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Prevention of Alzheimers Disease

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Prevention of Alzheimer's Disease. Heidi D. Klepin. Resident Grand Rounds. November ... Observational data contradictory regarding role in disease prevention. ... – PowerPoint PPT presentation

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Title: Prevention of Alzheimers Disease


1
Prevention of Alzheimers Disease
  • Heidi D. Klepin
  • Resident Grand Rounds
  • November 28, 2000

2
Case History
  • 58 y/o WF presenting for routine office visit
  • Review of systems negative
  • PMH arthritis
  • FH colon cancer and CAD
  • SH office work, no tobacco, social ETOH
  • Medications HRT (cuts into quarters)
  • PE normal Labs normal

3
Case History
  • The patient has read in Prevention magazine that
    vitamin E will prevent Alzheimers disease.
  • She asks if there is anything she can take to
    help prevent Alzheimers disease.
  • Clinical Question Are there any medications
    that prevent Alzheimers disease?

4
Definition of Alzheimers Disease
  • Progressive neurologic disorder characterized by
    memory loss, cognitive dysfunction, personality
    changes and global functional decline.
  • Develops gradually
  • Diagnosis often missed in early stages

5
Pathology
  • Neuritic plaques
  • Neurofibrillary tangles
  • Loss of synapses and neurons
  • Abnormal amyloid deposits
  • Increased inflammation
  • Neurotransmitter disturbances

6
Pathology Amyloid Cascade Hypothesis
  • Central role in AD neuropathology
  • Amyloid- beta is found in abnormal amounts in the
    brains of AD patients
  • A-beta exerts toxic effects on neuronal tissue
    through oxidative damage and disturbances in
    calcium metabolism
  • A-beta is liberated from APP through a secondary
    (minor)pathway
  • Most risk factors for AD increase production of
    A-beta

7
Pathology Multiple Mechanisms
Amyloid
Inflammation
AD
Neurotransmitter
Oxidation
Plaques, Tangles
8
Epidemiology
  • Most common form of dementia
  • 4 million people affected
  • Incidence 0.5 per year at 65
  • Incidence 8 per year at 85
  • Prevalence 3 of 65 year olds
  • Prevalence 47 of 85 year olds

9
Medical Complications
  • Increased incidence of the following
  • Stroke
  • Infection (UTI and aspiration pneumonia)
  • Hip fractures
  • Nursing home placement

10
Financial Burden
  • Cost of caring for 1 patient 47,000 / year
  • Combined cost for all patients 100 billion
  • Delay onset of disease by 1 year would decrease
    number of cases by 210,000 in 10 years and
    provide a savings of 10 billion
  • (47,000X 210,000 fewer patients)

11
Rationale for Prevention
  • Socially devastating disease
  • Economic burden
  • Medical complications
  • No available cure for AD
  • Aging population

12
Rationale for Prevention
  • My name is Hal.
  • I dont recognize my own shoes.

13
Goals for Prevention
  • Identify high risk populations
  • Identify low risk interventions

14
Risk Factors
  • Definite
  • Age
  • Family history
  • Downs syndrome
  • Genetic (ApoE-4)
  • Suggested
  • Female gender
  • History of head trauma
  • Small head circumference
  • Low intelligence
  • Low education level

15
Protective Factors
  • Genetics (apoE-2 allele)
  • Education
  • Challenging occupations
  • Remaining mentally and socially active
  • ?? Medications (estrogen,NSAIDs, antioxidants)

16
Medical Prevention
  • Estrogen
  • Anti-inflammatory agents
  • Anti-oxidants
  • Ginkgo biloba
  • Vaccine

Amyloid
Inflammation
AD
Neurotransmitters
Oxidation
17
EstrogenPathophysiologic effects
  • Increased cholinergic activity
  • Decreased catabolism of catecholamines
  • Stimulation of neurite growth and synapse
    formation
  • Decreased production of beta-amyloid
  • Anti-inflammatory effect
  • Improved regional blood flow
  • Suppression of apoE-4 expression

18
Clinical TrialsEstrogen
  • Observational Trials
  • Risk of Alzheimers disease
  • Effect on cognitive function
  • Randomized controlled trials
  • Effect on cognitive function

19
Observational TrialsEstrogen and risk of AD
  • 6 cross-sectional trials address the risk of
    Alzheimers disease in estrogen users
  • Retrospectively compare estrogen use in patients
    with AD and matched controls

20
Observational TrialsEstrogen and Risk of AD
  • Decreased Risk
  • Henderson (1994)
  • Paganini-Hill (1994)
  • Mortel (1994)
  • Baldereschi (1998)
  • Waring (1999)
  • No difference
  • Brenner(1994)

21
Estrogen and Risk of ADProspective Trials
  • Tang et al. (1996)
  • Methods prospective cohort
  • 1124 non-demented women
  • followed for 1-5 years
  • estrogen use obtained at study entry

22
Estrogen and Risk of AD
  • Tang (cont.)
  • Results 167 (14) developed AD
  • 16 of non-estrogen users and 5.8 of estrogen
    users
  • RR of developing AD while using estrogen was 0.4
    (95 CI 0.22-0.9)

23
Estrogen and Risk of AD
  • Conclusions Estrogen exposure decreased the
    risk of developing AD
  • This was the first prospective trial addressing
    this issue
  • Limitations Nonrandomized design- cannot rule
    out inherent differences between study groups.
    Recall bias.

24
Estrogen and Risk of AD
  • Kawas et al. (1997)
  • Methods Prospective cohort
  • 514 women followed for 16 years
  • 2 year follow-ups with interviews and cognitive
    testing
  • Hormone history determine at interview

25
Estrogen and Risk of AD
  • Kawas et al. (cont.)
  • Results 45 of women used HRT
  • 34 cases of AD diagnosed with only 9 in HRT users
  • RR of developing AD with estrogen use was 0.457
    (CI 0.209-0.997), p value not given

26
Summary of Observational TrialsEstrogen and Risk
of AD
  • Evidence suggests a negative relationship between
    estrogen and development of AD
  • Cannot assume cause and effect without
    randomization
  • Most data on HRT subject to recall bias

27
Cross Sectional TrialsEstrogen and Cognition
28
Prospective TrialsEstrogen and Cognition
  • Jacobs et al. (1998)
  • Methods 727 elderly women
  • cognitive testing at base-line and 2.5 years
  • estrogen use per patient interview
  • only 11 used HRT in past and 2 at evaluation

29
Prospective TrialsEstrogen and Cognition
  • Jacobs et al. (cont.)
  • Results Estrogen users improved on immediate
    and delayed recall after 2.5 years while
    non-users declined (plt0.01 and plt0.001)
  • Conclusions Estrogen use was associated with
    protective effect on recall over time

30
Prospective TrialsEstrogen and Cognition
  • Jacobs et al. (cont.)
  • Limitations Nonrandomized design. Large time
    interval between estrogen use and study (avg. 25
    years)
  • Largest effect seen with patient taking estrogen
    lt 1 year

31
Prospective TrialsEstrogen and Cognition
  • Mathews (1999)
  • Methods 9651 women mean age 72
  • estrogen use obtained from interview
  • cognitive testing at base-line and 4-6 years

32
Prospective TrialsEstrogen and Cognition
  • Mathews (cont.)
  • Results Estrogen users performed better at
    baseline but did not exhibit less decline over
    time
  • Limitations Nonrandomized design, high drop-out
    rate

33
Summary- Observational TrialsEstrogen and
Cognition
  • Four of six cross-sectional trials showed
    improvement in at least one parameter of
    cognitive function
  • Three large trials demonstrated no benefit
  • One of two prospective trials demonstrated
    decreased cognitive decline
  • No clearly reproducible benefit

34
Randomized Controlled TrialsEstrogen and
Cognition
  • Ten available RCTs
  • Limited by small size, short duration,
    non-uniform cognitive testing, poorly controlled
  • 8 of 10 studies showed some benefit of unclear
    significance

35
ConclusionsEstrogen for Prevention of AD
  • Observational trials suggest a protective effect
  • There is no consistently reproducible benefit of
    estrogen on cognitive function
  • A large RCT of many years duration is necessary

36
Future StudiesEstrogen for Prevention of AD
  • WHIMS Trial
  • Large double blind placebo controlled RCT
  • Testing the hypothesis that HRT reduces incidence
    of all-cause dementia in older women
  • 8300 subjects followed for 6 years with cognitive
    testing
  • Results some time this decade!!?

37
Anti-Inflammatory MedicationMechanism
  • Inflammatory changes in and around neuritic
    plaques
  • Increased acute phase reactants
  • Activation of complement system
  • ? APP itself acting as an acute phase reactant
  • AD may be a state of chronic neuro-inflammation

38
Summary of meta-analysisMcGreer (1996)
39
NSAIDsRisk of Alzheimers Disease
  • Veld et al (1998)
  • Methods 7046 non-demented patients followed for
    3 years
  • 101 new cases of AD were matched with controls
  • prescription data obtained from records
  • grouped into non-users, short term users and long
    term users (gt2 months)

40
NSAIDsRisk of Alzheimers Disease
  • Veld (cont.)
  • Results Non-significant tendency toward risk
    reduction in users gt6 months duration
  • Conclusion No significant association
  • Limitations Only 28 patients had been exposed gt
    6 months

41
NSAIDsRisk of Alzheimers Disease
  • Anthony et al. (2000)
  • Methods 5092 patients screened
  • 201 AD patients diagnosed
  • compared use of NSAIDs, aspirin, H2RAs with
    controls
  • used antacids, tylenol as control medications

42
NSAIDsRisk of Alzheimers Disease
  • Anthony et al. (cont.)
  • Results use of aspirin, NSAIDs and H2RAs
    associated with decreased prevalence of AD (OR
    0.5, 0.43,0.42)
  • Combination of ASA and NSAID increased
    significance (OR-0.17 with CI0.04-0.48, p0.027)

43
NSAIDsRisk of Alzheimers Disease
  • Anthony et al. (cont.)
  • Conclusions Significant negative association
    between anti-inflammatory agents, H2RAs and AD
  • Limitations Non-randomized. Duration and dose
    unknown. Recall bias.

44
Prospective TrialsNSAIDs and Cognition
  • Rozzini et al. (1996)
  • Methods 7671 elderly patients enrolled
  • Cognitive testing at baseline and 3 years
  • Medication use per patient interview

45
Prospective TrialsNSAIDs and Cognition
  • Rozzini et al (cont.)
  • Results 21 were chronic NSAID users (3 years)
  • Mean test score higher in NSAID group at
    termination of trial
  • Less decline in score in NSAID group

46
NSAIDs and Cognition
  • Rozzini et al. (cont.)
  • Conclusions Supports association between NSAIDs
    and reduction of cognitive decline in elderly
    patients
  • Limitations Non-randomized. No dosage
    information. Surrogate marker for AD

47
Prospective TrialsNSAIDs and Cognition
  • Prince et al. (1998)
  • Methods 2651 patients in HTN trial
  • Cognitive testing done at baseline and every 3
    months for 4.5 years
  • Medication info per patient interview

48
Prospective TrialsNSAIDs and Cognition
  • Prince et al. (cont.)
  • Results Negative association between NSAID use
    and decline in associative memory (plt0.04)
  • Limitations Non-randomized. No dosage or
    duration information. Recall bias. Clinical
    application?

49
Prospective TrialsNSAIDs and Risk of AD
  • Stewart et al. (1997)
  • Methods 1686 subjects followed for 15 years
    with cognitive testing every 2 years
  • Medication information obtained from interviews

50
Prospective TrialsNSAIDs and Risk of AD
  • Stewart et al. (cont.)
  • Results 81 cases of AD diagnosed
  • NSAID users had decreased incidence of AD with
    increasing duration of use
  • gt2 years RR 0.40 (CI 0.19-0.84)
  • Aspirin showed a non-significant trend
  • Acetaminophen showed no change (RR 1.35)

51
Relative Risk of AD
52
Prospective TrialsNSAIDs and Risk of AD
  • Stewart et al. (cont.)
  • Conclusions First prospective trial to
    demonstrate an inverse association between NSAIDs
    and risk of AD
  • Suggests longer duration required
  • Limitations Nonrandomized design. Recall bias.

53
Prospective TrialsNSAIDs and Risk of AD
  • Henderson et al. (1997)
  • Methods 945 elderly subjects
  • MMSE administered at baseline and 4 years
  • Medication use determined by interview

54
Prospective StudiesNSAIDs and Risk of AD
  • Henderson et al. (cont.)
  • Results No association found with cognitive
    decline or incidence of AD
  • Limitations No medication history obtained at
    the initial interview. Recall bias. 32 of
    patients not followed up.

55
SummaryAnti-inflammatory Medication
  • Multiple observational trials suggest protective
    benefit for risk of AD
  • Recent prospective trial suggests long term use
    (gt 2 yrs) necessary for benefit
  • Some evidence that NSAIDs may prevent cognitive
    decline

56
Anti-oxidantsMechanism
  • Oxidative damage demonstrated in AD pathology
  • Beta-amyloid may exert toxic effect though free
    radical formation
  • Vitamin E has prevented oxidative damage of
    amyloid in cell culture

57
Anti-oxidantsClinical Trials
  • Morris et al. (1998)
  • Methods prospective trial
  • 633 non-demented patients gt65yo
  • Cognitive testing at base-line and 4 years later
  • Information regarding vitamin supplements
    obtained by interview
  • compared vitamin E, vitamin C, MVI and controls

58
Anti-oxidantsRisk of Alzheimers Disease
  • Morris et al (cont.)
  • Results 91 cases of AD diagnosed- none found in
    anti-oxidant groups
  • Incidence in the Vitamin C group was
    statistically significantly decreased (p0.04)
    while Vitamin E trended lower (p0.23)
  • No difference was noted for MVI

59
Anti-oxidantsRisk of Alzheimers Disease
  • Morris et al.
  • Conclusions Possible protective effect of
    anti-oxidants on incidence of AD
  • Limitations Small number of patients. Cannot
    control for inherent differences

60
Anti-oxidants Risk of AD
  • Masaki et al. (2000)
  • Methods Longitudinal study.
  • 3734 men recruited for cognitive testing
  • pre-existing data available of vitamin
    supplementation use

61
Anti-oxidantsRisk of AD
  • Masaki et al. (cont.)
  • Results 47 patients diagnosed with AD
  • No significant association between anti-oxidant
    use and risk of AD
  • Significant decrease in risk of vascular dementia
  • Limitations Small number of AD patients. No
    dosage or duration info available

62
Anti-oxidants Randomized Controlled Trial
  • Sano et al. (1997)
  • Methods RCT
  • 341 patients with dementia
  • Randomized to selegiline, vitamin E, both or
    placebo
  • Followed 3 month intervals for 2 years
  • Primary outcome was time to endpoints death,
    institutionalization, loss of ability to perform
    2 ADLs or severe dementia

63
Anti-oxidantsRandomized Controlled Trial
  • Sano et al (cont.)
  • Results After adjusting for baseline MMSE
    scores significant delay in reaching endpoint
    with all intervention groups
  • selegiline (RR 0.57, plt0.012)
  • Vitamin E (RR 0.47, plt0.001)
  • Combined (RR 0.69, p0.049)

64
Anti-oxidantsRCT
  • Sano et al. (cont.)
  • Conclusion Vitamin E and Selegiline are
    beneficial in delaying functional decline in AD
    patients.
  • Limitations Results only significant after
    adjusting for MMSE.

65
Anti-oxidantsSummary
  • Observational data contradictory regarding role
    in disease prevention.
  • Demonstrated to slow functional decline in
    patients with AD in one study which may carry
    over to a role in prevention
  • Large RCT necessary

66
Anti-oxidantsFuture Studies
  • A large multi-center RCT is planned by the
    Alzheimers Disease Cooperative Study to
    determine whether vitamin E can prevent or delay
    AD in patients with mild cognitive dysfunction.

67
Ginkgo BilobaMechanism
Anti-oxidant
MAOI
Egb 761
PAF inhibitor
Anti-inflammatory
68
Ginkgo biloba Prevention of AD
  • Multiple small trials suggest some benefit in
    cognitive function in non-demented subjects
  • Ginkgo is currently marketed as a memory enhancer
    to the public
  • There are no trials that address Ginkgo and
    prevention of AD

69
Ginkgo BilobaRCT
  • LeBars et al. (1997)
  • Methods Double blind RCT
  • 309 patients with AD (MMSE 9-26)
  • randomized to ginkgo or placebo
  • followed for 52 weeks
  • outcomes- cognitive and functional

70
Ginkgo BilobaRCT
  • LeBars et al. (cont.)
  • Results Treatment group improved in cognitive
    function test (p0.005) and caregiver assessment
    but not clinicians assessment

71
Ginkgo BilobaRCT
  • LeBars et al. (cont.)
  • Conclusions Ginkgo extract decreased rate of
    cognitive decline (per ADAS-Cog) and functional
    decline per caregiver
  • Limitations High drop out rate in both groups.
    Clinical significance of cognitive change
    questionable (small absolute change)

72
Summary Ginkgo BilobaPrevention of AD
  • No studies address prevention directly
  • Proposed mechanisms of action make this a
    potentially useful agent in treating or delaying
    AD
  • Usefulness may be limited by difficulty obtaining
    pure abstract

73
Vaccine
  • Schenk et al (1999) created a vaccine used on
    rodents to prevent amyloid deposition.
  • A vaccine using amyloid fragment given to 6-week
    old mice which over produce APP and prevented
    plaque formation
  • A second study with 11 month old mice
    significantly decreased plaque formation

74
Summary of Vaccine
  • Potential future preventative tool if it proves
    affect clinical outcomes and is shown to be safe.
  • However, given the potential multifactorial
    nature of AD this approach may not be sufficient
    to prevent disease

75
Final Conclusions
  • Currently there is no cure or prevention for AD
  • Research has helped identify risk factors
    including age, family history and genetics
  • Factors that have been associated with protective
    benefit such as education, and remaining mentally
    and socially active should be stressed to patients

76
More Conclusions
  • The final word on the protective benefit of
    estrogen is pending (await WHIMS)
  • No indication to prescribe for cognitive benefit
  • Anti-inflammatory agents hold promise in
    observational studies. Side effects may be
    problematic. Look for studies with COX-2
    inhibitors in the future

77
Still More Conclusions
  • Anti-oxidants may be beneficial and are currently
    being studied for preventative benefit.
  • Given the low side effect profile and potential
    benefit, consider recommending vitamin E to high
    risk patients (vitamin E 1000IU BID).

78
Blah Blah Blah
  • Ginkgo biloba has not been studied but holds
    potential for a role in prevention or treatment
    based on mechanism of action.
  • Look for H2 receptor blockers and vitamin C in
    future studies
  • Mice will continue to be sacrificed for a
    potential vaccine

79
Special Thanks to
Dr. Herman
HAL
Dr. Ebright
All my supporters
Me
The authors of all the Journal Ariticles
My cats
My Mom
80
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