Alzheimers Disease

1
Alzheimers Disease
2
Neuropathology

• Cellular level
• Amyloid plaques in intercellular space
• Neurofibrillary tangles in intracellular space
• Structural level
• Early changes nucleus basalis (basal
  forebrain), hippocampus, related structures (e.g.
  amygdala)
• Later changes Frontal, temporal and parietal
  lobes

3
Subtypes

• Early onset subtype
• Begins before age 65, usually in 50s
• Probable genetic factors
• Associated cerebral atrophy (75 of cases)
• Less visuospatial impairment, more language
  impairment than in later onset AD
• More associated with parietal lobe dyfunction and
  syndrome
• More rapid progression--at 5 years
• Mortality 24
• Nursing home admission 63

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Epidemiology

• Overall rates
• 5-7 of people over age 65
• 20 of people over age 80
• Rates higher in areas with concentrations of
  older adults (e.g. Southern California)
• Wide variation in published rates due to
  methodology

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Epidemiology (cont.)

• Largest source of dementia cases
• 50-60 vs. 16 for MID in US, W Europe
• 41 vs 45 for MID in Japan
• Associated with increased mortality in late stage
  dementia

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Risk Factors

• Poor education
• Especially grade school level or less
• Not clear whether this is a correlation or actual
  protective factor
• Head trauma
• Myocardial infarction (possible)

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Risk Factors (cont.)

• Genetics
• 75 have no clear family history of AD
• 5-10 of cases are familial in some way
• 1-2 inherit in autosomal dominant fashion, this
  termed Familial Alzheimers Disease
• FAD associated with mutation of genes that
  produce amyloid precursor protein
• 50 of FAD related to chromosome 14
• Also links to chromosomes 21, 1
• Associated with earlier age of onset, mostly in
  age range 40-60

8
Risk Factors (cont.)

• Presence of ?4 version of apolipoprotein E (Apo
  E) gene
• Found on long arm of chromosome 19
• Mediates uptake of lipid particles
• May affect development, maintenance and repair of
  myelin and neuronal membranes
• Related to deposits of ?-amyloid in AD and
  nondemented elderly

9
Risk Factors (cont.)

• Possibly more common in women
• Varies by geographic region and race
• US whites 13
• US blacks 19- 26
• US latinos 11
• China, Japan 7-8
• Sweden, Finland 20-23

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Risk Factors (cont.)

• Effects of Apo E subtype
• 60-70 will not develop AD
• Has greatest effect on people in their 60s
• Increases risk of AD by factor of 8
• Decreases age of onset by up to 12 years

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Protective Factors

• Replacement estrogen
• Decreases risk by factor of 2
• Estrogen may improve cognition in women AD
  patients
• Inflammation
• AD less common in people with some inflammatory
  diseases, e.g. rheumatoid arthritis
• Use of non-steroidal anti-inflammatory drugs
  associated with lower rate of AD

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Early Symptoms

• What problems are reported by family and patients
  as the first noticeable symptom?
• Memory problems/disorientation (62)
• Work problems (20)
• Personality changes (19)
• Inability to function (15)

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Problem Symptoms

• What symptoms are reported as most troubling,
  often resulting in institutionalization?
• Memory difficulties (25)
• Catostrophic reactions (25)
• Physical violence (18)
• Accusations (16)
• Suspiciousness (16)
• Incontinence (13)

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Early Stage Cognition

• Problems
• Decreased verbal memory (encoding problems)
• Constructional problems
• Anomia
• Decreased auditory comprehension
• Impaired self-monitoring

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Early Stage Cognition (cont.)

• Strengths
• General activity level
• Following simple commands
• Visuoperception and visual memory
• Body part and color naming
• Continence
• Orientation
• Basic communication ability, especially
  repetition content empty
• Average mathematical abilities
• Partial management of responsibilities

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Biodiagnostics

• Imaging
• PET scans differences not reliable in early
  stages, when diagnosis most critical
• SPECT scans same problem as PET, also more
  subjective interpretation
• CT, MRI scans can help rule out other causes,
  also document relative atrophy in various brain
  areas that may have diagnostic significance

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Biodiagnostics (cont.)

• CSF studies
• CSF tau (main component of tangles) highly
  elevated in many AD patients even in very early
  stages, but many false negatives and not specific
  for AD
• CSF ?-amyloid (main component of plaques)
  reduced in certain forms in some AD patients
  test may prove useful in combination with CSF tau
  test
• Other blood tests to rule out infections,
  metabolic, kidney or liver problems that can
  result in cognitive decline

18
Treatment Medications

• Cholinesterase inhibitors
• Produces mild to moderate impairment in some
  cognitive symptoms
• Examples
• tacrine (Cognex) effects smaller, problems with
  sustainability, toxicity better response in
  women taking estrogen
• donepezil (Aricept) similar to best effects of
  tacrine, with less toxicity and better
  sustainability (1 year or more)

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Treatment Meds (cont.)

• Estrogen
• Mixed evidence about whether it reduces AD
  symptoms or improves performance in normal
  elderly
• Does reduce risk of AD by about 50
• Antioxidants
• Appears to slow progression of AD, assist in
  retention of ability to be independent
• Example Vitamin E

20
Treatment Meds (cont.)

• Antipsychotics
• Used for treatment of psychosis or agitation
• Should be used only if symptoms are problematic
• Low dosages should be used
• Examples
• Thioridazine (Mellaril, dose range 40-800 mg)
• Haloperidol (Haldol, dose range 1-100 mg)
• Respiridone (Risperdal, dose range 4-6 mg)
• Olanzapine (Zyprexa, dose range 5-20 mg)
• Quetiapine (Seroquel, dose range 150-750 mg)

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Treatment Meds (cont.)

• Antidepressants
• SSRI in low doses best, drugs with strong
  anticholinergic side effects may worsen cognition
• Examples
• Fluoxetine (Prozac, normal dose 20-80 mg)
• Sertraline (Zoloft, normal dose 50-200 mg)
• Paroxetine (Paxil, normal dose 20-50 mg)