Alzheimer’s Disease Latest Advances in Prevention & Treatment

1. Alzheimer’s DiseaseLatest Advances in Prevention & Treatment GERARD BYRNE BSc(Med), MBBS(Hons), PhD, FRANZCP Alzheimer’s Disease Research Unit School of Medicine, University of Queensland Royal Brisbane & Women’s Hospital gerard.byrne@uq.edu.au

2. German neuropathologist & psychiatrist. In a 1906 lecture he first described the disease which now carries his name. Dr Alois Alzheimer 1864 - 1915

3. Auguste D. • First seen by Dr Alzheimer in 1901 when she was in her early 50s • Memory impairment • Hallucinations • Executive dysfunction

4. Franz Nissl Emil Kraepelin

5. Brain Shrinkage in Alzheimer’s Disease Autopsy specimen showing generalized atrophy.

6. Amyloid plaque Neurofibrillary tangles (from Prof Simon Lovestone, UCL)

7. Relative Prevalence of DementiaAustralia Rate per 100,000 population [AIHW & Other Sources]

8. Prevalence of DementiaCases per 100 persons Jorm et al. Acta Psychiatrica Scandinavica 1987; 76: 465-479

9. Economic Costs of Dementia • TOTAL: $6.6 billion (2002 figures) • Direct health costs – $3.2 billion • Residential care $2.9 billion • Home & community care $175 million • Real indirect costs - $1.75 billion • Mainly carer replacement costs • Transfer costs - $968 million • Including tax foregone, carer payments, welfare payments Access Economics Report for Alzheimer’s Australia, March 2003

10. Can Dementia be Prevented? Autopsy specimen showing large ventricles (coronal section).

11. Preventive Approaches • Immunisation • Vitamins • Oestrogen • Anti-inflammatory drugs • Vascular risk factors • Lifestyle

12. Immunisation with A42 Sections of Mouse Brain Unvaccinated Vaccinated Schenk D, Barbour R, Dunn W, et al. (1999) Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature, 400: 173-177.

13. Neuritic Plaque Bacskai et al. (2003) PNAS Fluorescent stained amyloid plaque

14. Immunisation with A42 Sections of Mouse Brain Unvaccinated Vaccinated Schenk D, Barbour R, Dunn W, et al. (1999) Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature, 400: 173-177.

15. Immunotherapy • Autopsy findings from 2 patients from the AN-1792 study • Kokjohn et al 2006 found that active immunotherapy disrupted amyloid plaques but lead to an increase in soluble amyloid that was not adequately cleared • Second generation active immunisation trials are underway

16. Human Vaccination with A42Major problems! Nicoll et al. Neuropathology of human Alzheimer’s disease after immunization with amyloid-β peptide: a case report. Nature Medicine 9(4):448-452, 2003 Meningoencephalitis developed in 18 of 298 (6%) of patients treated with Aβ42

17. Immunotherapy 2 • Passive immunotherapy involves administration of antibodies created in the laboratory rather than inside the person’s own body • A monoclonal antibody directed against the central domain of the amyloid molecule had been developed (Siemers et al. 2006) • Beta amyloid 40 increased in plasma & CSF in a small group of volunteers • Clinical trial is now recruiting in the United States

18. Immunotherapy 3 • An 18 month open-label clinical trial of IV immunoglobulin in 8 patients with AD (Adamiak et al. 2006) • Decline in cognition slowed • Randomized controlled clinical trial now underway

19. Can we take something to prevent dementia?

20. Vitamins That DO NOT Prevent Dementia • Vitamin E 2000IU over 3 yrs • Folic acid 2.5mg over 5 yrs • Vitamin B6 (pyridoxine) 50mg over 5 yrs • Vitamin B12 1mg over 5 yrs • Vitamin B2 (riboflavin) 25mg over 12 months

21. Oestrogen • Women’s Health Initiative Memory Study (WHIMS) - total N = 7510 aged 65+ years • 4532 postmenopausal women randomized to conjugated equine estrogens (CEE) 0.625mg/day + medroxyprogesterone acetate 2.5mg/day or placebo & 2947 women who had undergone a hysterectomy randomized to CEE 0.625mg/day or placebo for 3 years • Increased rate of progression to dementia Craig et al. (2005) Lancet Neurol 4(3): 190-194

22. However, the impact of oestrogen in the immediate post-menopausal period remains unclear

23. R-flurbiprofen • Flurbiprofen is similar in chemical structure to the anti-inflammatory drug ibuprofen (Brufen) • Reduces beta amyloid 42 • Flurbiprofen was better than placebo in relation to activities of daily living & overall function in a preliminary study of 207 patients with mild to moderate Alzheimer’s disease after 12 months (Wilcock et al. 2006)

24. PBT-2 • PBT-2 an 8-OH quinoline • Ashley Bush presented the mouse findings: • Improved spatial memory in 7 month old transgenic mice • Reduced soluble Abeta40 & Abeta42 by 60% within 24 hours of oral PBT2 in 15 month old mice • Phase 1 clinical trial in 55 young male volunteers (18-45yrs) & 32 older male and female volunteers (45-75yrs) • Generally well tolerated • Pivotal human trial has commenced in Sweden & an international study is planned

25. What is the impact of lifestyle factors on the risk of dementia?

26. Walking & Dementia in Older MenCases per 1000 person-years Miles/day N = 2257; mean age 77; BMI 23; 6-yr F/U Abbott et al (2004) JAMA 292:1447-1453 [Honolulu-Asia Aging Study]

27. Social Networks & Alzheimer’s Disease Pathology Cognitive Performance Prior to Death N = 89 Mean age at enrolment 84.3 years Mean age at proximate assessment prior to death 87.2 years Female 55.1% Education 14.4 years Social networks 6.9 High Network (90th%) Low Network (10th%) 90th % = 13 people; 10th % = 2 people Neurofibrillary tangles Bennett et al. (2006) Lancet Neurology 5: 406-412

29. Social Networks & Alzheimer’s Disease Pathology Cognitive Performance Prior to Death N = 89 Mean age at enrolment 84.3 years Mean age at proximate assessment prior to death 87.2 years Female 55.1% Education 14.4 years Social networks 6.9 High Network (90th%) Low Network (10th%) 90th % = 13 people; 10th % = 2 people Neurofibrillary tangles Bennett et al. (2006) Lancet Neurology 5: 406-412

30. Effortful mental activity and risk of dementia N = 459; mean age 79 years; median follow up 5.1 years; 124 developed dementia; 61 AD Coyle (2003) N Engl J Med 348:2489-2490 Verghese et al. (2003) N Engl J Med 348:2508-2516

31. Board games 0.26* Reading 0.65* Playing a musical instrument 0.31* Crossword puzzles 0.59 Writing 1.00 Group discussions 1.06 Dancing 0.24* Housework 0.88 Walking 0.67 Climbing stairs 1.55 Bicycling 2.09 Swimming 0.71 Team games 1.00 Babysitting 0.81 Leisure Activities & Dementia HRs for frequent participation; asterisks indicate statistical significance

32. Can Transgenic Mice Help Us?

33. Environmental Enrichment • Environmental enrichment enhances recovery from experimentally induced traumatic brain injury, epilepsy and stroke in animal models. • Environmental enrichment also forestalls innate cognitive decline associated with normal ageing. • Does environmental enrichment help transgenic mice with AD pathology?

34. Rodent Living Conditions Normal Cage Enriched Cage

35. Environmental EnrichmentAPPswe/PS1dE9 mice Enriched cages contained two running wheels, plastic play tubes, cardboard boxes and nesting material that was rearranged weekly to provide novel stimulation Jankowsky et al. (2005) J Neurosci 25(21):5217-5224

36. Morris Water Maze

37. Mouse Model of AD • Transgenic APPswe/PS1dE9 mice that over express both APP and Aβ who are kept in standard cages develop substantial deficits in learning and memory • Exposure to complex housing before amyloid plaque formation eliminates these deficits in single transgenic APPswe mice and mitigates them in doubly transgenic APPswe/PS1dE9 mice Jankowsky et al. (2005) J Neurosci 25(21):5217-5224

38. Mouse Model of AD • This finding is consistent with the cerebral reserve hypothesis • It is also consistent with human work indicating that some older people with AD neuropathology do not have dementia Jankowsky et al. (2005) J Neurosci 25(21):5217-5224

39. Should we all be playing Nintendo?

40. Can we tell the difference between Alzheimer’s disease and vascular dementia?

41. Are too many of these bad for you? Double staining showing an amyloid plaque surrounded by astrocytes Yu et al. Experimental Neurology 2005 192: 215-225

42. Are too many of these bad for you? MRI T2

43. The Nun Study

45. The Nun Study - 1 • This US study of the School Sisters of Notre Dame found that low linguistic ability in early life (low idea density & low grammatical complexity in autobiographical essays) was associated with the development of AD neuropathology (but not cerebrovascular pathology) in later life.

46. The Nun Study - 2 • Among those nuns with neuropathological features of AD at autopsy, those with additional cerebrovascular disease were much more likely to have had clinical dementia during life.

47. The Washington Heights – Inwood Columbia Aging Project (New York City) • The odds ratio (OR) for AD developing following stroke was 1.6 (95% CI: 1.02 – 2.4) • Participants with hypertension, type 2 diabetes mellitus or heart disease, AND stroke had higher ORs • Stroke + HTN = OR 2.14 (1.40 – 3.27) • Stroke + DM = OR 4.12 (2.35 – 7.23) • Stroke + Heart disease = OR 1.81 (1.18 – 2.77) Honig et al. Archives of Neurology 2003; 60: 1707-1712

48. MRC Cognitive Function & Ageing Study (MRC CFAS) • Community-based population 70-103 yrs • 209 participants have come to autopsy • Median age at death: 85yrs (M); 86yrs (F) • Cerebrovascular pathology 78% • Alzheimer pathology 70% Fernando MS, Ince PG; MRC Cognitive Function and Ageing Neuropathology Study Group.(2004) Vascular pathologies and cognition in a population-based cohort of elderly people. J Neurol Sci. 226:13-7. The Neuropathology Group MRC CFAS. Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. (2001) Lancet, 357, No. 9251 169-175

49. MRC CFAS • Dementia in 100 (48%) (of these, 64% had probable or definite AD) • 33% of non-demented individuals had equivalent degree of neocortical neuritic plaques • 34% of non-demented individuals had neurofibrillary pathology • Multiple vascular lesions in 46% of demented individuals & 33% of non-demented individuals

50. MRC CFAS • 25% of individuals misclassified as demented or non-demented on the basis of neuropathology • Vascular pathology so common that few cases of dementia lacked mixed AD & vascular features (only 21% of dementia cases were pure AD) • White matter lesions found in 94% of brains