Peter Schofield, Neuroscience Research Australia: Genetic screening; A risky approach?

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Peter Schofield, Executive Director and Chief Executive Officer, Neuroscience Research Australia delivered this presentation at the 2014 National Dementia Congress. The event examined dementia case studies and the latest innovations from across the whole dementia pathway, from diagnosis to end of life, focusing on the theme of "Making Dementia Care Transformation Happen Today. For more information on the annual event, please visit the conference website: http://www.healthcareconferences.com.au/dementiacongress2014

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Peter Schofield, Neuroscience Research Australia: Genetic screening; A risky approach?

  1. 1. Genetic Screening: A Risky Approach? Prof Peter R Schofield
  2. 2. Dementia risk One quarter of all people aged 55 years and older have a family history of dementia. A frequently asked question is “my mother had dementia, do I have „the gene‟ and can I test for it?”
  3. 3. Dementia Dementia Alzheimer’s disease Vascular dementia Dementia with Lewy bodies Frontotemporal dementia Dementias AD VD DLB FTD mixed Mixed dementia
  4. 4. The biology of Alzheimer’s disease Age Plaques Genes Tangles Plaques abnormal clusters of b-amyloid protein between cells Cell Death Alzheimer’s disease Tangles twisted strands of phosphorylated tau protein within cells
  5. 5. Genetic mutations & risk variants Effect Size Risk of Disease Disease Causing PSEN1 PSEN2 APP High Risk APOE TREM2 Medium Risk CLU, PICALM, CR1, SORL1, & many more Low Risk Very Rare Rare Low Medium Common Variant Frequency in the Population
  6. 6. Alzheimer’s disease gene mutations Patient - Auguste D APP 21 PSEN1 14 Seen by Alzheimer in 1901. Aged in early 50s PSEN1 F176L mutation PSEN2 1
  7. 7. Alzheimer’s disease mutations ~1-2% of AD Early onset (< 65 years) Autosomal dominant inheritance • strong family history • 50% probability of inheritance Genetic mutations in three genes: APP, PSEN1, PSEN2
  8. 8. Probability of a genetic mutation for AD Pattern of Inheritance Age of Onset Probability of having a genetic mutation Affected family members In three generations < 60 years 86 % Two or more affected first degree relatives < 61 years 68% Two or more affected first degree relatives < 65 years 15 % Two or more affected first degree relatives < 75 years <1%
  9. 9. Genetic testing for AD mutations Diagnostic and predictive testing available • Genetic counseling and testing (public) • Definitive diagnosis • Predictive testing • Reproductive decisions eg pre-implantation genetic diagnosis Motivations • Prepare for disease • Curiosity about genetic status • Help research • Relieve uncertainty • Inform children • Plan for the future
  10. 10. DIAN – longitudinal biomarker study
  11. 11. Clinical and memory changes Clinical Dementia Rating Sum of Boxes Estimated Years to Symptom Onset Mini-Mental State Examination MMSE Estimated Years to Symptom Onset Mutation Carrier Estimated Years to Symptom Onset Non Carrier Bateman et al, NEJM 2012, 367: 795. Logical memory
  12. 12. Structural and functional imaging changes Hippocampal Volume (3T MRI) Ab accumulation (PiB) in the Precuneus FDG Glucose Metabolism in the Precuneus Estimated Years to Symptom Onset Estimated Years to Symptom Onset Estimated Years to Symptom Onset Mutation Carrier Non Carrier Bateman et al, NEJM 2012, 367: 795.
  13. 13. Amyloid seen 15 years prior to onset Bateman et al, NEJM 2012, 367: 795.
  14. 14. Genetic mutations & risk variants Effect Size Risk of Disease Disease Causing PSEN1 PSEN2 APP High Risk APOE TREM2 Medium Risk CLU, PICALM, CR1, SORL1, & many more Low Risk Very Rare Rare Low Medium Common Variant Frequency in the Population
  15. 15. Apolipoprotein E e4 variant confers risk 100% APOE is involved in cholesterol transport 80% 3/3 3/4 60% APOE e4 confers increased risk for AD • e4 gives 3-fold increase • e4/e4 gives 15-fold increase APOE e2 is a protective factor 2/3 Percentage Unaffected 40% 2/4 20% 0% 60 65 70 75 4/4 80 85 90 Age (years)
  16. 16. Genetic contributors - APOE Majority of AD – estimated 40% of genetic contribution Late onset (> 65 years) Co-dominant inheritance • e4 gives 3-fold increase • e4/e4 gives 15-fold increase Susceptibility testing available • Testing available but little used clinically • Provides an adjunct to aid in diagnosis • Not suitable for predictive testing • Direct-to-consumer testing becoming widely available
  17. 17. REVEAL Study – APOE susceptibility testing Risk Evaluation and Education for ALzheimer disease led by Robert Green, Harvard University Examined children of a parent with late onset AD REVEAL I • disclosure - genotype and lifetime risk information • non-disclosure – lifetime risk information only REVEAL II All participants received genotype • Brochure used to explain genotype and AD risk • Counseling protocol to explain genotype and AD risk
  18. 18. Genetic testing – reasons for interest Interest in APOE Susceptibility Testing • • • • • • Memory concerns Prepare family for disease Younger age (<60 years) Higher educational levels Positive attitudes towards genetic tests Knowing someone with AD Note Interest in testing, or testing in confidentiality protected research settings may not reflect community attitudes of ‘real world’ testing Rahman et al, Genetic Testing & Molecular Biomarkers 2012, 16: 935.
  19. 19. Genetic testing - motivations Motivations for APOE Susceptibility Testing • • • • • • Information for future planning Arrangement of personal affairs Contribute to research/altruism Organize long term care Learn about own and children’s risk Gain knowledge – fulfils a ‘need to know’ and allows ‘feeling in control’ of ones health Rahman et al, Genetic Testing & Molecular Biomarkers 2012, 16: 935.
  20. 20. Genetic testing - risks Risks arising from APOE Susceptibility Testing • • • Disclosure did not lead to significant psychological risks Only about 10% showed anxiety/depression Feels of relief/reassured regardless of the test result Rahman et al, Genetic Testing & Molecular Biomarkers 2012, 16: 935.
  21. 21. Genetic testing – impact on health behaviour Health behaviours arising from APOE Testing • • • Significant increase in long-term care insurance, eg 2% if e4 negative increased to 17% if e4 positive (NB US GINA does not apply to long-term care insurance) Significant increase in health behaviours, eg increased dietary supplements (vitamin E, gingko biloba, green tea) – despite lack of proven benefits No data on impact of APOE disclosure to a general population sample Rahman et al, Genetic Testing & Molecular Biomarkers 2012, 16: 935.
  22. 22. Australian attitudes to genetic testing If the genetic test showed you were at LOWER than average risk for depression: You would get peace of mind 81.0 You would see yourself as being resilient to depression regardless of any stresses in your life 57.5 If the genetic test showed you were at HIGHER than average risk for depression: You would be ready to get early psychological help 85.7 You would be able to start to minimise stress factors in your life It could tell you what treatment might be most effective for you 83.2 82.2 It could help legitimise depression as a biological disorder 81.7 0 20 40 60 Percentage Wilde et al, Psychological Med 41, 1605, 2010 80 100
  23. 23. Australian attitudes to genetic testing If the genetic test showed you were at HIGHER than average risk for depression: You would be afraid of being discriminated against by insurance companies or employers 64.0 You would start worrying about depression that may never develop 62.4 You may be more likely to feel depressed 58.7 You would worry the result may not stay private 53.7 You would be afraid of being labelled or stigmatised 52.4 It could trigger a mental illness just by knowing you might have an increased risk 46.4 0 20 40 60 Percentage Wilde et al, Psychological Med 41, 1605, 2010 80 100
  24. 24. Factors influencing attitudes Variable B Odds Ratio Personal history of mental illness Self-estimation of risk for depression higher than average Endorsement of perceived benefits of genetics 0.93 0.61 2.53 1.84 1.16 3.18 Belief genetic evidence for mental illness will increase social stigma Abuse 0.42 1.52 0.21 1.24 Wilde et al, Psychological Med 41, 1605, 2010
  25. 25. Personalised medicine The application of genetic information to predict disease development, influence decisions about lifestyle choices, and tailor preventative interventions or medical treatment to the individual needs of each patient. Alzheimer’s Disease Genetic Testing • • • • • Prediction Diagnosis Prevention Intervention Treatment
  26. 26. Personalised medicine The application of genetic information to predict disease development, influence decisions about lifestyle choices, and tailor preventative interventions or medical treatment to the individual needs of each patient. Alzheimer’s Disease Genetic Testing • • • • • Prediction Diagnosis Prevention Intervention Treatment 3 3 3 7 7
  27. 27. Resources Loy CT, Schofield PR, Turner AM & Kwok JB. (2013) Genetics of dementia. The Lancet. Published online August 6, 2013 http://dx.doi.org/10.1016/S0140-6736(13)60630-3 Rahman B, Meiser B, Sachdev P, Barlow-Stewart K, Otlowski M, Zilliacus & Schofield P. (2012) To know or not to know: An update on the literature on the psychosocial and behavioral impact of genetic testing for Alzheimer disease risk. Genetic Testing and Molecular Biomarkers. 16: 935-942. http://dx.doi.org/10.1089/gtmb.2011.0300
  28. 28. A very personal question … If you were given the option, would you use a genetic test to determine your risk of developing Alzheimer’s disease?

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