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Alzheimer's Disease Therapeutics: Alternatives to Amyloid 2019

Available via

WEBINAR

Alzheimer's Disease Therapeutics: Alternatives to Amyloid 2019

Wednesday, November 20, 2019, 8:30 AM - 5:30 PM

The New York Academy of Sciences, 7 World Trade Center, 250 Greenwich St Fl 40, New York

Presented By

Brain and Behavior Discussion Group

The New York Academy of Sciences

 

For the last 25 years, research in Alzheimer’s disease has focused on amyloid as the key driver of disease pathogenesis. However, the recent failure of several Phase III clinical trials targeting amyloid has reinforced the need to critically evaluate these trials and consider different approaches.  There is burgeoning interest in identifying alternative drug targets: over half of ongoing preclinical research in Alzheimer’s disease now focuses on neuro-inflammation, bioenergetics, epigenetics, protein homeostasis and other alternative pathways.

This conference will consider the landscape of Alzheimer’s disease research including the current state of the amyloid hypothesis, emerging disease mechanisms, and strategies to develop novel therapeutic approaches.

Registration

Member
By 10/11/2019
$90
After 10/11/2019
$130
Nonmember Academia, Faculty, etc.
By 10/11/2019
$180
After 10/11/2019
$260
Nonmember Corporate, Other
By 10/11/2019
$250
After 10/11/2019
$350
Nonmember Not for Profit
By 10/11/2019
$180
After 10/11/2019
$260
Nonmember Student, Undergrad, Grad, Fellow
By 10/11/2019
$100
After 10/11/2019
$145
Member Student, Post-Doc, Fellow
By 10/11/2019
$50
After 10/11/2019
$70
Member
$30
Nonmember Academia, Faculty, etc.
$65
Nonmember Corporate, Other
$85
Nonmember Not for Profit
$65
Nonmember Student, Undergrad, Grad, Fellow
$45
Member Student, Post-Doc, Fellow
$15
Deadline:
0
days
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Scientific Organizing Committee

Howard Fillit, MD
Howard Fillit, MD

Alzheimer's Drug Discovery Foundation

Rudolph Tanzi, PhD
Rudolph Tanzi, PhD

Harvard Medical School

George Zavoico, PhD
George Zavoico, PhD

B. Riley FBR

Sara Donnelly, PhD
Sara Donnelly, PhD

The New York Academy of Sciences

Sonya Dougal, PhD
Sonya Dougal, PhD

The New York Academy of Sciences

Speakers

David Holtzman, MD
David Holtzman, MD

Washington University School of Medicine

Roberta Brinton, PhD
Roberta Brinton, PhD

University of Arizona

Marco Colonna, MD
Marco Colonna, MD

Washington Unversity School of Medicine

Cheryl Wellington, PhD
Cheryl Wellington, PhD

University of British Columbia

Joel Dudley, PhD
Joel Dudley, PhD

Icahn School of Medicine at Mount Sinai

Sangram Sisodia, PhD
Sangram Sisodia, PhD

University of Chicago

Manolis Kellis
Manolis Kellis, PhD

Massachusetts Institute of Technology

Lisa Mosconi, PhD
Lisa Mosconi, PhD

Weill Cornell Medical College

Bradley Hyman, MD, PhD
Bradley Hyman, MD, PhD

Massachusetts General Hospital, Harvard Medical School

Marilyn Albert, PhD
Marilyn Albert, PhD

Johns Hopkins University

Malú Tansey, PhD
Malú Tansey, PhD

University of Florida College of Medicine

Wednesday

November 20, 2019

8:30 AM

Breakfast and Registration

9:00 AM

Introduction and Welcome Remarks

Session 1: Perspectives on the Future of Alzheimer’s Disease Research

9:15 AM

What Would be Good Targets to Prevent or Treat Alzheimer's Disease?

Speaker

David Holtzman, MD
Washington University School of Medicine

There is a lot of evidence that amyloid-β (Aβ) is a key trigger in Alzheimer’s disease (AD) pathogenesis. It begins to accumulate in the brain beginning ~ 20 years prior to the onset of cognitive decline. It is an accompanied by an innate immune response which appears to protect against some of the downstream consequences of Aβ. Just before cognitive decline, tau accumulation spreads from the medial temporal lobe to neocortical regions. This spread is accompanied by an additional innate immune response which together appears to drive neurodegeneration in the regions in which this process occurs as well as corresponding cognitive changes. These data suggest that targeting Aβ may be beneficial in delaying the onset of AD when done before it builds up (primary prevention) or possibly when it is building up (secondary prevention) but prior to cognitive decline. Activating the innate immune response when Aβ is accumulating may also be beneficial. However, inhibiting the brain’s innate immune response once significant tau accumulation begins to occur or with symptoms onset may be the best approach as the disease progresses. Preventing the spreading of tau pathology, decreasing tau levels, and clearing abnormally phosphorylated, aggregated tau may prove beneficial both as a secondary prevention as well as a treatment during the symptomatic phase of AD. As apoE contributes to both amyloid deposition as well as to tau-mediated neurodegeneration, decreasing apoE levels in the brain may prove useful as a primary prevention, secondary prevention, or during the early symptomatic phase of AD.

9:45 AM

Panel Discussion: Therapeutic Strategies and New Targets

Speakers

Moderator: Rudolph Tanzi, PhD
Harvard Medical School
Roberta Brinton, PhD
University of Arizona
Brad Hyman, MD, PhD
Massachusetts General Hospital
Marilyn Albert, PhD
Johns Hopkins University
David Holtzman, MD
Washington University School of Medicine
10:30 AM

Networking Coffee Break

Session 2: Neuroinflammation and Tau as Drivers of Disease

11:00 AM

Targeting Soluble TNF to Reduce Risk for Alzheimer's Disease

Speaker

Malú Tansey, PhD
University of Florida
11:30 AM

Innate Immunity in Neurodegeneration

Speaker

Marco Colonna, PhD
Washington University School of Medicine
12:00 PM

Differential Rates of Progression Correlate with Differences in Tau Properties in Alzheimer Disease

Speaker

Brad Hyman, MD, PhD
Massachusetts General Hospital

Individuals with Alzheimer disease have substantially different rates of progression – for largely uncertain reasons. We tested the hypothesis that different properties in the likelihood that tau propagation efficiency might underlie part of this variation. Tau isolated from postmortem frontal cortex showed different biochemical properties from different individuals, including a spectrum of protease resistance, behavior on size exclusion columns, behavior on an in vitro seeding assay, and differences in specific phosphorylation patterns as assessed by ELISA or Mass Spec. We postulate that these differences in tau cross cases may impact the rate of tau propagation across neural systems, and thus clinical rate of progression.

12:30 PM

Networking Lunch and Poster Session

Speakers

Odd Number Poster Boards
12:30 PM - 1:00 PM
Even Number Poster Boards
1:00 PM - 1:30 PM

Session 3: Risk Factors, Biomarkers and Early Detection

1:30 PM

Single-Cell Dissection of Alzheimer’s Disease

Speaker

Manolis Kelis, PhD
Massachusetts Institute of Technology
2:00 PM

Regenerating the Degenerated Alzheimer’s Brain: Challenges and Innovation Opportunities

Speaker

Roberta Brinton, PhD
University of Arizona
2:30 PM

Sex Differences in Alzheimer's Risk and The Weill Cornell Women's Brain Initiative

Speaker

Lisa Mosconi, PhD
Weill Cornell Medical College

After advanced age, female sex is the major risk factor for late-onset Alzheimer’s disease (AD). While AD is not unique to females, women constitute roughly two-thirds of patients living with AD-dementia, with postmenopausal women accounting for over 60% of all those affected.

While previously, the 2:1 ratio was attributed to women’s longer life expectancy relative to men, several emerging lines of evidence point to sex- and gender-specific AD risk factors rather than life span. Recent studies have identified over thirty AD risk factors that impact the sexes differently, with female sex generally being more severely impacted. These include chiefly genetic (e.g. family history, APOE genotype), medical (e.g., depression, stroke, diabetes), hormonal (e.g., menopause, thyroid disease), and lifestyle risks (e.g., smoking, diet, exercise, intellectual activity). As many of these AD risk factors are modifiable, especially if addressed in midlife, identification of sex-specific risks is pivotal towards development of targeted AD risk reduction strategies.

The mission of the NIH-sponsored Weill Cornell Women’s Brain Initiative is to help understand how sex differences affect brain aging and AD risk, and discover sex-based molecular targets and precision therapies to prevent, delay, and minimize this risk. Our multi-modality brain imaging studies implicate the menopause transition as an early initiating risk factor for AD in women. As women approach midlife, there seems to be a critical window of opportunity not only to detect signs of early AD but to then intercede with strategies to reduce or prevent that risk.

3:00 PM

Alzheimer’s Disease Biomarkers

Speaker

Marilyn Albert, PhD
Johns Hopkins University
3:30 PM

Networking Coffee Break

Session 4: Emerging Mechanistic Insights for Alzheimer’s Disease

4:00 PM

New Insights into the Role of Lipoproteins in Alzheimer’s Disease

Speaker

Cheryl Wellington, PhD
University of British Columbia

Alzheimer’s disease (AD) is defined by amyloid beta (Aβ) plaques and neurofibrillary tangles and characterized by neurodegeneration and memory loss. Apolipoprotein E (apoE) is the major genetic risk factor for AD with multiple roles in AD pathogenesis, primarily assumed to occur within the brain. Importantly, as many AD patients also have vascular co-morbidities including Aβ deposition in cerebral vessels known as cerebral amyloid angiopathy (CAA) and microhemorrhages, promoting cerebrovascular resilience may therefore be a promising therapeutic or preventative strategy for AD. Plasma high-density lipoproteins (HDL) have several vasoprotective functions and are associated with reduced AD risk in epidemiological studies. In mice, deficiency of apoA-I, the primary protein component of HDL, increases CAA and cognitive dysfunction, whereas overexpression of apoA-I from its native promoter in liver and intestine has the opposite effect and lessens neuroinflammation. Similarly, acute peripheral administration of HDL reduces soluble Aβ pools in the brain. New animal model data support a role for apoA-I, the major apolipoprotein in HDL, in reducing astrocyte reactivity to parenchymal and vascular amyloid in the cortex and attenuating parenchymal and vascular ICAM-1 in the hippocampus. Studies using novel 3-dimensional engineered human cerebral vessels show that HDL, especially the fraction of HDL enriched in apoE, reduces Aβ deposition and Aβ-induced endothelial activation and is providing new insights into multiple mechanisms by which HDL can protect the cerebrovasculature. Taken together, HDL may be an attractive non-amyloid approach to prevent or treat cerebrovascular dysfunction for AD.

4:30 PM

Sex-Specific Modulation of Amyloid Deposition and Neuroinflammation by the Microbiome

Speaker

Sangram Sisodia, PhD
University of Chicago

Objectives: Animal models of Alzheimer’s disease (AD) recapitulate the severe amyloidosis and neuroinflammation that is evident in the human disease. Neuroinflammation is associated with activation of astrocytes and microglia in response to injury, but the role of peripheral tissues and more importantly, the microbiota in regulating innate immunity that in turn leads to CNS dysfunction has not been defined. We have tested the hypothesis that the composition of the intestinal microbiome plays a role in modulating neuro-inflammation that will ultimately influence amyloid deposition in two established mouse models of A
amyloidosis.


Methods: We orally administered a combination of antibiotics to induce rapid and sustained alterations in gut microbial populations. The antibiotic cocktail was administered either postnatally or throughout the lifetime of the animal prior to cull and we employed IHC, biochemical and transcriptomic assays to evaluate amyloid deposition and neuroinflammation in the mouse models.


Results: Our studies indicate that alterations in the microbiome parallel changes in plasma cytokines and chemokines, reductions in amyloid deposition and modulation of morphological and transcriptional landscapes of microglia that only occurs in male, but not female animals.


Conclusions: Our studies reveal an unexpected, but significant alteration in amyloid deposition and microglial phenotypes in the brains of transgenic mice upon treatment with orally administered antibiotics.
Acknowledgments This work was supported by Cure Alzheimer’s Fund (CAF), Open Philanthropy Fund and Good Ventures Foundation

5:00 PM

Role of Human Herpesvirus in Alzheimer’s Disease

Speaker

Joel Dudley, PhD
Icahn School of Medicine at Mount Sinai
5:30 PM

Closing Remarks

5:45 PM

Networking Reception and Poster Session

6:45 PM

Adjourn