Prevention of Alzheimers Disease

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Prevention of Alzheimers Disease

• Heidi D. Klepin
• Resident Grand Rounds
• November 28, 2000

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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

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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?

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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

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Pathology

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

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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

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Pathology Multiple Mechanisms
Amyloid
Inflammation
AD
Neurotransmitter
Oxidation
Plaques, Tangles
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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

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Medical Complications

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

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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)

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Rationale for Prevention

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

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Rationale for Prevention

• My name is Hal.
• I dont recognize my own shoes.

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Goals for Prevention

• Identify high risk populations
• Identify low risk interventions

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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

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Protective Factors

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

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Medical Prevention

• Estrogen
• Anti-inflammatory agents
• Anti-oxidants
• Ginkgo biloba
• Vaccine

Amyloid
Inflammation
AD
Neurotransmitters
Oxidation
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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

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Clinical TrialsEstrogen

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

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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

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Observational TrialsEstrogen and Risk of AD

• Decreased Risk
• Henderson (1994)
• Paganini-Hill (1994)
• Mortel (1994)
• Baldereschi (1998)
• Waring (1999)

• No difference
• Brenner(1994)

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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

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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)

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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.

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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

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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

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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

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Cross Sectional TrialsEstrogen and Cognition
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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

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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

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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

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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

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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

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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

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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

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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

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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!!?

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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

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Summary of meta-analysisMcGreer (1996)
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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)

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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

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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

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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)

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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.

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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

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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

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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

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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

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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?

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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

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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)

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Relative Risk of AD
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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.

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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

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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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.

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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

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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.

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Ginkgo BilobaMechanism
Anti-oxidant
MAOI
Egb 761
PAF inhibitor
Anti-inflammatory
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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

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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

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Ginkgo BilobaRCT

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

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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)

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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

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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

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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

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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

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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

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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).

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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

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