Genetics of Alzheimer’s Disease by Denise Harold
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Genetics of Alzheimer’s Disease by Denise Harold

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  • Alzheimer’s is the most common form of dementia and as you may have heard in the news dementia is becoming more prevalent and is estimated to double in the next 40 years.
  • there are currently no effective treatments for Alzheimer’s disease. The drugs that are administered to AD patients tend to treat the symptoms rather than the causes and on average might only achieve a 6-12 month delay in the progression of those symptoms.
  • there are currently no effective treatments for Alzheimer’s disease. The drugs that are administered to AD patients tend to treat the symptoms rather than the causes and on average might only achieve a 6-12 month delay in the progression of those symptoms. So a real driving force behind the work that we’re doing at the MRC Centre is to try and identify the causes of Alzheimer’s disease and as we know there’s a strong genetic basis to the disease that’s where we’ve focused our efforts.
  • We inherit our DNA from our parents and it is in almost every cell in our bodiesOur DNA is made up of about 25000 genesWithin a gene, the sequence of nucleic acids contains the instructions to make a proteinEven a slight alteration or mutation can cause abnormal proteins to be madeOver time, a build-up of abnormal proteins can sometimes lead to diseaseSo there are many sites in our DNA that can vary between individuals and one of our fundamental strategies is to look at these variant sites in both healthy individuals and people with Alzheimer’s.
  • A photo taken at the Reiswig family reunion in Perryton Tex. in August 1959. Of the 14 siblings (age 29 -52 here) 10 carried a genetic mutation that causes early-onset Alzheimer’s and all 10 died from it. The odds that their children will also have the mutation are 1 in 2.Early-onset mutations cause the over production of beta-amyloid, the toxic brain protein found in the plaques of AD
  • In the past 5 years I’ve been involved in a number of these studies where we’ve look at thousands of patients and thousands of healthy individuals and we look at DNA variants spread throughout the genome and simply compare the frequency of each variant in patients and healthy people.

Genetics of Alzheimer’s Disease by Denise Harold Genetics of Alzheimer’s Disease by Denise Harold Presentation Transcript

  • Genetics of Alzheimer’s Disease Denise 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 Alzheimer’s disease Liability/Risk
  • 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
  • From 20092013, Alzheimer’s Research UK helped fund studies that discovered 19 variants in genes linked to an altered risk of Alzheimer’s. Around 2% of the population have two copies of APOE4, which could make them more than 10 times more likely to develop the disease. 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. CLU PICALM CR1 BIN1 ABCA7 MS4A CD2AP EPHA1 HLA PTK2B SORL1 SLC24A4 INPP5D MEF2C NME8 ZCWPW1 CELF1 FERMT2 CASS4
  • 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%
  • Sequencing in Early-Onset AD (Complex) • 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
  • From 2009-2013, Alzheimer’s Research UK helped fund studies that discovered 19 variants in genes linked to an altered risk of Alzheimer’s. Around 2% of the population have two copies of APOE4, which could make them more than 10 times more likely to develop the disease. 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. CLU PICALM CR1 BIN1 ABCA7 MS4A CD2AP EPHA1 HLA PTK2B SORL1 SLC24A4 INPP5D MEF2C NME8 ZCWPW1 CELF1 FERMT2 CASS4
  • Utility of Genetic Findings • Diagnosis? • Identifying disease pathways • Drug targets • Gene-environment interactions
  • Progress! • >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
  • 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