Post on 10-Jun-2015
Genetics of Alzheimer’s DiseaseDenise Harold
MRC Centre for Neuropsychiatric Genetics & Genomics Cardiff University
The Escalating Problem of Dementia
The Escalating Problem of Dementia
The Escalating Problem of Dementia
Protein Deposits in the Brain
Senile Plaques (β-amyloid)
Neurofibrillary Tangles
Alzheimer’s Disease Process
Tangles and protein deposits
Brain cell loss Brain atrophy, neurotransmitter loss
Symptoms
Genetics and Alzheimer’s Disease
• A family history of Alzheimer’s disease increases a person’s risk of developing the disease themselves
• 2-3 fold increased risk of AD in 1st degree relatives of AD patients
• Although environmental factors play a role, twin studies indicate that 60-80% of disease is due to genetics
Genetic Variation
Genetics and Alzheimer’s Disease
Early-Onset AD (Dominantly Inherited)
Early-Onset AD (Complex
Inheritance)
Late-Onset AD (Complex
Inheritance)
Cause:Inherited Genetic
Mutations
Genetic and Environmental
Risk Factors
Genetic and Environmental
Risk Factors
Age at Onset: Usually 30-60 years <65 years >65 years
Proportion of Cases:
~1% ~4% ~95%
Genetics and Alzheimer’s Disease
Early-Onset AD (Dominantly Inherited)
Early-Onset AD (Complex
Inheritance)
Late-Onset AD (Complex
Inheritance)
Cause:Inherited Genetic
Mutations
Genetic and Environmental
Risk Factors
Genetic and Environmental
Risk Factors
Age at Onset: Usually 30-60 years <65 years >65 years
Proportion of Cases:
~1% ~4% ~95%
Genetics and Alzheimer’s Disease
Early-Onset AD (Dominantly Inherited)
Early-Onset AD (Complex
Inheritance)
Late-Onset AD (Complex
Inheritance)
Cause:Inherited Genetic
Mutations
Genetic and Environmental
Risk Factors
Genetic and Environmental
Risk Factors
Age at Onset: Usually 30-60 years <65 years >65 years
Proportion of Cases:
~1% ~4% ~95%
Genetics and Environmental Factors
Threshold
Liability/Risk
Alzheimer’s disease
Genetics and Alzheimer’s Disease
Early-Onset AD (Dominantly Inherited)
Early-Onset AD (Complex
Inheritance)
Late-Onset AD (Complex
Inheritance)
Cause:Inherited Genetic
Mutations
Genetic and Environmental
Risk Factors
Genetic and Environmental
Risk Factors
Age at Onset: Usually 30-60 years <65 years >65 years
Proportion of Cases:
~1% ~4% ~95%
Dominantly Inherited Early-Onset AD
• Mutations in 3 genes identified: APP, PSEN1 & PSEN2
• If a parent is affected, child has 50:50 chance of inheriting the mutation
• Presence of the mutation directly causes disease
Genetics and Alzheimer’s Disease
Early-Onset AD (Dominantly Inherited)
Early-Onset AD (Complex
Inheritance)
Late-Onset AD (Complex
Inheritance)
Cause:Inherited Genetic
Mutations
Genetic and Environmental
Risk Factors
Genetic and Environmental
Risk Factors
Age at Onset: Usually 30-60 years <65 years >65 years
Proportion of Cases:
~1% ~4% ~95%
Genetic Association Studies
Late-Onset Alzheimer’s Disease
• Candidate gene studies: APOE
• Genome-wide association studies: CLU, PICALM, CR1, BIN1, ABCA7, MS4A, CD2AP, EPHA1, HLA, PTK2B, SORL1, SLC24A4, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, CASS4
• Sequencing studies: TREM2
Late-Onset Alzheimer’s Disease
• Candidate gene studies: APOE
• Genome-wide association studies: CLU, PICALM, CR1, BIN1, ABCA7, MS4A, CD2AP, EPHA1, HLA, PTK2B, SORL1, SLC24A4, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, CASS4
• Sequencing studies: TREM2
Late-Onset Alzheimer’s Disease
• Candidate gene studies: APOE
• Genome-wide association studies: CLU, PICALM, CR1, BIN1, ABCA7, MS4A, CD2AP, EPHA1, HLA, PTK2B, SORL1, SLC24A4, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, CASS4
• Sequencing studies: TREM2
CLU PICALM CR1 BIN1 ABCA7 MS4A CD2AP
EPHA1 HLA PTK2B SORL1 SLC24A4 INPP5D MEF2C NME8 ZCWPW1 CELF1
FERMT2 CASS4
From 2009-2013, Alzheimer’s Research UK helped fund studies that discovered 19 variants in genes linked to an altered risk of Alzheimer’s.
Over half the population may carry these variants, but each one has a small effect on risk. Some of them reduce the risk of Alzheimer’s slightly, whereas others may make a person around 1.2 times more likely to develop the disease.
Around 2% of the population have two copies of APOE4, which could make them more than 10 times more likely to develop the disease.
Genetics and Alzheimer’s Disease
Early-Onset AD (Dominantly Inherited)
Early-Onset AD (Complex
Inheritance)
Late-Onset AD (Complex
Inheritance)
Cause:Inherited Genetic
Mutations
Genetic and Environmental
Risk Factors
Genetic and Environmental
Risk Factors
Age at Onset: Usually 30-60 years <65 years >65 years
Proportion of Cases:
~1% ~4% ~95%
• About 4% of AD cases have an early-onset of symptoms but do not have a dominantly inherited mutation in APP, PSEN1 and PSEN2
• The more extreme phenotype could result from risk variants with a stronger effect than those seen in late-onset AD
• MRC funding to ascertain and sequence EOAD individuals from the UK
• Sample collection and sequencing over the course of the next 3 years
Sequencing in Early-Onset AD (Complex)
CLU PICALM CR1 BIN1 ABCA7 MS4A CD2AP
EPHA1 HLA PTK2B SORL1 SLC24A4 INPP5D MEF2C NME8 ZCWPW1 CELF1
FERMT2 CASS4
From 2009-2013, Alzheimer’s Research UK helped fund studies that discovered 19 variants in genes linked to an altered risk of Alzheimer’s.
Over half the population may carry these variants, but each one has a small effect on risk. Some of them reduce the risk of Alzheimer’s slightly, whereas others may make a person around 1.2 times more likely to develop the disease.
Around 2% of the population have two copies of APOE4, which could make them more than 10 times more likely to develop the disease.
• Diagnosis?
• Identifying disease pathways
• Drug targets
• Gene-environment interactions
Utility of Genetic Findings
• >20 genes influencing Alzheimer’s disease risk identified
• Effects on disease risk are individually subtle but work in aggregate
• Risk genes highlight processes that may be dysfunctional in Alzheimer’s disease
Progress!
Thank you!Thank you to all the patients and their families who have
volunteered to be part of our research
Alzheimer’s Research UK
Alzheimer’s Society
Welsh Government
Medical Research Council
The Wellcome Trust