Genetics of Alzheimer Disease

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Genetics of Alzheimer Disease

• Mohammed Al- Jumah MD,FRCPC
• King Abdulaziz Medical City
• National Guard Health Affairs

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Alzheimer Disease

• Alzheimer disease (AD) is characterized by
  adult-onset slowly progressive dementia
• The diagnosis is based on clinical bases and the
  histological findings in brain tissue of
  ß-amyloid plaques and intraneuronal
  neurofibrillary tangles.
• No accurate clinical diagnostic test for AD
  exists.

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Prevalence

• AD is the most common cause of dementia
• (Larson et al., 1984 Schoenberg et al., 1987)
• The prevalence of dementia in individuals over
  the age of 85 years is estimated to be 25 to 45.
  
• Max 1993 , Ebly et al 1994
• Kukull et al 2002

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Causes of Alzheimer Disease
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Late-Onset Familial Alzheimer Disease Molecular
Genetics I

• Well-documented association of late-onset FAD
  with the APOE e4 allele
• APOE e4, by unknown mechanisms, appears to affect
  age of onset by shifting the onset curve toward
  an earlier age.
• Corder et al 1993 Meyer et al 1998
• Pericak-Vance et al 1997

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Human Apolipoprotein E

• Mature ApoE is a 299-amino acid polypeptide
• (Rall et al. (1982).
  
• Chromosomal locus 19q13.
• There are 3 major isoforms of ApoE (apoE2, -E3,
  and -E4) coded for by 3 alleles.
• The E2, E3 and E4 isoforms differ in amino acid
  sequence at 2 sites
• (Weisgraber et al., 1981 Rall et al., 1982).

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APOE Allele Frequencies in Controls and Patients
with AD
Modified from Jarvik et al (1996)
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Percent of APOE Genotypes
Modified from Jarvik et al (1996)
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ApoE4 allele Alzheimer Disease

• ApoE4 was found to significantly associate with
  sporadic Alzheimer disease
• Poirier et al. 1993, Meyer et al. 1998
• The risk for AD increased from 20 to 90 and mean
  age of onset decreased from 84 to 68 years with
  increasing number of ApoE4 alleles.
• Homozygosity for ApoE4 was virtually sufficient
  to cause AD by age 80 ???
• Corder et al. 1993

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ApoE4 allele Ethnic Groups

• In 3 ethnic groups resedent in New York City,risk
  for AD was associated with ApoE4 homozygosity
  compared to the risk with ApoE3 homozygosity.
• The risk was increased for ApoE4 heterozygous in
  Caucasians and Hispanics, but not for African
  Americans
• Tang et al. 1996

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ApoE4 allele Alzheimer DiseaseEthnic Groups

• In a French group of 132 patients with late onset
  Alzheimer disease, the homozygosity for the E4
  allele was associated with AD onset at a younger
  age
• Lucotte et al. 1994
• In a Japanese study ApoE4 was associated with
  LOAD,the frequency was lower compared to that of
  North American families
• Yoshizawa et al. 1994
• In elderly Nigerians, there was no stronge
  association between E4 and Alzheimer disease
  Osuntokun
  et al. 1995

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ApoE4 allele Alzheimer DiseaseGender Issues

• In late-onset familial AD, women have a
  significantly higher risk of developing the
  disease than do men.
• A significant gender difference for the ApoE4
  heterozygous genotype was observed.
• Comparison of ApoE4 heterozygous men and women
  revealed a significant 2-fold increased risk in
  women.
• Payami et al., 1996

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ApoE4 allele Alzheimer Disease

• In 13 dizygotic twin pairs discordant for
  Alzheimer disease, the frequency of the ApoE4 was
  increased in Alzheimer compared to healthy
  cotwins
• Lannfelt et al. 1995.

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APOE Genotypes Alzheimer Disease

• The risk of AD is lower in subjects with the
  E2/E3 genotype, with an additional 23 of AD
  attributable to the absence of an E2 allele
• (Corder et al. 1994).
• It was suggested that the E2 allele may confer
  protection against Alzheimer disease and that its
  effect is not simply the absence of an E4 allele
• ( Talbot et al. 1994).

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Late-Onset Familial Alzheimer Molecular
Genetics II

• Chromosome 12 may contain a susceptibility gene
  for late-onset AD
• An association of 2 macro-globulin with
  late-onset FAD with both positive and negative
  association studies
• Evidence for linkage of late-onset FAD to markers
  on chromosome 10. No gene has been identified.
• Blacker et al 1998 , Dodel et al 2000Gibson et al
  2000Bertram et al 2000, Ertekin-Taner et al
  2000Myers et al 2000

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Late-Onset Familial Alzheimer Disease Molecular
Genetics
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Late-Onset Familial AD.  

• The association of the APOE allele e4 (i.e.,
  genotypes e2/e4, e3/e4, e4/e4) with late-onset AD
  is well documented
• The usefulness of APOE genotyping in clinical
  diagnosis and risk assessment remains unclear.
• Presence of an APOE e4 allele or alleles is
  neither necessary nor sufficient to establish a
  diagnosis of AD.
• Roses 1995 Saunders et al 1996
• Welsh-Bohmer et al 1997, Mayeux et al 1998
• Green et al 2002Romas et al 2002

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Causes of Alzheimer Disease
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Early-Onset Familial AD.

• Less than 2 of families with AD have early-onset
  familial AD (EOFAD)
• Refers to families in which multiple cases of AD
  occur with the mean age of onset usually before
  age 65
• Age of onset is usually in the 40s or early 50s
• Bird et al 1989. Campion et al (1999)

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Early-Onset Familial Alzheimer Disease (EOFAD)
Molecular Genetics
Campion et al 1999
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APOE Genotypes Alzheimer Disease (EOAD)

• It was also found that the ApoE genotype is a
  risk factor for early-onset AD in families with
  no lesion detectable in the presenilin or APP
  gene
• (Houlden et al. 1998)

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Summary Genetics of AD
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Alzheimer Disease

• Genetic counseling
• First-degree relatives of individuals with
  sporadic AD have about a 20 (approximately
  four-fold )lifetime risk of developing AD.
• When several individuals in a family have AD, the
  risk is further increased.
• EOFAD is inherited in an autosomal dominant
  manner.The risk to offspring of individuals with
  EOFAD is 50.

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Related Genetic Counseling Issues

• Data suggest that a young asymptomatic person
  with the APOE e4/e4 genotype may have an
  approximately 30 lifetime risk of developing AD.
  
• Further refinement of this risk reveals that
  females with an APOE e4/e4 genotype have a 45
  probability of developing AD by age 73 years,
  whereas males have a 25 risk.
• Breitner 1996 Breitner et al 1999

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Risk to Family Members Late-Onset Sporadic
Alzheimer Disease

• Lifetime risk of developing dementia is
  approximately 10-12.
• For Parents, sibs, and offspring of a proband
•  First-degree relatives of a person with AD have
  typically reported as a 20-25 risk .
• While an association exists between AD the APOE
  e4 allele, the APOE genotype is not useful for
  accurate prediction of AD in asymptomatic
  persons.
• Farrer et al 1989 Bird et al (1993)

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Risk to Family MembersEarly-Onset Familial
Alzheimer Disease

• Sibs of a proband
• The risk to sibs depends upon the genetic status
  of the proband's parent.
• EOFAD is inherited in an autosomal dominant
  manner.The risk to offspring of individuals with
  EOFAD is 50.
• Offspring of a proband 
• Individuals with early-onset familial Alzheimer
  disease have a 50 chance of transmitting the
  mutant allele to each child.

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Down Syndrome

• Family members of persons with Down syndrome
  are not at increased risk for AD.

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Local Arabic Experience in Genetic study
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Importance of Genetic Studies

• Possible future disease marker
• Identifying subjects at risk
• Family DNA banking for future studies