studies. In these clinical studies, several plasma biomarkers assessments (Aβ42/40 ratio, p-tau181, GFAP, and p-tau217) showed improvements comparing lecanemab with placebo. Herein, we utilized modelling and simulations to evaluate the long-term effects of lecanemab on biomarkers of neurodegeneration in plasma.

Drug Development.

A 10 mg/kg every 2 week (Q2W) dose of the humanized IgG1 monoclonal antibody lecanemab was approved after demonstrating significant clinical benefit in slowing cognitive decline in early Alzheimer's disease (AD) in two clinical studies (the phase 2 Study 201 and phase 3 Clarity AD). A less frequent every 4 weeks lecanemab 10 mg/kg maintenance dosing (Q4W) has been proposed after a sufficient initial Q2W treatment. To further understand long-term benefit of continued Q4W lecanemab treatment, a quantitative systems pharmacology (QSP) model was developed which mechanistically describes AD pathophysiology using multivariate data from clinical studies.

Drug Development.

Background: Lecanemab is an approved anti-amyloid monoclonal antibody that binds with highest affinity to soluble Aβ protofibrils, which are more toxic than monomers or insoluble fibrils/plaque. In clinical studies, biweekly lecanemab treatment demonstrated a slowing of decline in clinical (global, cognitive, functional, and quality of life) outcomes, and reduction in brain amyloid in early Alzheimer's disease (AD). Herein, we describe the impact of lecanemab treatment on tau PET.

Drug Development.

Lecanemab is a humanized IgG1 monoclonal antibody binding with high affinity to protofibrils of amyloid-beta (Aβ) protein. In 18-month clinical studies, lecanemab has been shown to reduce a complex group of protein interactions associated with early symptomatic Alzheimer's disease (AD) and slow decline on clinical endpoints of cognition and function for up to 30 months to date. In prior research, results from the phase 2 study gap period (no study drug treatment) between the end of the study core and the beginning of retreatment in the open-label extension (OLE) provides evidence regarding the need for continued maintenance therapy beyond 18 months.

Dementia Care Research and Psychosocial Factors.

Background: Effect and Safety of Electroconvulsive Therapy plus Usual Care for the Acute Management of Severe Agitation in Dementia (ECT-AD) is a multi-site NIA-funded FDA-regulated pioneering clinical trial to investigate the effectiveness of electroconvulsive therapy (ECT) in treating severe and treatment-refractory agitation and aggression among individuals with advanced dementia, a condition that has a profound negative impact on patient quality of life and caregiver burden. Here we present baseline demographics of the patient population in this ongoing trial.

Method: To date we have enrolled 18 participants, with a mean age of 74.

Drug Development.

Background: Irsenontrine (e2027) is a potent and selective PDE9 inhibitor that increases cellular cGMP which is important for glutamatergic synaptic function. Irsenontrine was investigated to improve cognition in Lewy Body Dementia (LBD; DLB and PDD), and recent phase 2 study data suggests that irsenontrine could be more effective in DLB patients without amyloid copathology. Here, we evaluated differential change from baseline levels in proteins associated with cGMP pathway in DLB participants without amyloid co-pathology (DLB A-) compared to DLB participants with amyloid co-pathology (DLB A+).

Dementia Care Research and Psychosocial Factors.

Background: Over the past 3 years, the Global Council on Alzheimer's Disease (GCAD) has conducted research on lived experience and care partner journeys. Specifically, this research has focused on the experiences of individuals from historically underrepresented populations, including LGBTQ+, Black, Hispanic/Latino, and Asian communities. The goal has been to identify how these journeys might diverge across communities, understand various nuances that exist across cultures, and recognize the impact these might have on seeking diagnosis, care, and support.

Dementia Care Research and Psychosocial Factors.

Background: The COVID-19 pandemic had a major impact on healthcare, contributing to a mass exodus of the workforce. This poses a concern for Alzheimer's disease and related dementias (ADRD) care, which benefits from consistent care routine and staff that know the resident. Therefore, it is important to understand nursing home staff perspectives on maintaining high staff morale, which impacts recruitment, retention, and care quality.

Dementia Care Research and Psychosocial Factors.

Background: The recent breakthrough in monoclonal antibody treatment for Alzheimer's disease (AD) has ushered in a new phase in AD healthcare. However, associated amyloid-related imaging abnormalities (ARIA) present a significant risk to patients, necessitating careful monitoring. Detection by radiologists can be challenging and may suffer from inconsistency.

Dementia Care Research and Psychosocial Factors.

Background: Cerebral amyloid angiopathy (CAA) is a significant contributor to hemorrhagic stroke, notably lobar intracerebral hemorrhage (ICH) and convexity subarachnoid hemorrhage (SAH), both of which have been observed in patients with MCI/AD. To evaluate all-cause mortality among veterans with mild cognitive impairment (MCI) and Alzheimer's dementia (AD) with/without Intracerebral hemorrhage and subarachnoid hemorrhage (ICH/SAH) in the United States (US) Veterans Affairs Healthcare System (VAHS).

Method: Veterans with MCI or AD were identified based on having clinical notes or diagnostic codes in the VAHS database (2010-2019).

Dementia Care Research and Psychosocial Factors.

Background: Hyperbaric oxygen therapy (HBOT) is a treatment in which oxygen-enriched air (up to 100%) is administered to patients in a chamber at a pressure above one atmosphere absolute and is approved for the treatment of T2D ischemic wounds. Type 2 diabetes (T2D) is a risk factor for dementia. Ischemia due to vascular pathology is hypothesized to be an underlying mechanism for this association.

Dementia Care Research and Psychosocial Factors.

Background: The National Plan to Address Alzheimer's Disease (AD) prioritizes timely diagnosis of mild cognitive impairment (MCI) as one of its key goals. Studies describing the downstream consequences of not having a timely diagnosis in this vulnerable population are limited. The study objective will evaluate the relationship between a timely MCI diagnosis and decline in functional outcomes compared to a missed diagnosis.

Dementia Care Research and Psychosocial Factors.

Background: Disparities in the quality and timeliness of care for Alzheimer's disease (AD) are well documented. This study assessed the impact of demographic characteristics on the diagnosis and management of early AD patients in community-based settings.

Method: This cross-sectional study abstracted medical chart data for patients aged 50-89 years who had newly diagnosed early AD (mild cognitive impairment [MCI] or mild AD) within the past 2 years and a clinic visit within the past 12 months.

Dementia Care Research and Psychosocial Factors.

Background: Previous What Matters Most (WMM) research identified and verified patient-important concepts among a diverse population of people living with Alzheimer's disease (PLWAD) and their care partners across all stages of Alzheimer's disease (AD). Additionally, a conceptual model of disease was developed using hypothesized domains and was further refined using qualitative data (Figure 1). This next phase of WMM research aims to quantify the importance of concepts, impacts, and outcomes and to determine priorities among PLWAD and care partners within a diverse sample including underrepresented ethnic and racial groups at each level of disease severity.

Dementia Care Research and Psychosocial Factors.

Background: Language serves as a powerful tool in shaping perceptions and reinforcing societal norms. Current understanding suggests that the language used to describe dementia can impact how the condition is perceived, understood, and addressed within various cultural contexts. Further, language can play a pivot role in shaping caregiving practices, willingness to seek medical care, and the openness, or lack thereof, to speak about the condition.

Dementia Care Research and Psychosocial Factors.

Background: Cerebral amyloid angiopathy (CAA) is a significant contributor to hemorrhagic stroke, notably lobar intracerebral hemorrhage (ICH) and convexity subarachnoid hemorrhage (SAH). This study describes the natural occurrence of ICH and SAH events among veterans, including those with AD, within the United States Veterans Affairs Healthcare System (VAHS).

Method: The VAHS database was evaluated to identify ICD-10 codes for ICH (I61.