The Evolving Role of Anti-Amyloid Therapies for Alzheimer's Disease*

Date/Time: Tuesday, September 12, 2023 - 8:45 AM – 10:30 AM
Track: Plenary
Room: Salons E-F (5th Floor)
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Chair: Beau Ances, MD, PhD, MSc, FANA

Co-Chair: Krishnankutty Sathian, MBBS, PhD, FANA

This session will discuss the current role of recently approved anti-amyloid therapies for AD. This session will evaluate the mechanisms of action of previous and current anti-amyloid therapies. This will be followed by discussion of how to ensure implementation of these new therapies in the clinical setting (including implementation of strategies that focus on under-represented minorities). Finally, a pro and con debate regarding use of anti-amyloid therapies will be provided.

Learning Objectives:

  • Understand the mechanism of action of current anti-amyloid therapies
  • Understand the risks, benefits and limitations of current therapies
  • Understand how to administer and follow patients who are receiving anti-amyloid therapies

Anti-amyloid monoclonal antibodies: mechanisms of action and clinical trials 

Speaker: Michael Rafii, MD, PhD

Alzheimer's disease (AD) is the leading cause of dementia worldwide and follows a pathological cascade involving amyloid plaques, neurofibrillary tangles and neurodegeneration. The FDA has granted accelerated approval for aducanumab and traditional approval for lecanemab, both amyloid-directed monoclonal antibodies and members of a new class of disease-modifying treatments for Early AD.  Another amyloid-lowering monoclonal antibody, donanemab, is expected to receive approval later this year.  Gantenerumab and Solanezumab are anti-amyloid monoclonal antibodies that did not significantly lower brain amyloid levels and both of these drugs failed to demonstrate clinical efficacy. I will discuss these treatments and the studies supporting their clinical use.

Pros of anti-amyloid monoclonal antibodies

Speaker: Gil Rabinovici, MD, FAAN, FANA

This presentation will summarize results from recent clinical trials of anti-amyloid monoclonal antibodies in early stage Alzheimer's disease, including data from the EMERGE/ENGAGE (aducanumab), CLARITY-AD (lecanemab) and TRAILBLAZER-ALZ 1-2 (donanemab). We will focus on clinical and safety outcomes and also explore biomarker effects, as well as the evidence for disease modification. The overall evidence will demonstrate that potent antibodies that effectively clear amyloid plaques from the brain significantly slow clinical decline, providing a modest but clinically meaningful benefit.

Cons of anti-amyloid monoclonal antibodies

Speaker: Madhav Thambisetty, MD, PhD, FANA

The clinical benefit associated with anti-amyloid immunotherapies, a new class of drugs for the treatment of Alzheimer's disease, is predicated on their ability to modify disease course by lowering brain amyloid levels. Two amyloid-lowering antibodies, aducanumab and lecanemab, have obtained United States Food and Drug Administration accelerated and full approval respectively. Further agents of this class are in the Alzheimer's disease treatment pipeline. Based on limited published clinical trial data to date, regulators, payors and physicians will need to assess their efficacy, clinical effectiveness and safety, as well as cost and accessibility. Attention to three important questions related to treatment efficacy, clinical effectiveness and safety should guide evidence-based consideration of this important class of drugs. These are: (1) Were trial statistical analyses appropriate and did they convincingly support claims of efficacy? (2) Do reported treatment effects outweigh safety concerns and are they generalizable to a representative clinical population of people with Alzheimer's disease? and (3) Do the data convincingly demonstrate disease course modification, suggesting that increasing clinical benefits beyond the duration of the trials are likely? I will propose specific approaches to interpreting trial results for these drugs and highlight important areas of uncertainty where additional data and a cautious interpretation of existing results is warranted. Safe, effective and accessible treatments for Alzheimer's disease are eagerly awaited by millions of patients and their caregivers worldwide. While amyloid-targeting immunotherapies may be promising disease-modifying Alzheimer's disease treatments, rigorous and unbiased assessment of clinical trial data is critical to regulatory decision-making and subsequently determining their provision and utility in routine clinical practice.

Challenges of Implementing anti-amyloid therapies in the clinic

Speaker: Liana G. Apostolova, MD, MSc, FAAN

The recent FDA and CMS approval of anti-amyloid therapies places our healthcare system under unprecedented demands. There will be an urgent need to establish a carefully thought-out workflow for the evaluation of patient eligibility and for the safe and efficient administration of MAB infusions. This necessitates an unprecedented coordination of care between neurologists, radiologists, emergency room and intensive care unit physicians with the necessary training and skills to address potential treatment side effects. In addition, the modest number of racial and ethnic minority individuals included in MAB trials to date has led to a limited insight into potential ethnic/racial differences in efficacy and risk/benefit ratio.

Improving inclusiveness in research and clinical settings

Speaker: Monica Parker, MD

AA are disproportionately affected by Alzheimer's disease, consistently underserved by social and health care systems, and greatly underrepresented in Alzheimer's research. To better engage the Metropolitan Atlanta population of African Americans, the Goizueta Alzheimer's Disease Research Center (GADRC), has established a 10- year dedicated focus on the recruitment and retention of African American (AA) individuals into ADRC research and brain donation programs. We have increased the percentage of active AA clinical research participants, URM investigators and investigations focused on ethnic differences in Alzheimer's and Related Dementias. Equity in research participation has been improved by creating an educational outreach whereby the population of older adults, regardless of color, are similar in age, educational attainment, and overall health status. African American and European Americans, who committed to research enrollment in Emory's NACC- UDS longitudinal study 2015-2020, demonstrate different behaviors in response to educational outreach programming

A Genome-wide CRISPR Interference Screen Reveals Genetic Modifiers Of Lysosomal Glucocerebrosidase Activity

Emerging Scholar Speaker: Georgia Minakaki, MSc, PhD

Mutations in GBA1 gene, leading to decreased activity of lysosomal glucocerebrosidase (GCase), represent a relatively common risk factor for development of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB)[1-3]. As the penetrance of pathogenic GBA1 variants is incomplete, additional genetic factors could play a role in disease onset. Therefore, identifying genes and cellular pathways specifically modulating lysosomal GCase activity may provide novel insights into disease risk. In the present study, we performed an unbiased genome-wide pooled CRISPR interference (CRISPRi) screen to identify genetic modifiers of lysosomal GCase activity. Upon transduction with the sgRNA library hCRISPRiv2[4], lysosomal GCase activity was assessed by measuring single cell fluorescence intensity resulting from hydrolysis of the β-glucosidase substrate 5-(pentafluorobenzoylamino)fluorescein di-ß-D-glucopyranoside (PFB-FDGlu). Approximately 340 genes either reduced or increased GCase activity by a Z-score exceeding |3|, and were called as hits. Importantly, GBA and SCARB2 were identified as hits associated with reduced lysosomal GCase activity, thus confirming internal validity of our approach. A subset of genes from the primary screen were selected for follow-up studies, based on previous genetic link to disease, implication in disease-relevant pathways, and expression in cell types of the central nervous system. Three complementary approaches were used: 1) individual gene knock down via siRNA, 2) pharmacological modulation of druggable targets in iPSC-derived neurons and microglia, 3) CRISPR/Cas9 knock out of selected top hit genes in iPSCs-derived neurons and microglia. Mechanistic studies focusing on a subset of genes validated using this workflow are ongoing. Our unbiased screen and systematic validation of genetic modulators of GCase activity could provide novel insight into disease penetrance, with potential therapeutic implications for PD, DLB, and additional neurodegenerative diseases with underlying lysosomal dysfunction.

Pyramidal Neurodegeneration is Linked to Select Cytoarchitecture and Cognitive Impairment in Behavioral Variant Frontotemporal Dementia with Tau or TDP-43 Pathology

Emerging Scholar Speaker: Daniel Ohm, PhD

Background: The behavioral variant of frontotemporal dementia (bvFTD) is primarily caused by either tauopathies (bvFTD-tau) or TDP-43 (bvFTD-TDP) proteinopathies. Frontal cortices are often the earliest sites of degeneration in bvFTD, and previous studies suggest bvFTD-tau and bvFTD-TDP share similar patterns of pyramidal neurodegeneration in infragranular layers of agranular cortices. However, neurodegeneration in other cortical layers in more laminated (dysgranular-to-granular) cytoarchitecture in bvFTD remain poorly understood. We recently reported that infragranular layers throughout agranular-to-granular regions accumulate more protein inclusions in bvFTD-tau than bvFTD-TDP. Thus, the current study tested the hypothesis that pyramidal neurodegeneration is greater in more laminated regions of bvFTD-tau than bvFTD-TDP and relates to frontal-mediated cognitive impairment. Methods: In 49 bvFTD-TDP, 28 bvFTD-tau, and 33 cognitively normal (CN) participants, we examined 11 subregions of anterior cingulate, medial orbitofrontal, and mid-frontal cortices representing a cytoarchitectonic gradation of agranular-to-dysgranular-to-granular cortex (i.e., Brodmann areas 33, 24, 32, 14, 11, 46). We immunostained 6μm-thick serial sections of each region using antibodies to total (NeuN) and pyramidal (SMI-32) neurons, and digitally quantified immunoreactivity of each antibody per subregion. We z-scored measures in bvFTD using the CN group, producing neurodegeneration metrics analyzed in linear mixed-effect models adjusted for demographics and biological variables. Exploratory analyses compared region-specific neurodegeneration to letter fluency performance (an executive functioning test) available within five years from symptom-onset (n=23). Results: While total (NeuN) neurodegeneration in each type of cortex was similar between bvFTD-TDP and bvFTD-tau, pyramidal (SMI-32) neurodegeneration in granular cortex (not agranular or dysgranular cortex) was greater in bvFTD-tau than bvFTD-TDP (beta=-0.946, SE=0.306, p=0.003). Pyramidal neurodegeneration progressively worsened across the agranular-to-granular arrangement of six Brodmann areas sampled in bvFTD-TDP (beta=-0.104, SE=0.032, p=0.001) and bvFTD-tau (beta=-0.191, SE=0.04, p<0.001). Executive dysfunction worsened with greater pyramidal neurodegeneration in dysgranular/granular cortex (beta=0.105, SE=0.044, p=0.042), not agranular cortex (p=0.449). Conclusions: In clinically similar bvFTD participants, we find greater pyramidal neurodegeneration in more laminated (granular) cytoarchitecture that is more prominent in bvFTD-tau than bvFTD-TDP. Furthermore, selective pyramidal neurodegeneration in more laminated cytoarchitecture may differentially contribute to early executive dysfunction characteristic of bvFTD, suggesting tauopathies may have a clinically relevant and distinctive neurodegenerative pattern in the bvFTD spectrum.