1. Coconut oil to fish oil: update on brain health and Alzheimer’s prevention Diana R. Kerwin, MD Chief, Section of Geriatric Medicine Director, Texas Alzheimer’s and Memory Disorders Texas Health Presbyterian Hospital Dallas Clinical Instructor, Department of Medicine-Education, UT Southwestern

2. What Is Dementia? Dementia is a clinical syndrome. It may be defined as a loss of cognitive functions significant enough to cause functional disability in everyday life. It can be caused by Alzheimer’s disease, Frontotemporal dementia, Vascular infarcts etc. Alzheimer’s disease Vascular dementia Frontotemporal dementia Lewy Body disease Primary Progressive Aphasia Etc. Dementia Do not replicate or redistribute this material without permission

3. Dementia Risk AGE is the most significant risk factor Age 65 - 70: 1 in 50 Age 80+: 1 in 5

4. Memory Stages Widely distributed network Ability to learn new information Requires attention Focus on important and tune out irrelevant info Stage one: ENCODING

5. Memory Stages Stage two: STORAGE New info must be stored in order to remember later

6. Memory Stages Stage three: Retrieve Finding the right memory when you want to

7. Pathology of Alzheimer’s Disease Plaques Beta-Amyloid Protein Tangles Tau protein

9. Current clinical biomarkers

10. FDG-PET Biomarker-glucose metabolism

12. Development of Alzheimer Pharmacotherapy 19931997 20002001 Rivastigmine Pre-19801980s2000s2010s NOOTROPICS IMMUNOTHERAPY CHOLINESTERASE INHIBITORS 1990s ANTI-OXIDANTS (VITAMIN E) ANTI-INFLAMMATORIES ORAL ANTI-AMYLOID AGENTS AChE PRECURSORS, ACh AGONISTS Memantine 2003 NMDA ANTAGONISTS HORMONE REPLACEMENT DonepezilTacrine RELKIN 2006 Galantamine SYMPTOMATIC TREATMENT Neurochemical Deficit CHOLINERGIC HYPOTHESIS IDIOPATHIC Systemic Deficiency AMYLOID HYPOTHESIS Protein Misfolding Modified AMYLOID HYPOTHESIS

13. Pathway to Your Medicine Cabinet PhRMA 2012 Annual Report

14. Interventional Therapies in Phase I and II Clinical Trials Target Diverse Mechanisms AADvac1 ABT-126 ABT-354 AC-1204 ACC-001 (vanutide cridificar) AFFITOPE-AD02/03 Anatabloc Atomoxetine AZD3293 AZD 3480 BAN2401 Bexarotene BIIB037 CERE-110 Crenezumab (MABT5102A) Curcumin DBS-f (Deep brain stimulation of the fornix) Epothilone D (BMS-241027) EVP-0962 EVP-6124 (MT-4666) Exendin-4 Gantenerumab Insulin Isotretinoin IVIg Ladostigil L-arginine Lipoic Acid LY3002813 Mesenchymal stem cells Minocycline MSDC-0160 NIC5-15 Nicotinamide Omega-3 PM-012 Resveratrol RO4602522 RPh201 R-Pramipexole SAR228810 Saracatinib Sargramostim Simvastatin Sodium oligo-mannurarate Tetrahydrobiopterin Thalidomide Transcranial magnetic stimulation (TMS) VI-1121 (Sept. 24, 2013) Tau NGF Insulin Mitochondria Monoamine oxidase

15. Therapeutic Agents in Phase III Clinical Trials for Alzheimer’s Disease Gantenerumab –Hoffman and La Roche –Monoclonal antibody against beta- amyloid –DIAN-TU and preclinical AD IVIg and Albumin –Intravenous immunoglobulin Lu AE58054 – Lundbeck and Otsuka – An add-on agent Masitinib MDX-8704 – Adamas Pharmaceuticals – Memantine-donepezil combination therapy MK-8931 –Merck –BACE inhibitor Pioglitazone –Takeda –PPAR-gamma activator Solanezumab –Eli Lilly –Humanized antibody against beta-amyloid –Two studies: DIAN-TU and mild Alzheimer’s disease TRx0237 –TauRX –Tau aggregation inhibitor

16. Possible Prevention of Alzheimer’s?

17. Overview Risk factors Prevention of dementia Alzheimer’s Disease Cooperative Studies Group –Fish oil (DHA study) –Gingko biloba (GEM study) –Vitamin E –Exercise –Coconut oil (active)

18. Exercise may alter risk of dementia and improve cognitive function

19. Archives of Neurology 2001 4,600 cognitively normal Canadians 65 years or older followed for 5 years Physical activity measured from questionnaire 50% reduction! nonelowhighmod nonelowhighmod

20. Background: why fish oil?  Epidemiologic studies find a reduced risk of Alzheimer’s disease in people consuming increased amounts of fish in diet Kalmijn, et al, 1997 n=5386 18.5 grams fish/day-decreased risk of Alz. vs. <3 grams/day (p=0.005) Barberger-Gateau et al, 2002 n=1416 fish consumption > 1x/week - reduced risk of dementia (p=0.009); Morris et al, 2003 n=815 fish consumption > 1x/week - 60% risk reduction of developing AD (p=0.07); Of Omega-3 fatty acids, only DHA significant Schaefer, et al, 2003 n=1137, 10 years Fish consumption=3x/week-48% risk reduction for dementia; positive association with plasma DHA

21. Fish oil and Alzheimer’s Fish contains omega 3 fatty acids, including docosahexaenoic acid (DHA) and eicosapentanoic acid (EPA), which are thought to mediate health benefits of fish. DHA is abundant in the brain, whereas EPA is virtually absent. Animal models have shown that DHA modulates Alzheimer-like brain pathology.

22. Sources of dietary DHA  Although some DHA can be synthesized, most of it comes from the diet  Dietary DHA determines tissue levels, including brain levels

23. What is the best fish choice Sardines, anchovies Atlantic salmon Trout Oysters are about the same as 2 g fish oil Lowest: –Tilapia, catfish, orange roughy, cod, shrimp

24. Ginkgo biloba is among the most popular dietary supplements for brain health. In 2007, Americans spent $107 million on gingko supplements

25. Can gingko prevent dementia GEM Study completed by ADCS Group 2010 3069 community living persons >75yrs Gingko 120 mg twice a do or placebo 523 developed dementia during course of study (16%placebo; 18% gingko) NO statistical difference in dementia development between group

26. TEAM- VA AD Results Patients with mild to moderate AD, 2000 IU/d alpha tocopherol versus placebo showed slower functional decline and decreased caregiver burden

27. Coconut Oil and Ketones

28. What is the science. Ketone hypothesis: ketones provide an alternative energy source to neurons, not dependent on insulin presence Coconut oil contains medium chain triglycerides (MCTs) form ketones May provide energy source to neurons unable to take up glucose due to AD

29. The viral video: can the response be replicated in a RCT?

30. Dose, side effects, efficacy A RCT is underway at University of South Florida Currently most internet sites recommend 3 tablespoons/day Caveats: 115 calories per tablespoon GI side effects, diarrhea at high doses, ?? Effect on triglycerides, does this diminish benefit

31. Late breaking study: resveratrol

32. Brain Health Diet

33. Nutrition Dietary Recommendations: Foods rich in antioxidants Green leafy vegetables Cold water fish as protein and omega 3 FA source – 2-3 servings/week – Lean poultry 2-3/week Nuts-walnuts, almonds peanuts Legumes 3-4 servings/week Vitamin E and C rich foods – Almonds, kale, pumpkin seeds, parsley, papaya – Healthy fats, no butter (sorry) REMEMBER TO STAY HYDRATED

34. Ginkgo biloba –Herbal supplement does not slow progression of dementia and has not been shown to prevent it –Risk of bleeding with aspirin Coconut oil –Inadequate data, study underway Vitamin E possibly for treatment of AD B12 and folic acid-possibly beneficial, low risk Estrogen not for the treatment OR prevention of dementia at this time. Which pharmacologic agents are ineffective avoided?

35. Possible recommendations in current practice  Lifestyle factors that reduce risk  Diet Omega-3, DHA, folic acid, Vitamin E, C –Dietary sources BETTER than pill –coconut oil, Axona –Alternate “fuels” for the brain  Exercise-Physical AND Cognitive  Moderate exercise IMPROVES memory immediately and with a sustained effect  How much? 3 times a week, 30 minutes, moderate intensity  Alcohol Moderate intake studies, red wine –Resveratrol clinical trial beginning in ADCS  Body Weight  Higher body mass associated with increased risk  Maintain ideal body weight

36. Optimize Memory Focus on diet and exercise Incorporate more physical activity into every day activities Reduce distractions in the environment Avoid multi-tasking; focus on one thing Take your time Ask for repetition (e.g., names) Actively use all senses to aid in detail of memory General Tips: