Alzheimer's disease

1
Alzheimer's disease

• Beta amyloid protein and the potential for
  anti-oxidants drugs

2

• Approximately 4.5 million people in the U.S. have
  Alzheimers disease (AD). It is the 4th or 5th
  leading cause of death.
• The prevalence is 3 for persons 65-74 years old,
  19 for those 75-84 years old and 47 for those
  over 85 years old.
• The cost of care for patients with Alzheimers
  disease in the U.S. is 83.9 billion annually (in
  1996 dollars) and rising.
• With the aging U.S. population, the number of
  people in the U.S. with Alzheimers disease is
  expected to rise to 9 million by 2040.

3

• Current therapies have extremely limited
  efficacy, with a typical benefit of 6 to 12
  months delay in the progression of symptoms.
• Evidence that oxidative damage occurs in patients
  with mild cognitive impairment (MCI), a precursor
  of Alzheimers, may provide more opportunities
  for an anti-oxidant compound.

4
Pathophysiology of Alzheimers

• In a 2004 review on Alzheimers disease in the
  New England Journal of Medicine, Jeffrey Cummings
  described current knowledge of the
  pathophysiology of Alzheimers (Cummings 2004)

5

• There is increasing consensus that the production
  and accumulation of beta-amyloid (AB) peptide is
  central to the pathogenesis of Alzheimers
  disease.
• Evidence for a pivotal role for AB includes the
  following mutations in the amyloid precursor
  protein lead to early-onset Alzheimers disease
• All currently known mutations associated with
  Alzheimers disease increase the production of AB

6

• In patients with trisomy 21 (Downs syndrome) and
  three copies of the gene for amyloid precursor
  protein, neuropathological characteristics of
  Alzheimers disease develop by midlife AB is
  neurotoxic in vitro and leads to cell death

7

• Overexpression of human amyloid precursor protein
  in transgenic mouse models of Alzheimers disease
  results in neuritic plaques similar to those seen
  in humans with Alzheimers disease

8

• Transgenic mice overexpressing the human amyloid
  precursor protein have evidence of learning and
  memory deficits, in concert with the accumulation
  of amyloid the apolipoprotein E4 genotype, a
  major risk factor for Alzheimers disease, leads
  to accelerated deposition of amyloid and the
  generation of antiamyloid antibodies in humans
  with Alzheimers disease seems to ameliorate the
  disease process.

9

• Formation of neurofibrillary tangles, oxidation
  and lipid peroxidation, glutamatergic
  excitotoxicity, inflammation, and activation of
  the cascade of apoptotic cell death are
  considered secondary consequences of the
  generation and deposition of AB.
• This hypothesized amyloid cascade underlies
  attempts to modify the onset and course of
  Alzheimers disease through identification of
  antiamyloid agents, antioxidants, and other drugs

10

• Alternate hypotheses regarding the
  pathophysiology of Alzheimers disease place
  greater emphasis on the potential role of
  tau-protein abnormalities, heavy metals, vascular
  factors, or viral infections.

11

• There are many studies of the role of oxidative
  stress in Alzheimers disease and more
  specifically the activity of AB in production of
  reactive oxygen species (ROS).
• Evidence supporting the role of AB and oxidative
  stress in Alzheimers disease includes the
  following.

12

• Amyloid beta generates free radicals
• The Met35 amino acid residue of AB is responsible
  for free radical production

13
Researchers have found a variety of oxidative
damage in AD brains

• increased lipid peroxidation and decreased
  polyunsaturated fatty acids in the AD brain, and
  increased 4-hydroxynonenal, an aldehyde product
  of lipid peroxidation in AD ventricular fluid
• increased protein and DNA oxidation in the AD
  brain diminished energy metabolism and decreased
  cytochrome c oxidase in the brain in AD
• advanced glycation end products (AGE),
  malondialdehyde, carbonyls, peroxynitrite, heme
  oxygenase-1 and SOD

14

• Oxidative damage appears to be one of the
  earliest pathophysiological events in Alzheimers
  preceding the formation of amyloid plaques and
  neurofibrillary tangles.
• Plasma levels of most antioxidants are lower in
  patients with Alzheimers and Mild Cognitive
  Impairment (MCI) compared to healthy age-matched
  controls.

15

• Transgenic mice expressing AB reproduce the
  clinical symptoms and pathological progression of
  AD including oxidative stress.
• In beta-amyloid transgenic mice, memory
  impairment is correlated with increased levels of
  beta amyloid
• Active and passive beta-amyloid-directed
  immunization removes beta-amyloid plaques and
  restores memory.

16

• In transgenic mice expressing both AB and
  presenilin 1, gene expression profiles using
  microarrays and Q-PCR showed reduced expression
  of genes required for long-term potentiation and
  memory formation.
• In studies of cortical tissue AD patients, the
  same memory-associated genes are down-regulated.

17

• Numerous studies have shown that free radicals
  cause neuron degeneration and death in vitro and
  in vivo, while anti-oxidants have been shown to
  protect against neurodegeneration and have shown
  efficacy in clinical trials for treating
  Alzheimers disease and in epidemiologic studies
  for reducing the risk of Alzheimers disease

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not proven that AB or ROS directly cause
Alzheimers disease.

• Because tissue injury itself can induce reactive
  oxygen species (ROS) generation, it is not known
  whether this is a primary or secondary event in
  Alzheimers disease. Even if free radical
  generation is secondary to other initiating
  causes, they are deleterious and part of a
  cascade of events that can lead to neuron death,
  suggesting that therapeutic efforts aimed at
  removal of ROS or prevention of their formation
  may be beneficial in AD (Markesbery 1997).

19

• Many but not all anti-oxidants have been shown to
  cross the blood-brain barrier and to have
  neuroprotective effects in vitro and/or in vivo
  in humans or in animal models.
• The major limitations of these anti-oxidants
  appear to be their relatively short half-life in
  vivo (ALA), their (possibly) relatively low
  bioavailability at the sites of free-radical
  production (Vitamins C and E) and the lack of
  patent protection.

20
Alzheimers drug development

• Many pharmaceutical companies are pursuing new
  treatments for Alzheimers, with a wide variety
  of targets, including AB and anti-oxidants.
• In a 2004 NEJM review, Cummings describes current
  research on treatments of Alzheimers

21
Antiamyloid therapies

• No antiamyloid therapies are currently available.
  
• The enzymes responsible for liberating AB, a
  toxic fragment of 42 amino acids, from the
  amyloid precursor protein are b and g secretases.
  Inhibitors of these enzymes are under active
  study.
• The metabolism of cholesterol is intimately
  involved in the generation of AB, and preliminary
  evidence suggests that statins may be beneficial
  in reducing the accumulation of AB.

22
Neuroprotective approaches

• AB protein seems to exert its neurotoxic effects
  through a variety of secondary mechanisms,
  including oxidative injury and lipid peroxidation
  of cell membranes, inflammation,
  hyperphosphorylation of tau protein, and
  increased glutamatergic excitotoxicity.
• Neuroprotective strategies have targeted these
  mechanisms in an effort to reduce the cell injury
  associated with the generation and aggregation of
  AB.

23
Antioxidants

• The principal antioxidant strategy has involved
  treatment with alpha-tocopherol (vitamin E).
• A randomized, placebo-controlled trial compared
  the effect of vitamin E, selegiline, the two
  drugs together, and placebo in patients with
  Alzheimers disease.

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• When the severity of cognitive decline at
  baseline was included as a covariate, a
  significant delay in the primary outcomes (time
  to death, placement in a nursing home,
  development of severe dementia, or a defined
  severity of impairment of activities of daily
  living) was observed for patients in the
  selegiline, alpha-tocopherol, and
  combination-therapy groups, as compared with the
  placebo group.

25

• The increase in median time to one of the primary
  outcomes, as compared with the time in patients
  receiving placebo, was 230 days for patients
  receiving alpha-tocopherol, 215 days for those
  treated with selegiline, and 145 days for those
  receiving both agents.
• No differences in cognitive function were evident
  among the four groups.

26

• On the basis of this study, many practitioners
  have added high-dose vitamin E supplements (2000
  IU daily) to their standard treatment regimen for
  Alzheimers disease.

27
Rutten review of antioxidant clinical trials in
Alzheimers disease

• Recent prospective studies have indicated that
  dietary intake of several exogenous antioxidants
  is associated with a lower risk for Alzheimer's
  disease.
• This suggests that people at risk for developing
  Alzheimer's disease or being in the early phases
  of this disease may benefit from intervention
  with exogenous antioxidants.
• The clinical studies carried out so far, however,
  do not provide the final answer to whether
  antioxidants are truly protective against
  Alzheimer's disease

28

• There is compelling evidence that oxidative
  stress is involved in Alzheimer's disease
  pathogenesis, and several lines of evidence
  indicate that administration of antioxidants may
  be useful in prevention and treatment of
  Alzheimer's disease.
• Further clinical studies, based on larger cohorts
  studied over a longer period of time, are needed,
  however, to test this hypothesis.
• Furthermore, for the future one might expect
  balanced upregulation of both exogenous and
  endogenous antioxidants as one of the best
  treatment strategies for preventing or at least
  slowing down the progression of Alzheimer's
  disease.