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

“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

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.

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”

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

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

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

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.

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

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 Becoming withdrawn and isolated can accelerate decline.

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?

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

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

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

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

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

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

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.

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

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

Chronic traumatic encephalopathy (CTE)

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

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

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