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
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.
Scientific Organizing Committee
Alzheimer's Drug Discovery Foundation
Harvard Medical School
B. Riley FBR
The New York Academy of Sciences
The New York Academy of Sciences
Washington University School of Medicine
University of Arizona
Washington Unversity School of Medicine
University of British Columbia
Icahn School of Medicine at Mount Sinai
University of Chicago
Massachusetts Institute of Technology
Weill Cornell Medical College
Massachusetts General Hospital, Harvard Medical School
Johns Hopkins University
University of Florida College of Medicine
November 20, 2019
Breakfast and Registration
Introduction and Welcome Remarks
Session 1: Perspectives on the Future of Alzheimer’s Disease Research
What Would be Good Targets to Prevent or Treat Alzheimer's Disease?
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.
Panel Discussion: Therapeutic Strategies and New Targets
Networking Coffee Break
Session 2: Neuroinflammation and Tau as Drivers of Disease
Targeting Soluble TNF to Reduce Risk for Alzheimer's Disease
Innate Immunity in Neurodegeneration
Differential Rates of Progression Correlate with Differences in Tau Properties in Alzheimer Disease
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.
Networking Lunch and Poster Session
Session 3: Risk Factors, Biomarkers and Early Detection
Single-Cell Dissection of Alzheimer’s Disease
Regenerating the Degenerated Alzheimer’s Brain: Challenges and Innovation Opportunities
Sex Differences in Alzheimer's Risk and The Weill Cornell Women's Brain Initiative
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.
Alzheimer’s Disease Biomarkers
Networking Coffee Break
Session 4: Emerging Mechanistic Insights for Alzheimer’s Disease
New Insights into the Role of Lipoproteins in Alzheimer’s Disease
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.
Sex-Specific Modulation of Amyloid Deposition and Neuroinflammation by the Microbiome
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
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
Role of Human Herpesvirus in Alzheimer’s Disease