Preventing Alzheimer Disease

1
Preventing Alzheimer Disease
2
Risks

• Advanced Age
• Half of those gt85 1/10 of those gt65
• Female Sex
• Mild Cognitive Impairment
• APOE4
• Family History
• Low Education
• ?Race
• ?Homocysteine?

3
Life Expectancy 1992
4
Future Burden

• 2011 first baby boomers turn 65
• 18 of population by 2025
• 85 now 4 million, 8.5 million by 2030
• 50 of Alz pts are at home, 50 in care

5
Ongoing Studies From May 16, 2002 ELEENA DE
LISSER, The Wall Street Journal
PATHWAYS TO PREVENTION?
Ongoing clinical trials related to
Alzheimeraposs disease and possible modes of
prevention
6
Strategies

• Vitamin E and Selegeline or donepezil
• Estrogens
• NSAIDs
• B12,B6,Folate (homocysteine)
• Statins
• Valproate ?Neuroprotective
• IPA (Indole-3-Propionic Acid) anti-oxidant

7
Estrogen

• 2/3 of Alzheimer Patients are women
• Onset After Menopause
• May increase cholinergic transmission
• Neurotrophic effects
• Anti-amyloidogenic properties
• Association with Neurotrophins
• Regulates synapse formation in hippocampus

8
Estrogen

• 3 studies in Neurology 200054 show no effect in
  women already Diagnosed
• Baltimore Long. Study After adjusting for
  education, the relative risk for AD in ERT users
  as compared with nonusers was 0.46
• Tang MX et al. Effect of oestrogen during
  menopause on risk and age at onset of Alzheimer's
  disease. Lancet 1996348429-432
• Jury Still Out
• Prospective treatment trials

9
Estrogen Reviews

• NEJM 3441242-1244 April 19, 2001 Number 16
  Richard Mayeux
• Neurology 2000542035-2037 Marder and Sano

10
Homocysteine

• Eight years
• RR 1.4 for each increase of 1 SD in the
  log-transformed homocysteine value either at base
  line or eight years earlier
• RR of Alzheimer's disease was 1.8 per increase of
  1 SD at base line
• RR1.6 per increase of 1 SD eight years before
  base line.
• Plasma homocysteine level greater than 14 µmol
  per liter doubled the risk of Alzheimer's
  disease.
• Seshadri et al. N Engl J Med 346476-483 February
  14, 2002

11
Homocysteine

• Does this mean that lowering H. levels will
  prevent As Disease?
• No one knows

12
Homocysteine

• 50 Mg pyridoxine
• Up to 4 mg. of Folate
• 500 mcg of B12

13
NSAIDs

• Inflammation is part of Aß Accumulation
• Longitudinal Studies show dose related effect of
  NSAIDs
• Nature Nov. 8, 2001 NSAIDs directly decrease
  deposition of Aß42
• ASA,Celebrex, Naprosyn no effect
• Others at very high doses decreased production in
  cells up to 80

14
NSAIDs

• Prospective, population-based cohort study of
  6989 subjects 55 years of age or older who were
  free of dementia at base line.
• Relative risk of Alzheimer's disease was 0.95 in
  subjects with short-term use of NSAIDs
• RR 0.83 with intermediate-term use
• RR 0.20 wit long-term use.
• Risk did not vary according to age
• Use of NSAIDs was not associated with a reduction
  in the risk of vascular dementia.
• Bas A. in 't Veld, N Engl J Med 2001
  3451515-1521, Nov 22, 2001

15
Baltimore Longitudinal Study of Aging

• Relative risk of Alzheimer's disease of 0.50
  among regular users of NSAIDs, as compared with
  nonusers
• Stewart et al Neurology 199748626-632

16
Selegiline and Vitamin E

• 2000 Units of Vitamin E and 10 mg. Selegiline
• S. -4 month delay in disease progression e.g. to
  NH placement
• E. 6 month delay in Disease progression
• No difference on cognitive scores
• Combined treatment did slightly worse than either
  treatment alone
• Sano et al. N Engl J Med 19973361216-1222

17
Gingko Biloba

• 1 year
• 120 mg.
• 2.4 decrease in Alzheimers disease Assessment
  scale Cognitive subscale
• Very little other evidence
• Le Bars PL et al.JAMA 19972781327-1332

18
(No Transcript)
19
Cholinergic Hypothesis

• Diffusely projecting area Nucleus Basalis of
  Meynert
• Layers I and II major cholinergic cortical
  innervation
• Amygdala and hippocampus lgest innervation

20
Acetylcholine

• Correlation with Dementia and markers of ACh
  metabolism
• CAT choline acetyl transferase
• AChE acetylcholinesterase (breaks down ACh)

21
Alzheimer Manifestations
Activity of Daily Living
Behavior
Cognitive Dysfunction
All aided by Anti-esterases
22
Anti-esterases
23
Cholinesterase Blockers
24
Acetylcholine

• Formation ChAT and Acetyl-CoA
• Degradation AchE and Butyryl-cholinesterase

25
Butyrylcholinesterase

• Role is minor in normal brain
• Proportionate activity increases in Alzheimer
  brain

26
AChE inhibitors Progression?

• Patients on AChE inhibitors had a slower rate of
  progression than placebo treated patients
• Raises the issue of possible biological effect of
  these agents to slow progression of disease

27
Galantamine (Reminyl)

• Start at 4 mg BID (8 mg/day) for at least 4
  weeks, then 8 mg bid Available in 4 mg, 8 mg, and
  12 mg tablets Most frequent adverse events that
  occurred with placebo, REMINYL 16 mg/day, and
  REMINYL 24 mg/day, respectively, were nausea (5,
  13, 17), vomiting (1, 6, 10), diarrhea (6,
  12, 6), anorexia (3, 7, 9), and weight
  decrease (1, 5, 5).

28
Reminyl

• Average approx. 4 pts on ADAS-Cog Scores

29
Galantamine

• Common snowdrop (Galanthus nivalis)
• Binds AChE
• Modulator of Nicotinic Receptors
• ?Enhanced Sexual Fxn
• Mythology
• Iliad, Circe, Atropine, Jimsonweed

30
Rivastigmine

• Exelon Approved in April 2000 for treatment of
  mild to moderate Alzheimer's disease.
• Benefits Improved activities of daily living,
  including eating, dressing, and household
  chores.  Reduce behavioral symptoms, such as
  delusions and agitation. Improved cognitive
  function Reduced use of psychotropic medications

31
Rivastigmine

• Shown to improve Global function, behavior, and
  Cognition

32
Rivastigmine

• Temporarily inactivates Cholinesterase by forming
  a Covalent Bond
• 3 mg bid decreases AChE in CSF by 46
• 6mg bid decreases AChE by 62
• Duration of signif inhibition lasts up to 6 hours.

33
Alzheimer Scales

• CIBIC-Plus 1-7
• Clinicians interview-based impression of change
  with caregiver input
• 1marked improvement, 4nc, 7marked worsening
• ADAS-Cog0-70
• Higher scoresgreater cognitive impairment
• Mild to moderate15-25
• 6-12 points/yr average deterioration

34
Rivastigmine GI Effects

• 18 Men, 26 Women at Max dose

35
ADAS-Cog Effects
36
Rivastigmine

• Dose titrate dosage to achieve optimal effect.
  Usual dose 6 to 12 mg/day given BID. Start 1.5
  mg bid, increase by 3 mg every 2 weeks. 
  Available in capsule doses of 1.5, 3, 4.5, 6 mg.
• Half life 2 hours Few interactions with other
  drugs Side effects No hepatotoxicity GI
  disturbances, occur mainly during dose
  adjustment. 

37
(No Transcript)
38
Aricept (donepezil)

• Indicated for mild to moderate Alzheimer's
  dementia
• More selective for acetylcholinesterase, the
  cholinesterase common in the brain, believed to
  account for the low incidence of GI side effects
• 5 mg qd for 4 to 6 wk, if tolerate increase to 10
  mg qd

39
Aricept

• Pharmacology  Half life 72-hour Steady states
  are achieved in 15 days. 94 protein-bound
  metabolized by the hepatic P450 enzyme system,
  but few drug interactions have been identified.
  Adverse effect  nausea, vomiting,
  gastrointestinal cramping, diarrhea and muscle
  cramping. Does not have hepatoxicity.

40
Upshot

• Many of the same protagonists as in
  Atherosclerois (stroke)
• B vitamins, vitamin E, NSAIDs, Ginkgo,
  Cholinesterase blockers.

41
Treat the High risk patient

• Anyone over a certain age?
• Cocktail