REGIONAL SYMPOSIUM ON REGIONAL SYMPOSIUM ON

ALZHEIMER’S DISEASE AND RELATED DISORDERS ALZHEIMER’S DISEASE AND RELATED DISORDERS

IN THE MIDDLE EASTIN THE MIDDLE EAST

Istanbul, TurkeyIstanbul, TurkeyOctober 1-2, 2005October 1-2, 2005Convener: Robert P. Friedland, MDConvener: Robert P. Friedland, MDLOC Chair: Murat Emre, MDLOC Chair: Murat Emre, MD

www.worldeventsforum.com/alz.htm

Gene environment interactions in Alzheimer’s Disease

Robert P. Friedland, Lindsay A. Farrer, Rivka Inzelberg, Amin Abuful, Magda Marsarwa, Rosa

Strugatsky, Clinton Baldwin, Grace Petot

Cleveland, Ohio, USA; Boston, Massachussetts USA; Hadera, Israel

CWRULab.NeurogeriatricsS. Debanne, PhDR. Friedland, MDT. Fritsch, PhDE. Grady, BAK. Gustaw, MD, PhDS. Humphrey, BAA. Lerner, MDG. Petot, MS

CWRUDept. PathologyG. Perry, PhDM. Smith, PhD

Boston Univ.C. Baldwin, PhD L. Farrer, PhD

Sun Health Res. Inst.L. Sparks, PhD  

Cleveland ClinicD.Jacobsen,PhD

Hillel Yaffe Med.Center/TechnionA. Abuful, RN R. Inzelberg, MDM. Masarwa, MDR. Stugatsky

Hadassah HospHebrewUniv, JerusalemI. Biran, MDJ. Kark, MD, PhDY. Newman, PhD

State University of New York, Stony Brook

D. Goldgaber, PhD

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

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.

Helmuth, 2002

secretase----

secretase ----

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

Why is this important?

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

The second most important risk factor for AD is genetics

Autosomal dominantchromosome 21 APPchromosome 14 Presenilin 1chromosome 1 Presenilin 2~total > 160 rare but highly penetrant mutations~

Co-dominantchromosome 19 Apolipoprotein E

Recessivenone ?????????????????????????

What determines the function of a gene?

1. Nucleotide sequence

2. DNA repair

3. Expression accuracy

4. Expression levels

5. Interaction of gene products and environmental factors

What determines the function of a gene?

1. Nucleotide sequence

2. DNA repair

3. Expression accuracy

4. Expression levels – influenced by both genes and environment!

5. Interaction of gene products and environmental factors

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

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)

27424463 intron rs723744

27425782 intron rs1080094

27428958 intron rs3794884

Chromosome 18

TTR and AD• TTR levels decreased in plasma and CSF in

AD patients, cor. with dementia severityRiiosen 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

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

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

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

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.

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)

Obesity and Alzheimer’s disease

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

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)

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

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

Proposal:- Brain disease with aging are due to the

failure of protective mechanisms resulting from gene-environment interactions, including environmental effects on gene expression

Potentially modifiable protective factors for AD

• high education and occupational achievement

• vigorous participation in mental and physical activities

• no cardiac disease, diabetes, hypertension

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

Implications for public policy

• Lıfelong educatıon and opportunıtıes for mental and physıcal actıvıtıes

• Access to care

• Research fundıng

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 AgingPeter B. Lewis Building, CWRU

Nutritional properties of Meat

Fat Commercial FatAfrica (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)

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)

EURODEM prevalence rates 

 Age group Male  Female

 30-59  0.2%  0.1%

 60-64  1.6%  0.5%

 65-69  2.2%  1.1%

 70-74  4.6%  3.9%

 75-79  5.0%  6.7%

 80-84  12.1%  13.5%

 85-89  18.5%  22.8%

 90-94  32.1%  32.3%

 95-99  31.6%  36.0%

O2 Radical Absorbance Capacity

Fresh Fruit Veggies and LegumesBlueberries 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

Aging and dementia in the Middle East

• 22 countries

• Over 300 million people

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

Obesity and Apo E genotype

010

2030

4050

6070

8090

Cases ControlsPer

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orm

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ases

& c

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tro

ls

% with e4

% with noe4

n=53 n=160

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30

40

50

60

70

80

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Cases Controls

Per

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ses

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% with e4

% with no e4

n=13 n=17

Odds ratios for Alzheimer's disease adjusted for year of birth, education and APOEe4

16.0617.62 18.08

1.18 1.21

3.64.34 4.62

8.07

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5

10

15

20

Obese vs Normal Obese vsOverweight

With APOE e4Odd

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40

60

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Non-obesecases

Non-obesecontrols

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n=13 n=17 n=83 n=258

54%

18%

72%

19%

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

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)

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

Aging is inevitable?

• NO!

• It is an opportunity

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

secretases (Beyreuther et al, 2001)

Factors influencing Abeta clearance from brain to blood

Enhance ?• Anti-A Ab’s• TTR• Apo E 2-3• Apo J• Gelsolin• GM1

(Goldgaber et al, 1995; Matsuoka et al, 2003)

Diminish ?Apo E 4High fat dietHigh plasma lipid

levelsInsulinApo e4 has less affinity for

Abeta (Pillot et al, 1999)Insulin decreases Abeta

elimination (Shiiki et al, 2004)

The major lipid binding domain of apo E is also the C-terminal domain that binds ABeta (aa 244-271)

(Pillot et al, 1999, Huang et al, 2004)

Peripheral anti-A antibody alters CNS and plasma A clearance and decreases brain A burden in a mouse model of Alzheimer’s disease

R.B. DeMattos, K.R. Bales, D. J.Cummins, J-C. Dodart, S.M. Paul, D.M. Holtzman

PNAS 98:8850, 2001

Peripheral sink hypothesis

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

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