Alzheimer’s Disease Latest Advances in Prevention & Treatment

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Alzheimers DiseaseLatest Advances in Prevention
Treatment

• GERARD BYRNE
• BSc(Med), MBBS(Hons), PhD, FRANZCP
• Alzheimers Disease Research Unit
• School of Medicine, University of Queensland
• Royal Brisbane Womens Hospital
• gerard.byrne_at_uq.edu.au

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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

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Franz Nissl
Emil Kraepelin
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Brain Shrinkage in Alzheimers Disease
Autopsy specimen showing generalized atrophy.
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Amyloid plaque
Neurofibrillary tangles
(from Prof Simon Lovestone, UCL)
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Early Symptoms

• Changes in mood (often depression or anxiety)
• Changes in personality (especially apathy or
  irritability)
• Memory problems (particularly for recent events
  the names of people or things)
• Word-finding difficulties
• Difficulty calculating change managing
  financial affairs

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Later Symptoms

• Disorientation obvious confusion
• Difficulty with complex tasks
• Using the computer Programming the video
  recorder
• Planning a trip
• Completing a tax return
• Difficulty recognizing people objects
• Difficulty following a conversation making
  oneself understood
• Difficulty dressing doing other everyday tasks
• Delusions,Hallucinations

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Much Later Symptoms

• Challenging behaviours
• Agitation
• Noisy behaviour
• Aggressive behaviour
• Difficulty eating walking

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Relative Prevalence of DementiaAustralia
Rate per 100,000 population
AIHW Other Sources
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Number of Older People
000
ABS Cat 3101.0
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Prevalence of DementiaCases per 100 persons
Jorm et al. Acta Psychiatrica Scandinavica 1987
76 465-479
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Incidence of DementiaCases per 1,000 person years
Jorm Jolley, Neurology, 1998 51(3) 728-733
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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 Alzheimers
Australia, March 2003
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Can Dementia be Prevented?
Autopsy specimen showing large ventricles
(coronal section).
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Preventive Approaches

• Immunisation
• Vitamins
• Oestrogen
• Anti-inflammatory drugs
• Vascular risk factors
• Lifestyle

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Immunisation with A?42
Sections of Mouse Brain
Vaccinated
Unvaccinated
Schenk D, Barbour R, Dunn W, et al. (1999)
Immunization with amyloid-ß attenuates
Alzheimer-disease-like pathology in the PDAPP
mouse. Nature, 400 173-177.
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Neuritic Plaque
Bacskai et al. (2003) PNAS
Fluorescent stained amyloid plaque
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Immunisation with A?42
Sections of Mouse Brain
Vaccinated
Unvaccinated
Schenk D, Barbour R, Dunn W, et al. (1999)
Immunization with amyloid-ß attenuates
Alzheimer-disease-like pathology in the PDAPP
mouse. Nature, 400 173-177.
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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

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Human Vaccination with A?42Major problems!
Nicoll et al. Neuropathology of human Alzheimers
disease after immunization with amyloid-ß
peptide a case report. Nature Medicine
9(4)448-452, 2003
Meningoencephalitis developed in 18 of 298 (6)
of patients treated with Aß42
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Immunotherapy 2

• Passive immunotherapy involves administration of
  antibodies created in the laboratory rather than
  inside the persons 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

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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

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Can we take something to prevent dementia?
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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

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Vitamin E Donepezil in aMCI

• Petersen et al. (2005) N Engl J Med 352
  2379-2388
• N 769 aMCI 16 annual ? AD
• RCT vitamin E 2000IU vs donepezil 10mg vs
  placebo for 3 years
• Vitamin E AD HR 1.02 (0.74-1.41)
• Donepezil AD HR 0.80 (0.57-1.13)
• Some benefit from donepezil evident in first 12
  months interaction between ApoE e4 status
  donepezil over 3 years

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Kaplan-Meier Estimates of the Rate of Progression
from Mild Cognitive Impairment to Alzheimer's
Disease (AD)
Petersen, R. et al. N Engl J Med
20053522379-2388
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B Vitamins HOPE 2 Study

• N Engl J Med (2006) 354 published on-line 12
  March
• N 5522 patients with vascular disease or
  diabetes 55 years
• Randomized to placebo or folic acid 2.5mg
  vitamin B6 50mg vitamin B12 1mg for 5 years
• Reduced homocysteine but no clinical benefit

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More B Vitamins

• Stott et al. (2005) Am J Clin Nutr. 82(6)1320-6
• Folic acid 2.5mg vitamin B12 500mcg v vitamin
  B6 25mg v riboflavin 25mg v placebo (2x2x2
  factorial design)
• N 185, 65yrs, ischaemic vascular patients
• Homocysteine decreased by 5 over 3 months
• No improvement in cognition over 12 months

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Even More B Vitamins

• Mooijaart et al. (2005) Am J Clin Nutr 82(4)
  866-871
• Leiden 85-plus study
• N 599 longitudinal study
• Homocysteine folic acid associated with
  cognitive performance cross-sectionally but not
  longitudinally
• Association likely to be a consequence of disease
  not a cause

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Oestrogen

• Womens 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
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WHIMS Cognition
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However, the impact of oestrogen in the immediate
post-menopausal period remains unclear
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Raloxifene

• Selective oestrogen receptor modulator
• N 5,386 postmenopausal women with osteoporosis
• RCT raloxifene 60 or 120mg v placebo for 3 years
• Cognition was a secondary outcome
• Women taking raloxifene 120mg had a 33 lower
  risk of Mild Cognitive Impairment (MCI) than
  women taking placebo and a relative risk of
  Alzheimers disease of 0.52

Yaffe et al. (2005) Am J Psychiatry 162 683-690
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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 Alzheimers disease after 12 months
  (Wilcock et al. 2006)

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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

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What is the impact of lifestyle factors on the
risk of dementia?
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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 2921447-1453
Honolulu-Asia Aging Study
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Social Networks Alzheimers 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
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Social Networks Alzheimers 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
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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 3482489-2490 Verghese
et al. (2003) N Engl J Med 3482508-2516
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Leisure Activities Dementia

• 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

HRs for frequent participation asterisks
indicate statistical significance
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Can Transgenic Mice Help Us?
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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?

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Neurogenesis in the mouse dentate gyrus following
learning, running and enrichment Only running
and enrichment were associated with increased
survival of newborn neurons. Differential effects
of exercise, enrichment and novelty still debated.
Van Pragg et al. Nature Reviews, Neuroscience
(2000) 1 191-198
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Rodent Living Conditions
Normal Cage Enriched Cage
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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
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Morris Water Maze
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Mouse Model of AD

• Transgenic APPswe/PS1dE9 mice that over express
  both APP and Aß 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
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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
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Should we all be playing Nintendo?
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Can we tell the difference between Alzheimers
disease and vascular dementia?
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Is it easy to distinguish dementia due to
Alzheimers disease from dementia due to
cerebrovascular disease?
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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
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Are too many of these bad for you?
MRI T2
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The Nun Study
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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.

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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.

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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
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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.
22613-7. 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
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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

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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

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Can we improve our diagnostic predictions?
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Loss of Brain Volume in Alzheimers Disease
Volumetric MRI studies demonstrate 2.8 loss of
brain volume each year in patients with AD cf.
0.2 loss in normal older people.
Coronal Section
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MRI Prediction of DementiaHippocampal
Amygdalar Volumes

• Den Heijer et al. (2006) Arch Gen Psychiatry
  6357-62
• N 511 people aged 60-90 years (mean 73.4 yrs)
  without dementia followed for up to 6 years (3043
  person-years)
• 35 people developed dementia, 26 AD
• For each 1 SD decrease in hippocampal volume the
  HR for dementia was 3.0 (2.0-4.6)
• For each 1 SD decrease in amygdalar volume the HR
  for dementia was 2.1 (1.5-2.9)
• Volume reductions in those destined to develop
  dementia were 5-17

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MTL
Whole Brain
Graphs show atrophy rate in the MTL (left) and
whole brain (right) versus age.   Open circles
no cognitive decline,   Speckled circles
decline to MCI,   Black circles decline to
AD.
Rusinek et al. (2003) Regional Brain Atrophy Rate
Predicts Future Cognitive Decline 6-year
Longitudinal MR Imaging Study of Normal Aging
Radiology 229 691-696
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Rusinek et al. (2003) Regional Brain Atrophy Rate
Predicts Future Cognitive Decline 6-year
Longitudinal MR Imaging Study of Normal Aging
Radiology 229 691-696
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Labelling Amyloid FDG PIB PET in AD Controls
Klunk et al. Ann Neurol 200455306319
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PET for AD Diagnosis?
Summary Specificity of PET 86 (95 CI
76-93) Summary Sensitivity of PET 86 (95 CI
72-93)
If population prevalence is 6 then PV 28
Patwardhan et al. (2004) Alzheimer disease
Operating Characteristics of PET A
Meta-analysis. Radiology 231 73-80
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Biomarkers in MCI
de Leon et al. Journal of Internal Medicine
(2004) 256 205-223
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CSF Biomarkers MCI ? AD
Hansson et al. (2006) Lancet Neurology 5
228-234 N 137 MCI patients followed for 4-6
years 42 developed AD 15 other dementia 41
cognitively stable
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CSF Biomarkers MCI ? AD
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CSF Biomarkers MCI ? AD
CSF Total tau Aß MCI ? AD Sensitivity
95 Specificity 83 PPV 81 NPV 96
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What about neuropsychiatric symptoms?
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Neuropsychiatric Symptoms

• Approximately 90 of people with AD develop
  behavioural or psychological symptoms at some
  stage
• But only 50 of people with AD develop highly
  disruptive behaviour that leads commonly to
  nursing home placement

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Neuropsychiatric SymptomsPrevalence in Cache
County Study
Lyketsos et al. (2001) IJGP 161043-1053
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Neuropsychiatric SymptomsPrevalence in Cache
County Study
Lyketsos et al. (2001) IJGP 161043-1053
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Predictors of Behavioural Symptoms Multiple
Regression
t p

• Neuroticism 4.10 0.000
• Age 1.72 0.095
• Gender 0.70 0.486
• MMSE 0.76 0.452
• Dementia duration 0.16 0.874
• Age at onset -2.31 0.027
• P/H mental disorder 0.65 0.520

F(7,35) 6.09, p 0.0001
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Beta 0.4877, F(1,45) 14.04, p 0.0005
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Cholinesterase Inhibitor Drugs

• Donepezil (Aricept) once daily
• Rivastigmine (Exelon) twice daily
• Galantamine (Reminyl) once daily

All are modestly effective there are no
independent head to head studies comparing
efficacy
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Memantine (Ebixa)

• Memantine (Ebixa)10mg twice daily
• Memantine can be added to donepezil, rivastigmine
  galantamine
• Not on the PBS (170 per month)

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Depression in DementiaRCT Sertraline vs Placebo
(CSDD)
N 44 MDE AD MMSE 17.5 (S) 16.3 (P) Mean
max. S dose 108mg/day Any Response NNT 3 Full
Response NNT 6
F(1,41) 10.9, p 0.002 ES 0.68
Lyketsos et al. (2003) Arch Gen Psychiatry 60
737-746
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RCT Risperidone vs Placbo
N 345 dementia patients MMSE 5.14 (R), 5.78
(P) Mean R dose 0.95mg/day
p lt 0.01 vs. placebo


Brodaty et al. (2003), J Clin Psychiatry 64
134-143
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Agitated Aggressive Behaviour
N 345 dementia patients MMSE 5.14 (R), 5.78
(P) Mean Risperidone dose 0.95mg/day
p lt 0.01 vs. placebo



Brodaty et al. (2003), J Clin Psychiatry 64
134-143
87
Summary 1

• Await further news on vaccination (quite
  promising but early days)
• Vitamins do not prevent dementia
• Oestrogen does not prevent dementia in older
  women (and may actually cause it!)

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Summary 2

• Regular physical exercise may help prevent
  dementia
• Better social networks may modify the effects of
  AD on cognition
• Regular cognitive activities are associated with
  reduced risk of dementia

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Summary 3

• Brain size (hippocampus) predicts further
  cognitive decline
• Biomarkers in cerebrospinal fluid predict
  dementia
• Pre-morbid personality predicts behavioural and
  psychological symptoms in dementia

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• gerard.byrne_at_uq.edu.au