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Prevention of Alzheimer’s Disease

Prevention of Alzheimer’s Disease. Heidi D. Klepin Resident Grand Rounds November 28, 2000. 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

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Prevention of Alzheimer’s Disease

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  1. Prevention of Alzheimer’s 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 Alzheimer’s disease. • She asks if there is anything she can take to help prevent Alzheimer’s disease. • Clinical Question: Are there any medications that prevent Alzheimer’s disease?

  4. Definition of Alzheimer’s 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 don’t recognize my own shoes.

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

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

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

  16. Estrogen Anti-inflammatory agents Anti-oxidants Ginkgo biloba Vaccine Medical Prevention 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 Alzheimer’s 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 Alzheimer’s disease in estrogen users • Retrospectively compare estrogen use in patients with AD and matched controls

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

  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 (p<0.01 and p<0.001) • 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 < 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 Alzheimer’s 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 (>2 months)

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

  41. NSAIDsRisk of Alzheimer’s Disease • Anthony et al. (2000) • Methods: 5092 patients screened • 201 AD patients diagnosed • compared use of NSAIDs, aspirin, H2RA’s with controls • used antacids, tylenol as control medications

  42. NSAIDsRisk of Alzheimer’s Disease • Anthony et al. (cont.) • Results: use of aspirin, NSAIDs and H2RA’s associated with decreased prevalence of AD (OR= 0.5, 0.43,0.42) • Combination of ASA and NSAID increased significance (OR-0.17 with CI=0.04-0.48, p=0.027)

  43. NSAIDsRisk of Alzheimer’s Disease • Anthony et al. (cont.) • Conclusions: Significant negative association between anti-inflammatory agents, H2RA’s 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 (p<0.04) • 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 • >2 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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