ALZHEIMER DISEASE Can we prevent it

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ALZHEIMER DISEASECan we prevent it?

• Kamal KALLAB MD
• Arab Conference on Alzheimer Disease
• March 2-4, 2005 Beirut

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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

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ALZHEIMER DISEASE Can we prevent it?

• Two main difficulties
• Follow-up length
• Multiple variants to adjust

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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

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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,..)

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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

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

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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

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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,..

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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

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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

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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, gt 65, HRT group 2229,
  conjugated equine estrogenmedroxyprogesterone.
  40 of HRT group developped AD versus 21 in
  control group RR 2.05

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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.

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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,..
• Int Veld all,NSAID on risk of AD, N Engl J
  Med, 2001
• Metaanalysis
• Ongoing http//www.2stopAD.org ( Randomized
  control trial)

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ALZHEIMER DISEASE Can we prevent it?

• NSAIDs
• Int Veld all,NSAID on risk of AD, N Engl J
  Med, 2001
• 6989, gt55, Average FU 6.8 years
• computerized pharmacy records
• 394 dementia, 293 AD
• RR according to duration
• lt 1month 0.95
• 1-24 m 0.83
• gt 24 months cumulative use 0.20
• Critical period during wich NSAID use is
  protective?

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ALZHEIMER DISEASE Can we prevent it?

• NSAIDs
• Metaanalysis Etminan BMJ 2003 9 all NSAID gt55,
  ( 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)

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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

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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?

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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 ) ?

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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
  (plt0.001) 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.

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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

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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)
• gt60 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

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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.

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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)

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ALZHEIMER DISEASE Can we prevent it?

• Antioxidants
• Epidemiological studies
• Several observational studies
• Two large prospective cohort studies
• Engelhart JAMA 2002
• Morris JAMA 2002

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ALZHEIMER DISEASE Can we prevent it?

• Antioxidants
• Engelhart JAMA 2002
• 5395 pts, gt55, 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 ( gt15.5mg/d) group was found 43 less
  likely to develop AD than low intake (lt10.5mg/d)
• This effect was more pronounced for smokers
• Vitamine C intake has a positive effect

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ALZHEIMER DISEASE Can we prevent it?

• Antioxidants
• Morris JAMA 2002
• 815 men, /gt65, 3.9 y FU, Vit E intake from food
• Adjustement for age, education, sexe, race,
  ApoEepsilon 4 and FU length
• People with High intake (gt10.4IU/d) were 70 less
  likely to be diagnosed with AD than the lowest
  intaket group ( lt7.0IU/d)
• ApoE epsilon 4 negative Pts showed significant
  protection
• Antioxydant supplements ineffective

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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??

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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

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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

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ALZHEIMER DISEASE Can we prevent it?

• Alcohol
• Light to moderate drinking may be protective
• Alcoholism is associated with cognitive
  dysfunction

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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, /gt75y, 5.1y
  FU
• No relationship between physical activity and
  risk of dementia

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ALZHEIMER DISEASE Can we prevent it?

• Cognitive activity
• Verghese, N Engl J Med, 2003
• Observational study, 469 subjects, /gt75y, 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

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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

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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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Byblos
Byblos