1 / 56

REGIONAL SYMPOSIUM ON ALZHEIMER’S DISEASE AND RELATED DISORDERS IN THE MIDDLE EAST

www.worldeventsforum.com/alz.htm. REGIONAL SYMPOSIUM ON ALZHEIMER’S DISEASE AND RELATED DISORDERS IN THE MIDDLE EAST. Istanbul, Turkey October 1-2, 2005 Convener: Robert P. Friedland, MD LOC Chair: Murat Emre, MD.

holden
Download Presentation

REGIONAL SYMPOSIUM ON ALZHEIMER’S DISEASE AND RELATED DISORDERS IN THE MIDDLE EAST

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. www.worldeventsforum.com/alz.htm REGIONAL SYMPOSIUM ON ALZHEIMER’S DISEASE AND RELATED DISORDERS IN THE MIDDLE EAST Istanbul, Turkey October 1-2, 2005 Convener: Robert P. Friedland, MD LOC Chair: Murat Emre, MD

  2. Gene environment interactions in Alzheimer’s Disease Robert P. Friedland, Lindsay A. Farrer, Rivka Inzelberg, Amin Abuful, Magda Marsarwa, Rosa Strugatsky, Clinton Baldwin, Grace PetotCleveland, Ohio, USA; Boston, Massachussetts USA; Hadera, Israel

  3. CWRU Lab.Neurogeriatrics S. Debanne, PhD R. Friedland, MD T. Fritsch, PhD E. Grady, BA K. Gustaw, MD, PhD S. Humphrey, BA A. Lerner, MD G. Petot, MS CWRU Dept. Pathology G. Perry, PhD M. Smith, PhD Boston Univ. C. Baldwin, PhD L. Farrer, PhD Sun Health Res. Inst. L. Sparks, PhD Cleveland Clinic D.Jacobsen,PhD Hillel Yaffe Med. Center/Technion A. Abuful, RN R. Inzelberg, MD M. Masarwa, MD R. Stugatsky Hadassah Hosp Hebrew Univ, Jerusalem I. Biran, MD J. Kark, MD, PhD Y. Newman, PhD State University of New York, Stony Brook D. Goldgaber, PhD

  4. Interactions in Alzheimer’s disease • What’s going wrong in the AD brain? • Genes • Environment Africans, African Americans Caucasians Middle East • Implications for health and public policy

  5. Amyloid and aging vessels • All people over 60 have aortic amyloid • Medin: an integral fragment of aortic smooth muscle cell-produced lactadherin • Also found in temporal arteries • Comes from smooth muscle cells Haggqvist et al, 1999; Peng et al, 2002 Amyloid deposited on internal elastic lamina in a temporal artery without inflammation.

  6. a-secretase---- Helmuth, 2002

  7. a secretase ----

  8. Alzheimer physiology – choose your poison! 1. APP expression 2. APP cleavage 3. ABeta aggregation and toxicity 4. ABeta clearance from brain to blood 5. ABeta clearance from blood

  9. Why is this important?

  10. Age and Alzheimer’s disease • The risk of getting the disease doubles every 5 years after the age of 65 • The most important risk factor for AD is age

  11. The second most important risk factor for AD is genetics Autosomal dominant chromosome 21 APP chromosome 14 Presenilin 1 chromosome 1 Presenilin 2 ~total > 160 rare but highly penetrant mutations~ Co-dominant chromosome 19 Apolipoprotein E Recessive none ?????????????????????????

  12. What determines the function of a gene? • Nucleotide sequence • DNA repair • Expression accuracy • Expression levels • Interaction of gene products and environmental factors

  13. What determines the function of a gene? • Nucleotide sequence • DNA repair • Expression accuracy • Expression levels – influenced by both genes and environment! • Interaction of gene products and environmental factors

  14. TTR binds best to AB 42 (Tsuzuki et al 2000)

  15. TTR and Alzheimer’s disease • MIRAGE database (L. Farrer, PI) • 256 Caucasian AD cases ,  306  non-demented sibs, 227 African American AD cases, 165 non-demented sibs. • 119 (Caucasian) and 79 (African American) AD cases and non-demented spouses. SNP associations were evaluated using family-based association tests, generalized estimating equations and chi square tests of proportion. • No relationships between disease and 3 TTR polymorphisms were uncovered thus far. Farrer et al (preliminary data - unpublished) Chromosome 18

  16. TTR and AD • TTR levels decreased in plasma and CSF in AD patients, cor. with dementia severity Riiosen et al, 1988; Davidsson et al,1997; Serot et al,1997; Merched et al, 1998, Riisoen,1988 • In early life AD Tg mice have increased TTR expression (before ABeta deposition and neuronal loss)….also neutralization of TTR enhances AD pathology in AD Tg mice Stein and Johnson, 2002; Stein et al, 2004

  17. Worldwide distribution of AD • Age-related • Less in Asia, Africa, India • More in African-Americans and Hispanics than Caucasians or Africans • Few studies in the Middle East

  18. Wadı Ara studıes • Rıvka Inzelberg, Co-Prıncıpal Investıgator • Populatıon based survey of genetıc and envıronmental factors • Genes: inbreedıng, populatıon bottle-neck • Envıronment: educatıon, smokıng, diet, actıvıtıes, alcohol, hypertensıon

  19. Every hereditary monarch in Europe at the beginning of the 20th century was a descendent of Edward III (Manrubia et al, 2003) Edward III, 1312-1377

  20. Alzheimer’s disease in Wadi Ara • familial clustering of AD [with low Apo E e4 allele frequency, ~4%], perhaps related in inbreeding • genetic linkages of AD to sites on chromosomes 9, 10 and 12. • Environmental factors may include low levels of education and fish consumption, smoking, high fat diet, hypertension and physical inactivity.

  21. Alzheimer’s disease in Africans and African Americans • Higher e4 freq. in Africans and African -Americans • Lower AD prevalence and incidence in Africans and higher in African- Americans (compared to Caucasians) (Hendrie et al, 1999, Kalaria et al, 1999, Evans et al, 2000)

  22. Obesity and Alzheimer’s disease 96 cases, 275 Controls; adjusted for year of birth, Apo E genotype, gender and education. [Petot et al, unpublished]

  23. Dietary fat and AD • High fat diets during the 40-59 year age period were not a risk factor for AD, regardless of ApoE status, and they may be protective. • ApoE e4 risk for AD increased 2.7 times with high linoleic acid diets during the 40-59 year age period. 117 Cases 356 controls, adjusting for year of birth, Apo E genotype, gender and education Petot et al, (ANA, Sept. 2005)

  24. Fish, PUFA and AD • Fish consumption is linked to lower AD risk (also CAD, stroke, cancer) (Kalmijn et al, 2000; Morris et al, 2003, Friedland, 2003) • Dietary intake of omega 3 PUFAs influences the expression levels of many genes controlling resistance to endogenous free radicals and ABeta protein balance

  25. Gene expression changes induced by PUFAs increased decreased * TTR lipogenesis antioxidants ROS gelsolin COX2 anti-inflamm. iNOS pro-apoptotic casp. *Short-term administration of omega 3 fatty acids from fish oil increased TTR transcription 10X in aged rat hippocampus Puskas LG et al, 2003 Akba et al, 2002,Takahashi et al, 2003, Lapillonne et al, 2004

  26. Proposal: • Brain disease with aging are due to the failure of protective mechanisms resulting from gene-environment interactions, including environmental effects on gene expression

  27. Potentially modifiable protective factors for AD • high education and occupational achievement • vigorous participation in mental and physical activities • no cardiac disease, diabetes, hypertension

  28. Protective Factors for Alzheimer’s disease (cont). • dietary use of antioxidants • low level of alcohol consumption • avoidance of obesity, high fat diet and head injury

  29. Implications for public policy • Lıfelong educatıon and opportunıtıes for mental and physıcal actıvıtıes • Access to care • Research fundıng

  30. ACKNOWLEDGEMENTS • National Institute on Aging • Joseph and Florence Mandel Research Fund • Nickman Family • Philip Morris, USA • Fullerton Family • GOJO Corp. • Pfizer, Inc. • Institute for the Study of Aging Peter B. Lewis Building, CWRU

  31. Nutritional properties of Meat Fat Commercial Fat Africa (g/100g)Meat (g/100g) • Wildebeast 4.9 • Lamb 21.6 • Waterbuck 1.8 • Pork 22.6 • Cape buffalo 6.3 • Choice beef 23.8 • Eland 4.8 • Extra lean ground beef 17.1 (adapted from Eaton, 1992)

  32. Enhanced longevity • “In Western Europe… from 1950 to 2000 the probability of surviving from age 80 to 100 increased 20-fold.” (Vaupel et al, Science, 2003)

  33. EURODEM prevalence rates

  34. O2 Radical Absorbance Capacity Fresh FruitVeggies and Legumes Blueberries 2,400 Kale 1,770 Blackberries 2,036 Spinach 1,260 Cranberries 1,750 Brussel sp. 980 Strawberries 1,540 Alfalfa sp. 930 Raspberries 1,220 Broccoli 890 Plums 949 Beets 840 Avocado 782 Red Bell P. 460 Oranges 750 Kidney B. 460 Red Grapes 739 Onions 450 Cherries 670 Corn 402

  35. Aging and dementia in the Middle East • 22 countries • Over 300 million people

  36. MMWR Weekly, Volume 54, No. 8, March 4, 2005

  37. Obesity and Apo E genotype

  38. Other influences on TTR • TTR is also increased by Ginkgo biloba, nicotine, some NSAIDs • TTR may be decreased by insulin and inflammation Watanabe et al, 2001, Li et al, 2000

  39. Alzheimer’s disease and diet • Lipids (saturated fat and PUFAs) • Fish • Homocysteine/methionine & vitamins (folic acid, B12, B6) (Kalmijn, et al 1997, 2000; Morris et al, 2003; Clarke et al, 1999; Friedland, 2003)

  40. Homocysteine and TTR • TTR may bind to homocysteine (homocysteinylation, disulfide bonds to cysteine), possibly interfering with TTR’s ability to bind ABeta Lim et al, 2003

  41. Aging is inevitable? • NO! • It is an opportunity

  42. Statins and AD • Statins may lower AD risk (Jick et al, 2001, Wolozin et al, 2001) • Statins are anti-inflamatory as well as HMG-Co A reductase inhibitors (Hernadez-Presa et al, 2002) • Plasma lipid levels may influence balance of a,b,g secretases (Beyreuther et al, 2001)

More Related