1. 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

2. 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

3. 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

4. Normal Brain Structure and Function
Image:
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5. 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
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6. Beta Amyloid Plaques Amyloid is a naturally occurring protein
Image:
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

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

8. 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.

9. Disease Progression
Progression of disease leads to inflammation, cell injury, cell death and brain atrophy.
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10. 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

11. The Scope of Biomedical Research
Basic Research
Molecular
Animal Models
Human subjects
Images: http: npr.org
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12. The Scope of Biomedical Research
Symptomatic
Drug Trials
Disease Modifying
Epidemiology
Preventive
Clinical
Research
Genetics
Imaging/EEG
Diagnostics
Labs
Cognitive
Other Interventions

13. 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?

14. 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

15. 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

16. 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

17. 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

18. Monoclonal Antibodies
Selective for aggregated beta- amyloid
Bind to amyloid plaques
Signal to immune cells that then recognize plaque and remove it
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19. 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.

20. 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).

21. 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).

22. 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

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

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

25. Brain responses to it can be measured with EEG

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

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

28. 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

29. Thank You