APOE Genotype Effects on Alzheimer

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APOE Genotype Effects on Alzheimers Disease
Clinical Onset, Epidemiology, and Gompertzian
Aging Functions

• J.Wesson Ashford, M.D., Ph.D.
• Stanford / VA Alzheimer Center
• Palo Alto, CA
• New York Academy of Sciences
• May 29-30, 2003
• (several slides removed to save space, see other
  lectures)

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Diagnostic Criteria For Dementia Of The
Alzheimer Type (DSM-IV, APA, 1994)

• Multiple Cognitive Deficits
• 1. Memory Impairment
• 2. Other Cognitive Impairment
• B. Deficits Impair Social/Occupational
• Course Shows Gradual Onset And Decline
• Deficits Are Not Due to
• 1. Other CNS Conditions
• 2. Substance Induced Conditions
• E. Do Not Occur Exclusively during Delirium
• F. Not Due to Another Psychiatric Disorder

3
Estimating Age of Onset

• Clinical history
• Asking family members
• (considerable consistency, unclear validity)
• Review of old medical records
• Estimation of dementia severity
• Time-index back calculation to onset
• Functional brain scan severity analysis
• Back calculation to onset

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Assessment

• History Of The Development Of The Dementia
• Ask the Patient What Problem Has Brought Him to
  See You
• Ask the Family, Companion about the Problem
  (necessary)
• Specifically Ask about Memory Problems
• Ask about the First Symptoms
• Enquire about Time of Onset
• Ask about Any Unusual Events Around the Time of
  Onset, e.g., stress, trauma, surgery
• Ask about Nature and Rate of Progression
• Ask about the current level of difficulties
• Review of old medical records
• Psychological Exam (MMSE)
• SPECT scan (ECD)

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Relation of SPECT severity to duration of
dementia (years)Shih et al., 2000
SPECT severity SPECT grade Dementia Duration
Normal 0 0
Near-Normal 1 1
Mild 2 2
Mild-moderate 3 3
Moderate 4 4
Moderate-severe 5 5
Severe 6 6
Severe-profound 7 7
Profound 8 8
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Factors Influencing Variation in Age of Onset

• Genetics (especially APOE), family history
• Neurological factors
• Stroke
• Brain injury
• Medical factors
• Vascular disease
• Medications NSAIDS, statins, female HRT
• Education
• Gender
• Ageism (more concern for younger individuals)

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Problem of Pre-Alzheimer Condition

• Mild Cognitive Impairment (MCI) may
• early Alzheimers disease
• MCI
• Memory complaint
• Objective memory assessment showing dysfunction
• No impairment in daily living skills
• If memory impairment is not present, one other
  cognitive domain shows dysfunction

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Presymptomatic AD?

• 12 of normal elderly meet NIA-RI criteria for
  AD. These individuals show memory declines 3
  years before death -- Schmitt, et al., 2000,
  Neurology
• 60 of cases with questionable dementia
  (CDR0.5) progress to clinical AD over a three
  year interval.
• -- Morris et al., 2001, Archives of
  Neurology
• MCI appears to be early AD

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PREVALENCE

• Estimated 4 million cases in US (2000)
• (2000 - 46 million individuals over 60 y/o)
• Age is the main factor associated with AD
• Increase with age (prevalence)
• 1 of 60 - 65 (10.7m) 107,000
• 2 of 65 - 70 ( 9.4m) 188,000
• 4 of 70 - 75 ( 8.7m) 350,000
• 8 of 75 - 80 ( 7.4m) 595,000
• 16 of 80 - 85 ( 5.0m) 800,000

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Yesavage et al., 2002
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RELATIVE RISK FACTORS FOR ALZHEIMERS DISEASE

• Family history of dementia 3.5 (2.6 - 4.6)
• Family history - Downs 2.7 (1.2 - 5.7)
• Family history - Parkinsons 2.4 (1.0 - 5.8)
• Maternal age gt 40 years 1.7 (1.0 - 2.9)
• Head trauma (with LOC) 1.8 (1.3 - 2.7)
• History of depression 1.8 (1.3 - 2.7)
• History of hypothyroidism 2.3 (1.0 - 5.4)
• History of severe headache 0.7 (0.5 - 1.0)

Roca, 1994
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ETIOLOGY - considerations (AD is a disease of
cerebral memory mechanismsAshford Jarvik,
1985)

• GENETICS
• APO-E (19) e4 accounts for 50 cases
• IDE? (10), APP (21), PS (14,1)
• EDUCATION (? design vs protection)
• MEDICAL STRESSES
• cerebrovascular disease, surgery
• ENVIRONMENTAL STRESSORS
• trauma, loss, ?aluminum, ? viruses
• ENVIRONMENTAL FACTORS
• diet, exercise, smoking (? nicotine)

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Genes and Alzheimers disease(60 - 80 of
causation)(all known genes relate to bamyloid)

• Familial AD (onset lt 60 y/o) (lt5)
• Presenilin I, II (ch 14, 1)
• APP (ch 21)
• Non-familial (late onset)
• APOE
• Clinical studies suggest 40 50 due to e4
• Population studies suggest 10 20 cause
• Evolution over last 300,000 to 200,000 years
• At least 20 other genes

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APO-E genotype and AD risk46 Million in US gt 60
y/o //// 4 Million have AD(data from Saunders et
al., 1993 Farrer et al., 1997)
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Study Patients (n 54)
APOE genotype Possible AD Probable AD Definite AD Dementia NOS
e2/3 2 1
e2/4 1
e3/3 10 5 5
e3/4 7 7 3 3
e4/4 4 1 3 2
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Age at Onset (Hx, MMSE, SPECT)age of onset for
e3/3 vs e4/4, plt0.02 for e3/3 vs e3/4,
plt0.05(Ashford, Kindy, Shih, Aleem, Cobb,
Tsanatos, Cool)
APOE genotype Number Mean age of onset (years) Standard deviation (years
e3/3 20 73.6 4.7
e3/4 20 69.5 6.7
e4/4 10 68.3 5.6
MALE VETERANS - Memory Disorders Clinic n50
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APO-E genotype and AD onset

• e2 -- 7 of the population
• e3 -- 78 of the population (54 - 91)
• (Pygmies - Sardinians)
• e4 -- 15 of the population (5 - 41)
• (Mayans - Pygmies)
• (Fullerton et al., 2000)
• e3/3 - average age of onset 74 y/o
• e3/4 and e4/4 average age 69 y/o

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APOE AND EVOLUTION

• DOES APOE- e2 or e3 DO A SAFER JOB OF
  SUPPORTING THE REMODELLING OF DENDRITES, TO
  MINIMIZE THE STRESS ON THE NEURON OVER
  TIME?
• DEMENTED ELDERLY CAN NOT FOSTER THEIR YOUNG
  OR COMPETE
• APOE AS AN AGENT TO SUPPORT SUCCESSFUL
  AGING IN GRANDMOTHERS
• APOE AS AN AGENT TO SUPPORT THE DOMINANCE
  OF ELDERLY MALES

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APOE AND CHOLESTEROL

• CHOLESTEROL METABOLISM IS A CENTRAL PART OF
  SYNAPTIC PLASTICITY (Koudinov Koudinov, 2001)

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BIOPSYCHOSOCIAL SYSTEMS AFFECTED BY
ADNEUROPLASTIC MECHANISMS AFFECTED AT ALL
LEVELS (Ashford, Mattson, Kumar, 1998)

• SOCIAL SYSTEMS
• INSTRUMENTAL ADLs - EARLY
• BASIC ADLs - LATE
• PSYCHOLOGICAL SYSTEMS
• PRIMARY LOSS OF SHORT-TERM MEMORY
• LEARNING PROCESSES CLASSICAL, OPERANT
• LATER LOSS OF LEARNED SKILLS
• NEURONAL MEMORY SYSTEMS
• CORTICAL GLUTAMATERGIC STORAGE
• SUBCORTICAL
• (acetylcholine, norepinephrine, serotonin)
• CELLULAR PLASTIC PROCESSES
• APP metabolism early, broad cortical
  distribution
• TAU hyperphosphorylation late, focal effect,
  dementia related

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Implications of Genotype for Alzheimer diagnosis

• APOE genotype provides major information about an
  individuals risk of developing Alzheimers
  disease!!
• APOE genotype can strengthen or weaken diagnostic
  considerations, particularly in individuals with
  estimated age of onset less than 70 years of age.
• APOE genotype may influence the relevance of
  certain factors for prevention and treatment.

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Are we ready to do genetic testing to predict AD?

• The family members want it
• They consider recommendations against genetic
  testing to be paternalistic
• Family members can make more powerful financial
  decisions based on this knowledge than the
  relevance of insurance companies implementing
  changes in actuarial calculations
• Those at risk can seek more frequent testing
• This is the best opportunity for early
  recognition
• Those at risk will be better advocates for
  research
• Specific preventive treatments can be developed
  for each genetic factor

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CONCLUSION

• Non-familial AD is mainly caused by genetic
  factors.
• APOE-e4 accounts for at least 50 of AD.
• APOE genotype relative to e2 may explain more
  than 95 of AD cases.
• Several other genetic factors account for an
  additional proportion of AD.
• Environmental factors are likely to cause neural
  injury which leads to an unmasking and
  enhancement of AD symptoms, affecting the
  probability of developing and age of onset of AD.

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BLT/Ashford Memory Test(to detect AD onset)

• New test to screen patients for Alzheimers
  disease using the World-Wide Web based testing
• Test only takes 1-minute
• Test can be repeated often (quarterly)
• Any change over time can be detected
• Test is at www.ibaglobal.com/BLT
• For info, see www.medafile.com