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Alzheimer’s Disease Therapeutics: Alternatives to Amyloid 2021

WEBINAR

Only

Alzheimer’s Disease Therapeutics: Alternatives to Amyloid 2021

Friday, December 3, 2021, 10:00 AM - 5:00 PM EST

Webinar

Presented By

The Brain and Behavior Discussion Group

The New York Academy of Sciences

 

Alzheimer’s disease (AD) continues to be on the rise in the US and worldwide. Currently, more than six million Americans suffer AD while Alzheimer’s and dementia deaths have increased 16 % during the COVID-19 pandemic. Despite this, developing effective therapeutics has proven to be challenging and even with the FDA’s recent approval of Aducanumab, controversy about its disease-modifying efficacy remains. The results from targeting amyloid as a disease driver —which at best can be viewed as mixed, and at worst as disappointing— highlight the importance of identifying alternative drug targets. In addition, there is need for developing new tools for early detection and prediction of disease onset. This one-day symposium will feature the latest research on topics including neurogenesis, neuroprotection, lifestyle factors, and brain-peripheral organ interaction.

Registration

Member
$85
Nonmember Academia, Faculty, etc.
$105
Nonmember Corporate, Other
$130
Nonmember Not for Profit
$105
Nonmember Student, Undergrad, Grad, Fellow
$40
Member Student, Post-Doc, Fellow
$30
Deadline:
0
days
left

Speakers

Steven E. Arnold, MD
Steven E. Arnold, MD

Harvard Medical School, Massachusetts General Hospital

Samantha Budd Haeberlein, PhD
Samantha Budd Haeberlein, PhD

Biogen

Meryl Comer
Meryl Comer

Us Against Alzheimer's

Howard Fillit, MD
Howard Fillit, MD

Alzheimer's Drug Discovery Foundation

Miranda Orr, PhD
Miranda Orr, PhD

Wake Forest School of Medicine

Robert Paul, MD, PhD
Robert Paul, MD, PhD

Alector, Inc.

Rudolph Tanzi, PhD
Rudolph Tanzi, PhD

Harvard Medical School, Massachusetts General Hospital

Saul Villeda, PhD
Saul Villeda, PhD

University of California, San Francisco

Christiane Wrann, DVM, PhD
Christiane Wrann, DVM, PhD

Harvard Medical School, Massachusetts General Hospital

Tony Wyss-Coray, PhD
Tony Wyss-Coray, PhD

Stanford University School of Medicine

Filip Swirski, PhD
Filip Swirski, PhD

Icahn School of Medicine at Mt Sinai

Eva Schelbaum
Eva Schelbaum

Weill Cornell Medical College

Mihaly Hajos, PharmD, PhD
Mihaly Hajos, PharmD, PhD

Cognito Therapeutics

Scientific Organizing Committee

Howard Fillit, MD
Howard Fillit, MD

Alzheimer's Drug Discovery Foundation

Lisa Mosconi, PhD
Lisa Mosconi, PhD

Weill Cornell Medical College

Rudolph Tanzi, PhD
Rudolph Tanzi, PhD

Harvard Medical School, Massachusetts General Hospital

Sonya Dougal, PhD
Sonya Dougal, PhD

The New York Academy of Sciences

Barbara Knappmeyer, PhD
Barbara Knappmeyer, PhD

The New York Academy of Sciences

Friday

December 03, 2021

Welcome Remarks

Speaker

Barbara Knappmeyer, PhD
The New York Academy of Sciences

Session 1: Neurogenesis and Neuroprotection

Session Chairperson
Rudolph Tanzi, PhD, Harvard Medical School, Massachusetts General Hospital
10:10 AM

Peripheral Neuroprotective Factors

Speaker

Tony Wyss-Coray, PhD
Stanford University School of Medicine
10:40 AM

Exercise Hormone Irisin is a Critical Regulator of Cognitive Function

Speaker

Christiane Wrann, DVM, PhD
Massachusetts General Hospital, Harvard Medical School

Identifying secreted mediators driving the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in aging or Alzheimer’s disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the exercise benefits on cognitive function. Genetic deletion of FNDC5/irisin (global F5KO mice) impairs cognitive function in exercise, aging, and AD. Diminished pattern separation in F5KOs can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally, and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver, results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of cognitive benefits of exercise and potential therapeutic for treating cognitive disorders including AD.

11:10 AM

Break

Session 2: Brain and Peripheral Organ Interactions

Session Chairperson
Lisa Mosconi, PhD, Weill Cornell Medical College
11:25 AM

Systemic Mechanisms of Brain Rejuvenation

Speaker

Saul Villeda, PhD
University of California San Francisco

Aging drives cellular and cognitive impairments in the adult brain. It is imperative to gain mechanistic insight into what drives aging phenotypes in the brain in order to maintain, and even restore, functional integrity in the elderly. We, and others, have shown that systemic manipulations - such as heterochronic parabiosis (in which a young and old circulatory system are joined) and young blood plasma administration - can reverse age-related impairments in regenerative and synaptic processes, as well as rescue cognitive faculties in the aged brain. More recently, my lab demonstrated that administration of exercise-induced blood factors can likewise partially reverse age-related loss of plasticity in the aged brain. As a consequence, we can now consider reactivating latent plasticity dormant in the aged brain as a means to rejuvenate regenerative, synaptic and cognitive functions late in life. The goal of my research program is to elucidate cellular and molecular mechanisms that can be targeted to halt the aging process or promote rejuvenation in the old brain. Understanding how to reverse aging in the brain could enable us to sidestep the effects of aging that promote vulnerability to neurodegenerative diseases, including Alzheimer’s disease, providing a unique therapeutic approach.

11:55 AM

Astrocyte-Microglia Crosstalk in Alzheimer’s Disease

Speaker

Filip K. Swirski, PhD
Icahn School of Medicine at Mount Sinai
12:25 PM

Lunch Break

Session 3: Data Blitz Talks and Poster Session

Session Chairperson
Barbara Knappmeyer, PhD, New York Academy of Sciences
1:10 PM

Virtual Poster Session / Networking

2:10 PM

Blitz Talk: Association of Reproductive History with Brain MRI Biomarkers of Dementia Risk in Midlife

Speaker

Eva Schelbaum
Weill Cornell Medical College

Female-specific reproductive history events have been implicated in Alzheimer’s disease (AD) risk. We examined associations between indicators of estrogen exposure from women’s reproductive history and brain MRI biomarkers of AD in midlife. A total of 128 cognitively normal women and men ages 40-65 years were evaluated, with reproductive history data, neuropsychological testing, and volumetric MRI scans. Exposure variables included menopause status, age at menarche, age at menopause, reproductive span, hysterectomy status, number of children and pregnancies, use of menopause hormonal therapy (HT) and hormonal contraceptives (HC). We used multiple regressions to examine associations between exposures, voxel-wise gray matter volume (GMV), memory and global cognition scores, adjusting for demographics and midlife health indicators. We found that all menopausal groups exhibited lower GMV in AD-vulnerable regions as compared to men, with peri-menopausal and post-menopausal groups also exhibiting lower GMV in temporal cortex as compared to the pre-menopausal group. Reproductive span, number of children and pregnancies, use of HT and HC were positively associated with GMV in temporal cortex, frontal cortex, and precuneus, independent of age, APOE-4 status, and midlife health indicators. Our findings demonstrate reproductive history events signaling more estrogen exposure were associated with larger GMV in midlife women.

2:25 PM

Blitz Talk: Sensory-Evoked Gamma Oscillation Maintains Functional and Cognitive Abilities and Reduces Brain Atrophy in Patients with Alzheimer’s Disease

Speaker

Mihaly Hajos, PharmD, PhD
Cognito Therapeutics

Sensory-evoked 40Hz gamma oscillation diminishes Alzheimer’s disease pathology, neurodegeneration, and brain atrophy, synaptic and learning dysfunctions in transgenic mice carrying AD-related human pathological genes (Adaikkan & Tsai, 2020). These results initiated the development and validation of non-invasive, gamma sensory stimulation as a potential therapeutic for AD treatment. Participants on AD spectrum were randomized to receive daily, one-hour, EEG-calibrated, audio-visual stimulation, or sham stimulation in a 6-month clinical trial (NCT03556280) using Cognito Therapeutics medical device. Long-term sensory stimulation was found to be both safe and well tolerated. Over the 6-month period, changes in ADCS-ADL scores were significantly better in the treatment group (n=33) compared to sham group (n=20), indicating a 78% slowing in functional decline (P<0.0003). The treatment group also demonstrated a statistically significant 83% (p<0.013) reduction in cognitive decline, shown by changes in MMSE scores.  MRI analysis revealed that whole brain volume loss in the treatment group had a significant, 72% reduction in brain atrophy (p<0.01) compared to sham group.  Reduced lateral ventricle enlargement and diminished loss in cortical thickness in the occipital cortex have been also observed. Via multiple downstream mechanisms, sensory-evoked gamma oscillation leads to maintained cognitive and functional abilities and reduced brain atrophy in AD patients.

Session 4: Panel Discussion

Session Chairperson
Moderator: Rudolph Tanzi, PhD, Harvard Medical School, Massachusetts General Hospital
2:40 PM

Panel Discussion: What's Next in AD Drug Development?

Speakers

Samantha Budd Haeberlein, PhD
Biogen
Meryl Comer
Us Against Alzheimer's
Howard Fillit, MD
Alzheimer’s Drug Discovery Foundation
Steven Arnold, MD
Harvard Medical School, Massachusetts General Hospital
3:25 PM

Break

Session 5: Clinical Trials

Session Chairperson
Howard Fillit, MD, Alzheimer's Drug Discovery Foundation
3:40 PM

Reimagining Early-Phase Clinical Trial Designs for Neurodegenerative Dementias

Speaker

Steven E. Arnold
Massachusetts General Hospital, Harvard Medical School

There are many challenges faced by clinical trials in Alzheimer's disease (AD) and AD-related dementias (ADRD), hindering progress to better treatments and preventions. The parallel-group randomized controlled trial is a gold-standard for regulatory approval of new medicines in later stage development, and while still the overwhelming design used in early phase trials, it is inefficient and poorly informative. For AD/ADRDs in particular, this design requires very large sample sizes and broad outcome measures to accommodate the marked heterogeneity of symptoms, progression rates, co-morbidities, concomitant medications, risk factors, mixed pathologies and multiple pathophysiological drivers in older adults. Enabled by advances in digital health technologies and blood-based biomarkers, we consider novel "single case experimental design" (SCED) approaches as an alternative for early phase development. Individuals serve as their own controls in relatively short-term trials with frequently repeated biomarker and clinical outcome measures during placebo lead-in and active treatment periods. SCED trials can be personalized with biomarker profiles guiding assignment of treatment and outcomes can be selected to maximize sensitivity for hypothesized responses. Analyses of outcomes' values and variability repeated over time can determine differences or trends in biomarkers of target and disease engagement as well as clinical symptomatology under baseline and experimental conditions. Such trials may be especially efficient early phase screening tools to either quickly fail or advance a medicine into subsequent developmental trials.

4:10 PM

Senolytic Therapy to Modulate the Progression of Alzheimer's Disease

Speaker

Miranda Orr, PhD
Wake Forest School of Medicine
4:40 PM

AL002 and the INVOKE-2 Trial

Speaker

Robert Paul, MD, PhD
Alector
5:10 PM

Closing Remarks

Speaker

Barbara Knappmeyer, PhD
The New York Academy of Sciences
5:15 PM

Symposium Ends

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