Transcript Alzheimer disease - GEC-KO

Alzheimer disease
Developed by Dr. June Carroll, Ms. Shawna Morrison and Dr. Judith Allanson
Last updated April 2015
Disclaimer
• This presentation is for educational purposes only and should
not be used as a substitute for clinical judgement. GEC-KO
aims to aid the practicing clinician by providing informed
opinions regarding genetic services that have been developed
in a rigorous and evidence-based manner. Physicians must use
their own clinical judgement in addition to published articles
and the information presented herein. GEC-KO assumes no
responsibility or liability resulting from the use of information
contained herein.
Objectives
• Following this session the learner will be able to:
– Refer to their local genetics centre and/or order genetic
testing appropriately for Alzheimer disease (AD)
– Discuss and address patient concerns regarding AD
– Find high quality genomics educational resources
appropriate for primary care
Case 1
d.85
Stroke
d.68
AD
dx 55
63
d.65
AD
dx 57
60
58
AD
A&W AD
dx 61
dx53
25
A&W
55
A&W
• Mary, 25yo female in
good health
• Concerned about her
risk of Alzheimer
disease (AD) as her
father’s condition is
worsening quickly
Case 2
d.85
d.87
MI
90
arthritis
88
86
80
75
AD IDDM
dx 80
55
A&W
• Mandy, 55yo female in
good health
• Concerned about her risk
of Alzheimer disease due
to her father’s recent
diagnosis
Case 3
d.85
d.87
AD
dx78
90
d.88
AD
dx83
86
80
75
AD
dx 80
IDDM
55
A&W
• Morgan, 55yo female in
good health
• Concerned about her risk
of Alzheimer disease due
to her father’s recent
diagnosis and family
history
What is Alzheimer disease?
• Alzheimer disease (AD) is an adult-onset progressive
dementia that gradually reduces a person’s memory and
ability to learn, reason, make judgments, communicate and
carry out daily activities. Individuals may also experience
changes in personality and behaviour
• General population lifetime risk of developing dementia is 1012%
Sporadic, late onset, unknown cause
Late-onset familial AD (LOAD)
has a mean age of onset of >60-65
years (15-25%)
Early-onset familial AD (EOAD) has
a mean age of onset < 60-65 years
(<2%)
What do I need to know about the genetics
of Alzheimer disease?
• Early-onset AD (EOAD) has an autosomal dominant
inheritance pattern
• Three genes have been associated with EOAD:
– amyloid precursor protein (APP)
– presenilin 1 (PSEN1)
– presenilin 2 (PSEN2)
• Each of these genes is involved in production of the
amyloid ß (Aß) peptide, a major component of
amyloid plaques
What do I need to know about the genetics
of Alzheimer disease?
• Late-onset familial AD (LOAD) has been associated
with apolipoprotein E (APOE)
• APOE is considered a risk modifier, especially APOE
4
• Approximately 1% of the general population are
APOE 4 homozygotes (carry two copies of 4)
• Approximately 42% of persons with AD do NOT have
an APOE 4 allele
• APOE 4 is neither necessary nor sufficient to cause
LOAD
What do I need to know about the genetics
of Alzheimer disease?
• Alzheimer disease (AD) develops due to a
complex interaction between genetic and
environmental factors
• With one affected first-degree relative, the risk
of Alzheimer disease is approximately 20-25%
(approximately double the population risk)
Who should be offered referral for genetic
consultation?
Consider a genetics consult for:
Patients with Alzheimer disease (AD) with onset
<60-65 years
Patients with late-onset AD and multiple affected
close relatives
Close relatives of the above two types of patients
A member of a family in which there is an
identified mutation in the APP, PSEN1 or PSEN2
genes
Who will be offered genetic testing and
what do the test results mean?
• Genetic testing for Alzheimer disease (AD) is only
available for a small number of families with earlyonset AD (EOAD)
– Testing likely to be initiated in a living affected
relative
• If a gene mutation is found, other family members
are eligible for testing focused on the identified
family mutation
– Inheriting a mutation in APP, PSEN1 or PSEN2
gene causes early-onset Alzheimer disease (EOAD)
Who will be offered genetic testing and
what do the test results mean?
• Clinical testing is currently not available for lateonset AD (LOAD) or sporadic cases
• When there are multiple related affected individuals,
research testing may be available
• APOE 4 testing is not recommended for risk
assessment because of low sensitivity and specificity
• APOE 4 is neither necessary nor sufficient for the
disease
How will genetic testing help you and your patient?
• In the case of genetic testing for early-onset
Alzheimer disease (EOAD),
– A positive test result for a known family gene mutation
can result in:
• Relief from uncertainty
• An increased feeling of control
• Opportunity to plan life decisions
– A negative test result for a known family gene mutation
can result in:
• Relief from fear of developing EOAD
• Knowledge that children are not at risk for EOAD
Are there harms or limitations of genetic testing?
• Currently no cure or effective preventive therapy is
available if a gene mutation is found
• In the case of genetic testing for early-onset
Alzheimer disease (EOAD),
– A positive test result for a known family gene mutation
can result in:
• Adverse psychological reaction, family issues/distress
• Insurance/job discrimination, confidentiality issues
– A negative test result for a known family gene mutation
can result in survivor guilt
Case 1
d.85
Stroke
d.68
AD
dx 55
63
d.65
AD
dx 57
60
58
AD
A&W AD
dx 61
dx53
25
A&W
55
A&W
Case 1
d.85
Stroke
d.68
AD
dx 55
63
d.65
AD
dx 57
60
58
AD
A&W AD
dx 61
dx53
25
A&W
55
A&W
• Family history is
suggestive of early-onset
AD (EOAD – dx<60-65y)
and dominant inheritance
pattern
• Offer referral for genetics
consultation with option
of genetic testing
Case 2
d.85
d.87
MI
90
arthritis
88
86
80
75
AD IDDM
dx 80
55
A&W
Case 2
d.85
d.87
MI
90
arthritis
88
86
80
75
AD IDDM
dx 80
55
A&W
• Family history is
suggestive of sporadic AD
• Mandy’s AD risk is about
20-25% because of an
affected FDR
• No referral to genetics
indicated
Case 3
d.85
d.87
AD
dx78
90
d.88
AD
dx83
86
80
75
AD
dx 80
IDDM
55
A&W
Case 3
d.85
d.87
AD
dx78
90
d.88
AD
dx83
86
80
75
AD
dx 80
IDDM
55
A&W
• Family history suggestive
of late-onset AD (LOAD)
• Referral to genetics can be
considered for counselling
and personal risk
estimation
• No genetic testing is
available but participation
in research may be
possible
Pearls
• Informative genetic testing is currently available to
only a small number of families with early-onset (<6065 years of age) Alzheimer disease (EOAD)
• Genetic testing is not possible for most cases of AD
• Apolipoprotein E gene variations alone cannot be
used to predict risk of developing AD
References
• Alonso Vilatela ME et al., Genetics of Alzheimer’s disease. Arch Med Res.
2012; 43(8): 622-31 and Goldman JS et al., Genetic counseling and testing
for Alzheimer disease: Joint practice guidelines of the American College of
Medical Genetics and the National Society of Genetic Counselors. Genet
Med 2011; 13(6): 597-605
• American College of Medical Genetics/American Society of Human
Genetics Working Group on APOE and Alzheimer's disease (1995)
Statement on use of apolipoprotein E testing for Alzheimer's disease.
JAMA 1995; 274(20): 1627-1629
• Bird TD. Alzheimer Disease Overview. 1998 Oct 23 [Updated 2014 Jan 30].
In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews™ [Internet].
Seattle (WA): University of Washington, Seattle; 1993-2014. Available
from: http://www.ncbi.nlm.nih.gov/books/NBK1161/
• Genetics Education Project