Transcript ALZHEIMER DISEASE Can we prevent it?

ALZHEIMER DISEASE
Can 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?
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Two main reasons:
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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?
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Two main difficulties:
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Follow-up length
Multiple variants to adjust
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ALZHEIMER DISEASE Can we prevent it?
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Introductory remarks:
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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?
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Comprehensive concept of Dementia:
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Similarities with a treasure or a bank account
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Built up period ( learning)
Stabilization
Progressive loss
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Use
Regular devaluation (Normal aging?)
Rapid devaluation ( Degenerative?)
Bad management ( non healthy life?)
More acute phenomena:
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Bankrupt, Stock market crash ( Stroke, trauma,
infections,..)
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ALZHEIMER DISEASE Can we prevent it?
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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?
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Theses pathologic processes are:
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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?
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Comprehensive strategy in the management of AD
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Prevention
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Slowing (or stopping) disease course
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Substitution of chemical deficit / Inhibition of excitotoxicity
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Relieve other symptoms
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Better use of remaining skills
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ALZHEIMER DISEASE Can we prevent it?
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Prevention
Slowing ( or stopping) disease course
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Substitution of chemical deficit / Inhibition of excitotoxicity
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Cholinesterase inhib.
Anti-NMDA
Relieve other symptoms :
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Vaccination
Secretase inhibition?
Anti-NMDA?
GinkoBiloba?
Idebenone
Neurotrophic factors,..
Non pharmacological measures
antidepressants, antipsychotics, anxiolytics, ..
Better use of remaining skills :
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Environnement (emotional, psychological, familial, institutional,…)
Other medical problems
Speech therapy, occupationnal therapy,..
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ALZHEIMER DISEASE Can we prevent it?
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Prevention from AD: State of the art
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In contrast with the disease prevalence,
few amount of valid data
Randomized studies can be easily biaised
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Reliability of questionnaire in case of memory
disturbances
Multiple factors- statistical analysis pitfalls
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ALZHEIMER DISEASE Can we prevent it?
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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?
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HRT:
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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
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ALZHEIMER DISEASE Can we prevent it?
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HRT: Conclusions
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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?
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Non Steroidal Antiinflammatory Drugs
(NSAIDs)
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Epidemiologic studies:
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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)
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ALZHEIMER DISEASE Can we prevent it?
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NSAIDs
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In’t Veld & all,NSAID on risk of AD, N Engl J Med, 2001
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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?
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NSAIDs
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Metaanalysis: Etminan BMJ 2003: 9 all NSAID
>55, ( 6 cohort 13211 pts, 3 case control 1443
pts)
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Pooled RR: 0.72
According to duration:
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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?
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NSAIDs:
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Effect on cognitive function: Hee Kang, Neurology 2003:
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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:
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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?
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NSAIDs
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Mechanism of action:
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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?
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NSAIDs conclusions:
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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?
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Statins:
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Epidemiologic Studies:
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Wolozin, Arch Neurol, 2000:
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Jick, Lancet 2000:
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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.
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:
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“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?
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Statins:
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Mechanisms of action:
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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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Antihypertensive therapy
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Epidemiological studies:
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Rigaud, J Hum Hypertens, 2000
Birkenhager, Arch Intern Med, 2001
Forette, Arch Intern Med, 2002: (syst-euro
study)
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>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
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ALZHEIMER DISEASE Can we prevent it?
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Antihypertensive therapy
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Conflicting data
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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?
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Antioxidants:
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Theoretical Background
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AD lesions = Free radical exposure associated lesions (
Bell 1997, Christen 2000)
Exogenous antioxydants reduce the toxicity of betaamyloid 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?
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Antioxidants:
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Epidemiological studies:
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Several observational studies
Two large prospective cohort studies
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Engelhart JAMA 2002
Morris JAMA 2002
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ALZHEIMER DISEASE Can we prevent it?
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Antioxidants:
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Engelhart JAMA 2002:
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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
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ALZHEIMER DISEASE Can we prevent it?
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Antioxidants:
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Morris JAMA 2002
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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
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ALZHEIMER DISEASE Can we prevent it?
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Antioxidants:
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Limitation of these studies
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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?
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Antioxydants:
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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?
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Diet
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Consumption of fish and n-3 fatty acids:
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Morris, Arch Neurol 2003:
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Obsevational study, 815 people, 65-94y.
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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
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Mediterranean diet and cognitive decline, literature review
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“Essential components of the Mediterranean diet--MUFA, cereals
and wine--seem to be protective against cognitive decline”
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Alcohol
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Light to moderate drinking may be
protective
Alcoholism is associated with cognitive
dysfunction
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ALZHEIMER DISEASE Can we prevent it?
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Physical Activity
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Brnes, J Am Geriatr Soc, 2003:
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Observational study, 349 people, 55 or older, 6 y FU
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Higher level of cardiorespiratory fitness at baseline were
associated with better preservation of cognitive function
Verghese, N Engl J Med, 2003:
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Observational study, 469 subjects, =/>75y, 5.1y FU
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No relationship between physical activity and risk of
dementia
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Cognitive activity
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Verghese, N Engl J Med, 2003:
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Observational study, 469 subjects, =/>75y,
5.1y FU
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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?
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Cognitive activity:
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Critics
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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?
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CONCLUSION:
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Possible benefit:
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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
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Byblos
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