ALZHEIMER DISEASE Can we prevent it?

ALZHEIMER DISEASECan we prevent it? Kamal KALLAB MD Arab Conference on Alzheimer Disease March 2-4, 2005 Beirut

ALZHEIMER DISEASE Can we prevent it? • Two main reasons: • Alzheimer Disease (AD) Is a public health problem worldwide • AD is a source of fear especially in individuals who have a family history

ALZHEIMER DISEASE Can we prevent it? • Two main difficulties: • Follow-up length • Multiple variants to adjust

ALZHEIMER DISEASE Can we prevent it? • Introductory remarks: • Prevention from AD must be a part of a comprehensive concept of Dementia (Frequency of mixed dementia) • Prevention from AD must be a part of a comprehensive strategy of management of AD

ALZHEIMER DISEASE Can we prevent it? • Comprehensive concept of Dementia: • Similarities with a treasure or a bank account • Built up period ( learning) • Stabilization • Progressive loss • Use • Regular devaluation (Normal aging?) • Rapid devaluation ( Degenerative?) • Bad management ( non healthy life?) • More acute phenomena: • Bankrupt, Stock market crash ( Stroke, trauma, infections,..)

ALZHEIMER DISEASE Can we prevent it? • In case of AD, the mental status at a given time, is the result of AD lesions and possible other pathologic processes. Some are preventable or treatable

ALZHEIMER DISEASE Can we prevent it? Normal aging AD Trauma Stroke infection

ALZHEIMER DISEASE Can we prevent it? • Theses pathologic processes are: • Stroke: Second cause of dementia • Infections • Trauma • Toxic substances and drugs • Metabolic disorders • Other associated degenerative diseases

ALZHEIMER DISEASE Can we prevent it? • Comprehensive strategy in the management of AD • Prevention • Slowing (or stopping) disease course • Substitution of chemical deficit / Inhibition of excitotoxicity • Relieve other symptoms • Better use of remaining skills

ALZHEIMER DISEASE Can we prevent it? • Prevention • Slowing ( or stopping) disease course • Vaccination • Secretase inhibition? • Anti-NMDA? • GinkoBiloba? • Idebenone • Neurotrophic factors,.. • Substitution of chemical deficit / Inhibition of excitotoxicity • Cholinesterase inhib. • Anti-NMDA • Relieve other symptoms : • Non pharmacological measures • antidepressants, antipsychotics, anxiolytics, .. • Better use of remaining skills : • Environnement (emotional, psychological, familial, institutional,…) • Other medical problems • Speech therapy, occupationnal therapy,..

ALZHEIMER DISEASE Can we prevent it? • Prevention from AD: State of the art • In contrast with the disease prevalence, few amount of valid data • Randomized studies can be easily biaised • Reliability of questionnaire in case of memory disturbances • Multiple factors- statistical analysis pitfalls

ALZHEIMER DISEASE Can we prevent it? • Numerous possible preventive factors were studied. • Except for Hormone Replacement Therapy (HRT), No large scale randomized primary prevention trials completed

ALZHEIMER DISEASE Can we prevent it? • HRT: • Kawas, Neurology 1997: 472 peri or post-menopausal women, 16 years. Relative risk 0.46 • Tang, Lancet 1996: meopausal 156 ORT/1124 RR 0.4 • Shumaker, JAMA 2003 (WHI study): 4532 postmenopausal women, > 65, HRT group 2229, conjugated equine estrogen+medroxyprogesterone. 40 of HRT group developped AD versus 21 in control group RR 2.05

ALZHEIMER DISEASE Can we prevent it? • HRT: Conclusions • Lesson of Humility • Symptomatic action on cognition? • What about different types of drugs? • Role of early medication onset age? (Henderson, Neurol Neurosurg Psychiatry. 2005) • Risk-benefit: HRT is no more recommended for AD prevention, unless future data….

ALZHEIMER DISEASE Can we prevent it? • Non Steroidal Antiinflammatory Drugs (NSAIDs) • Epidemiologic studies: • Broe, Arch. Neurol, 2000 - / Beard, Mayo clinic process, 1998 +/ Rotterdam study, 1998+?/ Stewart, neurology, 1997+,.. • In’t Veld & all,NSAID on risk of AD, N Engl J Med, 2001 • Metaanalysis • Ongoing: http://www.2stopAD.org ( Randomized control trial)

ALZHEIMER DISEASE Can we prevent it? • NSAIDs • In’t Veld & all,NSAID on risk of AD, N Engl J Med, 2001 • 6989, >55, Average FU 6.8 years • computerized pharmacy records • 394 dementia, 293 AD • RR according to duration: • < 1month: 0.95 • 1-24 m: 0.83 • > 24 months cumulative use: 0.20 • Critical period during wich NSAID use is protective?

ALZHEIMER DISEASE Can we prevent it? • NSAIDs • Metaanalysis: Etminan BMJ 2003: 9 all NSAID >55, ( 6 cohort 13211 pts, 3 case control 1443 pts) • Pooled RR: 0.72 • According to duration: • Short 0.95 • Intermediate 0.83 • Long-term 0.27 • Pooled RR among Aspirin users 0.87 ( 0.7-1.07)

ALZHEIMER DISEASE Can we prevent it? • NSAIDs: • Effect on cognitive function: Hee Kang, Neurology 2003: • 13255 women, tests administered by telephone RR0.75 aspirin +15y, RR 0.79 NSAID ( mainly Ibuprofen) +8 y. For global cognitive decline, nonaspirine agents shoed lower RR ( 0.93 vs 0.77) • Protection from Parkinson disease: Chen, Arch Neurol 2003: • 44057 men, 98845 women • Nonaspirin NSAID: Pooled RR regular users vs non regular users 0.55 • Aspirin: Non significant difference

ALZHEIMER DISEASE Can we prevent it? • NSAIDs • Mechanism of action: • Cultured cells: Ibuprofen, Indomethacin and Sulindac lowered the production of the highly amyloidogenic Abeta42 peptide by as much as 80% • Mouse models: Similar effects with Ibuprofen on Abeta42 • Alteration of gamma secretase activity • This effect was not seen with all NSAIDs • Independent of cyclooxygenase inhibition • Protective NSAID mark: inhibit GTP-binding protein Rho?

ALZHEIMER DISEASE Can we prevent it? • NSAIDs conclusions: • Low dose nonaspirin NSAID, especially Ibuprofen 200 mg/d, have to be considered as possible preventive tool from AD. • Benefit Risk golden rule • High Risk group ( strong family history ) ?

ALZHEIMER DISEASE Can we prevent it? • Statins: • Epidemiologic Studies: • Wolozin, Arch Neurol, 2000: • Prevalence of AD in the groupe taking statins (lovastatin or pravastatin) was 60 to 70% (p<0.001) lower than the total patient population and patients taking other medications typically used in the treatment of Hypertension or cardiovascular disease. • Jick, Lancet 2000: • 284 AD, 1080 Control • RR ror statin users 0.2 VS 1 for non treated or treated with non statins • Zandi, Arch Gen Psychiatry. 2005: • “we found no association between statin use and subsequent onset of dementia or AD. Further research is warranted before costly dementia prevention trials with statins are undertaken”.

ALZHEIMER DISEASE Can we prevent it? • Statins: • Mechanisms of action: • Direct association between amyloid processing and cholesterol in the brain: Combined in vitro and guinea pig study found that simvastatin and lovastatin reduced intra and extracellular levels of amyloid peptides Abeta40 and 42 • Decreasing the risk of stroke

ALZHEIMER DISEASE Can we prevent it? • Antihypertensive therapy • Epidemiological studies: • Rigaud, J Hum Hypertens, 2000 • Birkenhager, Arch Intern Med, 2001 • Forette, Arch Intern Med, 2002: (syst-euro study) • >60 y, SBP 160 to 219, non dementia at randomization nitrendipine elanapril hydrochlorothiazide reduction of risk of dementia 55% including AD • Tzourio, Arch Intern Med, 2003

ALZHEIMER DISEASE Can we prevent it? • Antihypertensive therapy • Conflicting data • Length of follow-up • Type of antihypertensive therapy used • Frequent association of AD and Vascular dementia • In a comprehensive management of Dementia, HT should be treated actively • If further data will suggest clear advantage of one drug over other, then it will at least be a reason to choose it for HT treatment.

ALZHEIMER DISEASE Can we prevent it? • Antioxidants: • Theoretical Background • AD lesions = Free radical exposure associated lesions ( Bell 1997, Christen 2000) • Exogenous antioxydants reduce the toxicity of beta-amyloid in in-vitro studies of patients with AD ( Bell 1997, Christen 2000) • AD brain contains elevated levels of endogenous antioxydants (Morris 1998) • Controlled trial of selegiline and/or alphatocopherol suggested an efficacy in slowing disease progress ( Sano, N Engl J Med, 1977)

ALZHEIMER DISEASE Can we prevent it? • Antioxidants: • Epidemiological studies: • Several observational studies • Two large prospective cohort studies • Engelhart JAMA 2002 • Morris JAMA 2002

ALZHEIMER DISEASE Can we prevent it? • Antioxidants: • Engelhart JAMA 2002: • 5395 pts, >55, 6 y FU, 197 developped dementia, of whom 146 AD, Vitamine E intake from food • adustements for multiple variables made: Age, sexe, baseline MMS, alcohol intake, education, smoking, BMI, carotid plaque and antioxydant supplements • High intake ( >15.5mg/d) group was found 43% less likely to develop AD than low intake (<10.5mg/d) • This effect was more pronounced for smokers • Vitamine C intake has a positive effect

ALZHEIMER DISEASE Can we prevent it? • Antioxidants: • Morris JAMA 2002 • 815 men, =/>65, 3.9 y FU, Vit E intake from food • Adjustement for age, education, sexe, race, ApoEepsilon 4 and FU length • People with High intake (>10.4IU/d) were 70% less likely to be diagnosed with AD than the lowest intaket group ( <7.0IU/d) • ApoE epsilon 4 negative Pts showed significant protection • Antioxydant supplements ineffective

ALZHEIMER DISEASE Can we prevent it? • Antioxidants: • Limitation of these studies • Duration of FU • Food frequency questionnaire with possible cognitive dysfunction ( responses require sustained motivation, attention and memory) • Why only Antioxidants intake from food ( not supplements) affected outcomes??

ALZHEIMER DISEASE Can we prevent it? • Antioxydants: • Since the risk of vitamin E supplementation is small it may be appropriate to consider 400-800 IU/d in case of strong family history

ALZHEIMER DISEASE Can we prevent it? • Diet • Consumption of fish and n-3 fatty acids: • Morris, Arch Neurol 2003: • Obsevational study, 815 people, 65-94y. • high intake of fish(once or more weekly) had RR 0.4 compared to rarely or never ate fish (9.5% absolute reduction) • Methodological pitfalls: adjustement for ather variants • Panza,Public Health Nutr. 2004 • Mediterranean diet and cognitive decline, literature review • “Essential components of the Mediterranean diet--MUFA, cereals and wine--seem to be protective against cognitive decline”

ALZHEIMER DISEASE Can we prevent it? • Alcohol • Light to moderate drinking may be protective • Alcoholism is associated with cognitive dysfunction

ALZHEIMER DISEASE Can we prevent it? • Physical Activity • Brnes, J Am Geriatr Soc, 2003: • Observational study, 349 people, 55 or older, 6 y FU • Higher level of cardiorespiratory fitness at baseline were associated with better preservation of cognitive function • Verghese, N Engl J Med, 2003: • Observational study, 469 subjects, =/>75y, 5.1y FU • No relationship between physical activity and risk of dementia

ALZHEIMER DISEASE Can we prevent it? • Cognitive activity • Verghese, N Engl J Med, 2003: • Observational study, 469 subjects, =/>75y, 5.1y FU • Reading, playing board games and playing musical instruments, dancing were associated with reduced risk of dementia • Association with the cognitive-activity score persisted after exclusion of subjects with possible preclinical dementia at baseline • Results were similar for AD and Vascular demantia

ALZHEIMER DISEASE Can we prevent it? • Cognitive activity: • Critics • Given the same degree of AD pathology, people with better baseline cognitive reserve may still have enough skills to prevent the diagnosis of dementia

ALZHEIMER DISEASE Can we prevent it? • CONCLUSION: • Possible benefit: • NSAIDs low doses, long term exposure • Statins • Vitamine E • Fish • Cognitive activity • Physical activity? • Lessons from HRT • In the absence of definite approval, use of drugs must take in consideration the risk of developping AD vs the risk of medication • Prevention of cognitive decline must include other causes of dementia

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ALZHEIMER DISEASE Can we prevent it?