1. What will it take to develop an effective Alzheimer’s drug?
Sam Gandy, M.D., Ph.D.
Mount Sinai Chair in Alzheimer’s Disease Research
Professor of Neurology and Psychiatry
Director, Mount Sinai Center for Cognitive Health
and NFL Neurological Center
October 18, 2017

3. “Dementia” is an impairment of the ability to “mentate” (de-ment)
“Mentation” can involve memory, planning, and placing actions in the right sequence
“Alzheimer’s disease” is the most common specific illness that causes dementia

4. A key issue is that depression can mimic dementia.
Depression and dementia are treated with
entirely different medications, so
an accurate initial diagnosis is essential.

5. Inadequate blood flow to the brain plays a role in both Alzheimer’s disease and in another illness called “vascular dementia”, often described as “multiple small strokes”

6. Other:
Frontotemporal
Lewy Body
(Robin Williams)
Corticobasal
Progressive
supranuclear
palsy
(Dudley Moore)
CTE

7. The basic problem shared by Alzheimer’s and vascular dementias
Is the loss of brain substance

8. Clumps of material known as amyloid plaques are the first detectable change on the pathway to Alzheimer’s….
…and it is now possible to visualize amyloid plaques on special brain scans.
However, clinical memory trouble might not develop for decades after amyloid begins to build up. Important clinical problems may never show up.
“Resilience” describes the ability to maintain memory and thinking even when plaques and tangles are present.
It is possible for your brain to resist the functional changes
of Alzheimer’s. In other words, it is possible to have full
blown Alzheimer’s plaques and tangles and have normal
cognitive function

13. The main risk for Alzheimer’s disease involves genetics, especially if a parent was affected.
The most common identified risk gene is called APOE4.
Half of all people living with Alzheimer’s harbor at least one APOE4 gene.
Important to recognize that physical exercise regimens can neutralize the risk of APOE4.

14. More
risk
Exercise neutralizes the risky effect of APOE4 gene that causes brain amyloid build-up
Less
risk

15. Physical exercise and mental exercise and controlling cardiac risk factors are the two best established ways to reduce Alzheimer’s risk or to slow progression once Alzheimer’s begins.
Controlling cardiac risk factors slows progression of both
Alzheimer’s disease and vascular dementia.
Social engagement is also important. Becoming withdrawn and isolated can accelerate decline.

16. What kinds of exercise are proven to be helpful against Alzheimer’s?
Can this be reduced to a prescription?
How often must I do the exercises?
How long must I do the exercises at each session?

17. Brisk walking and resistance training (weightlifting) are the best studied types of exercise for reducing risk for Alzheimer’s

18. Standard exercise schedules
Experts recommend brisk walking or resistance training in 30 minute sessions and 3 sessions per week
Brisk walking not only neutralizes the effect of the risky APOE4 gene, but this also slows progression of dementia after onset
It is never too late to begin exercise

19. Can we reduce mental exercise to a “prescription”
Can we reduce mental exercise to a “prescription”? So far, not as easily to prescribe as is physical exercise
We recommend that seniors remain active in a range of mental activities that they enjoy including socialization

20. High blood cholesterol Type 2 diabetes
Both of the main causes of dementia (AD, VaD) share many risk factors with heart disease
Obesity
Sedentary lifestyle
High blood pressure
High blood sugar
High blood cholesterol
Type 2 diabetes
These risk factors exert their
effects on dementia risk
beginning in midlife

21. What other modifiable factors can increase risk for dementia or worsen dementia?
Poor diet
Poor hearing
Poor vision
Head trauma

23. Access to RELIABLE information is key.
Dementia Australia website and Alzheimer’s Australia Twitter Feed are
Two of the best sources for RELIABLE information

24. Following RELIABLE information about clinical trials is the best
way to learn about new breakthroughs in medicines and drugs
Not every breakthrough in information leads immediately to a new medicine or drug.
Dementia Australia plays a key role in interpreting breakthrough news for laypeople.

26. APP/PSEN1, TYROBP(+/-)xAPP/PSEN1 and TYROBP(-/-)xAPP/PSEN1
Plaque-associated microglia are reduced in Tyrobp deficient PSAPP mice at age 4 mo
APP/PSEN1, TYROBP(+/-)xAPP/PSEN1 and TYROBP(-/-)xAPP/PSEN1
 6E10/Iba1 :
Number of plaque associated microglia
APP/PSEN1
TYROBP (+/-)
xAPP/PSEN1
TYROBP (-/-)
xAPP/PSEN1

27. Fighting Alzheimer’s with Diet & Lifestyle
Resilience
Physical exercise
Mental stimulation
Control cardiac risks
Mediterranean diet
Never too late
Fighting Alzheimer’s with New Drugs
Prevention* with anti-amyloid drugs
Prevention/Rx with anti-tau drugs
Prevention/Rx with anti-microglial drugs

28. Chronic traumatic encephalopathy (CTE)

29. Tangle Brain Scans
Show Changes in the
Brains of Athletes
Playing Various Sports
Age: 62
Professional
Hockey
Age: 68
Professional
Football
Age: 56
Professional
Football
Age: 49
Healthy Control

30. “CTE” Chronic traumatic encephalopathy
Healthy control Repeated concussion
“CTE”
Chronic traumatic
encephalopathy

31. What is the importance of diagnosing CTE during life?
Accurate estimate of prevalence and risk
Counsel on possible risk of continuing exposure going forward
Biomarker to guide clinical trials of anti-tangle drugs