Overview of Alzheimer’s Research Roberto Fernandez MD, MPH, PhD Medical Director The Pat Summitt Clinic Brain and Spine Institute University of Tennessee Medical Center

Overview Normal brain structure and function Alzheimer’s pathology - What we know Alzheimer’s pathology - What we don't know The scope of research Clinical Trials in Alzheimer’s disease Clinical research at the Pat Summitt Clinic

Brain Function Motor function Spoken language Attention Planning Making Choices Suppression of unwanted behaviors Sensation Visuospatial function Integration of different Sensory systems Primary visual processing Language comprehension Visual recognition Auditory processing Memory Behavior

Normal Brain Structure and Function Image: http://www.nia.nih.gov Image: www.martinos.org/neurorecovery/images/tracts.png

Alzheimer’s Pathology. What we know… Not all brain regions are affected equally or at the same time Some areas are more vulnerable Hallmark changes are first seen in medial temporal lobes Images: www.alz.org

Beta Amyloid Plaques Amyloid is a naturally occurring protein Image: https://commons.wikimedia.org/ Image: wiki.brown.edu Amyloid is a naturally occurring protein Formed from by cleavage of amyloid precursor protein Beta-amyloid has tendency to aggregate forming plaques Plaques formation is potentially toxic to neurons

Tau and Neurofibrillary Tangles Normal tau protein changes configuration and forms clumps, called neurofibrillary tangles, cause cell dysfunction and eventually cell death.

X Loss of function and disease progression Loss of connections among brain cells and functional networks result in loss of function (memory, language, etc) and may contribute to spread of disease and cause further injury.

Disease Progression Progression of disease leads to inflammation, cell injury, cell death and brain atrophy. Images: www.alz.org

What causes the changes in amyloid and tau Alzheimer’s Pathology: What We Don't Know What causes the changes in amyloid and tau Why individuals with amyloid burden may not develop AD Why are some parts of the brain more vulnerable than others Why are there different variants of disease How does disease spread across brain regions What is the relationship with aging What’s the role of loss of connections between brain regions

The Scope of Biomedical Research Basic Research Molecular Animal Models Human subjects Images: http: npr.org Images: http://www.lpzoo.org/

The Scope of Biomedical Research Symptomatic Drug Trials Disease Modifying Epidemiology Preventive Clinical Research Genetics Imaging/EEG Diagnostics Labs Cognitive Other Interventions

Clinical Trials Clinical Trials A clinical research study is a scientific investigation designed to answer important questions about a specific intervention: Is it safe? Does it work? Which dose works best? What are the side effects?

Progression of Clinical Trials Phase I: Tests new drug or treatment in a small group of people to assess safety, safe dose range, and identify side effects Phase II: Tests safety and/or efficacy Phase III: Studies conducted in large groups to confirm effectiveness, monitor side effects and compare to standard treatments

Clinical Trials Study Design Most trials are double blinded placebo-control trials Some may be “open label” Some have open label extensions after completion of blinded portion of the study Most have strict inclusion criteria Duration, frequency of visits and procedures (e.g. tests) varies depending on protocol Close monitoring for possible side effects

When considering a clinical trial: Clinical Trials When considering a clinical trial: Know your rights Do not feel obligated to participate You can decide to stop at any time Make sure you inform yourself about research evidence backing the study It is OK to ask for second opinion Make sure you review and understand the informed consent. Don’t be afraid to ask questions Make sure trial is conducted by a reputable institution All research with human subjects must be conducted by entities who have an Institutional Review Board (IRB) Be aware that food supplements and natural products may not be regulated in the same manner as therapeutic drugs, but may still have risks and possible side effects

Current Therapeutic Research in Alzheimer’s There are currently no approved medications that can cure, slow down or revert Alzheimer’s Approved medications are intended to treat symptoms and may provide temporary improvement Experimental drugs target know mechanism of disease through different approaches: Beta-amyloid: Antibodies that help clear plaques, prevent aggregation or block enzymes involved in amyloid formation Neurofibrillary tangles: Vaccine that stimulates the body’s immune system to attack an abnormal form of tau protein that destabilizes the structure of neurons Inflammatory response: Drugs that can modulate inflammation Neuronal network dysregulation: Anti-epileptic drugs to modulate possible hyperexcitability of brain cells Neurotransmitter function

Monoclonal Antibodies Selective for aggregated beta- amyloid Bind to amyloid plaques Signal to immune cells that then recognize plaque and remove it Images: www.alz.org

ENGAGE Clinical Trial Clinical research at the Pat Summitt Clinic Study evaluating the efficacy and safety of an investigational drug in people experiencing symptoms of early Alzheimer’s disease. It is intended for “preclinical Alzheimer’s”, also known as mild cognitive impairment Study drug is aducanumab, a monoclonal antibody Prior studies showed statistically significant reduction in plaque and slowing of cognitive decline Aim to determine whether the investigational drug can remove the plaques and have an effect on the slowing of the progression of the condition Infrequent but potentially serious adverse events have been associated with this medication. These include brain swelling and brain bleeds.

ENGAGE Clinical Trial Approximately 1350 people with symptoms of early Alzheimer’s disease will take part in this study around the world. Two phases: a placebo-controlled phase, and an optional long- term extension phase. Placebo-Control phase: two-in-three chance of receiving investigational drug. This phase lasts 2 years Long-Term phase: All participants will receive the drug for 2 years Participants who meet eligible requirements will visit the clinic once or twice per month During placebo- controlled phase, participants will receive either the investigational drug or placebo every 4 weeks for approximately 18 months (1.5 years).

You may qualify for the study if: You are 50–85 years of age You are experiencing symptoms that might be related to early Alzheimer’s disease, such as problems with memory or thinking clearly You have someone who can be your study partner (accompany you to certain appointments and provide information about your health).

Visuospatial Impairments in Alzheimer’s Disease (AD) Clinical Research at the Pat Summitt Clinic Visuospatial Impairments in Alzheimer’s Disease (AD) Up to 1/3 of AD begins with visuospatial symptoms Associated with posterior cortical atrophy Disabling because it undermines independent living

Brain Areas for Visuospatial Orientation and Alzheimer’s disease Dorsal Where? Ventral What?

Optic Flow The visual motion seen during self movement Alzheimer’s can impair optic flow perception, leading to disorientation

Brain responses to it can be measured with EEG

Brainwaves evoked by optic flow can differentiate early stage Alzheimer’s from normal aging.

Optic flow responses are associated with poor driving performance and atrophy of specific brain regions that are affected in Alzheimer’s

Current Research To establish the parameters of OF-ERP components that will reliably differentiate normal aging from Alzheimers for early diagnosis and monitoring of disease progression Elucidate mechanism of Alzheimer’s disease that are poorly understood Evaluate optic flow brain responses as objective predictors of driving capacity

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