Clinical Genetics & Dementia

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1 Clinical Genetics & Dementia Dr Nayana Lahiri Consultant in Clinical Genetics & Honorary Senior Lecturer

2 Aims of the Session To appreciate the potential utility of family history and genetic investigations in the diagnosis of dementia To appreciate the difference between diagnostic and predictive genetic testing To consider the possibilities for genetic testing or DNA storage in your dementia patients

3 Why make a genetic diagnosis? To provide an explanation To access support/care To allow screening/monitoring for other symptoms There may be implications for other family members

4 How do we make a diagnosis? Have common non-genetic causes been excluded? Age at onset upto 10% of dementia cases Phenotype Family History? Other associated features? Diagnostic Testing Single Gene Testing Panel Testing Whole Exome/Genome Sequencing

5 Case 1 72y

6 Alzheimer s Disease Clinical signs Slowly progressive dementia Neuroimaging Gross cerebral cortical atrophy on CT or MRI Diffuse cerebral hypometabolism on PET Cerebrospinal fluid (CSF) Decreased Aβ amyloid 42 and increased tau Neuropathological Findings at postmortem 80-90% concurrence with clinical diagnosis

7 Alzheimer s Disease Lifetime risk of AD is 10-12% Approximately 25% of all AD is familial (i.e., 2 persons in a family) Of which 95% is late onset ( >60-65 years) 5% is early onset (<65 years)

8 Manic depressive psychosis Multifactorial disease Concordance Identical Non-identical (MZ) (DZ) 67% 5% Cleft lip and palate Rheumatoid arthritis Asthma Coronary artery disease 38% 34% 47% 19% 8% 7% 24% 9% Diabetes mellitus 56% Alhzeimer s Disease 55% 11% Both genetic and environmental factors important

9 Genetic susceptibility to disease

10 Early Onset Familial Alzheimer s Mean Onset <65 years Autosomal Dominant Chance of finding a mutation in a simplex case is LOW <6% In one lab the pickup was APP (10-15%) 1.4% PSEN1 (30-70%) 4% PSEN2 (<5%) 1% Other loci Genet Med May; 18(5):

11 Genetic susceptibility to disease

12 Genetic Risk Variants APOE encodes a polymorphic glycoprotein expressed in liver, brain, macrophages, and monocytes. ApoE participates in transport of cholesterol and other lipids and is involved in neuronal growth, repair response to tissue injury, nerve regeneration, immunoregulation, and activation of lipolytic enzymes. The APOE gene contains three major allelic variants at a single gene locus (ɛ2, ɛ3, and ɛ4), encoding for different isoforms (ApoE2, ApoE3, and ApoE4) that differ in two sites of the amino acid sequence.

13 Risks associated with APOE The APOE ɛ4 allele increases risk in familial and sporadic early-onset and late-onset AD x3 risk for APOE ɛ34 x15 for APOE ɛ44 The APOE ɛ2 allele is thought to have a protective effect 20 25% of the general population carries one or more ɛ4 alleles 40 65% of AD patients are ɛ4 carriers. The effect of APOE ɛ4 accounts for 27.3% of the estimated disease heritability of up to 80%

14 Figure 1: Manhattan plot of stage 1 for genome-wide association with Alzheimer's disease (17,008 cases and 37,154 controls). From Nature Genetics 45, (2013) Genetic Risk Variants

15 Direct to Consumer Testing

16 Should we test for risk variants? Up to 75% of individuals heterogeneous for APOE ɛ4 do not develop AD during life Up to 50% of people with AD do not carry the high-risk ɛ4 allele. The case for testing and the risks associated with other genes is even weaker

17 What is the point in finding them? Insight into pathogenic mechanisms Druggable targets Risk stratification in Clinical Trials?

18 Alzheimer s Disease Trials The TOMMORROW trial Phase III trial of pioglitazone to delay the onset of mild cognitive impairment of AD in individuals at high risk. Risk prediction is based on an algorithm including APOE and TOMM40 genotypes.

19 Case 2 Dementia, 80 s?? Schizophrenia onset 30 s Died aged 72 - dementia Psychotic episode, 57yrs Now 68yrs in care home. Progressive dementia with loss of ability to speak.

20 Collateral History Psychotic episode aged 58yrs?Frontal lobe seizures Primary Diagnosis of Alzheimers Disease aged 67yrs PET decreased update in temporal lobe MRI moderate atrophy of parietal lobe Now Behavioural presentation more FTD Poor speech Poor sleep Rapid personality change with outbursts of temper

21 Frontotemporal Dementia Neurodegeneration mainly involving Frontal and Temporal lobes Progressive change in personality and behaviour or progressive deterioration in language abilities 2 major subtypes Behavioural variant FTD (bvftd) Primary progressive aphasia (PPA) which includes progressive nonfluent aphasia, sematic dementia and logpenic aphasia

22 Genetics of FTD Approximately 30% of people with FTD have some family history of dementia In up to 30 of patients with FTD a single high-risk genetic mutation is identified More likely to find a genetic cause in Behavioural Variant C9orf72 most common and not on a gene panel TAU/MAPT GRN Rare genes VCP, CHMP2B, FUS, TARDP, SQSTM1, DCTN1

23 Diagnostic Testing Discussion with Father main carer and power of attourney Very helpful discussion with Consultant Psychiatrist He arranged a blood test Sent for C9orf72 C9orf72 expansion confirmed Follow up appointment arranged

24 Predictive testing Cannot offer predictive testing if the cause in an affected individual is unknown Why do people have predictive testing? - Need to know 55% - Planning life 51% - Reducing uncertainty 19% - Family planning 13% - Factor in marriage / relationship 13%

25 Predictive testing HD guidelines Initial visit discuss FHx, reasons for wanting presymptomatic testing, implications of a positive test, insurance, mortgages.?psychiatric assessment Cooling off period (40% drop out rate here) Second visit and blood test Follow-up with result Seen 2-4 weeks later and thereafter Not for <18yrs (testing of minors) Testing should be delayed in the pregnant or depressed

26 Case 2 Dementia, 80 s?? Schizophrenia onset 30 s Died aged 72 - dementia C9orf72 expansion

27 Case 2 Dementia, 80 s?? Schizophrenia onset 30 s Died aged 72 - dementia C9orf72 expansion Negative result

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33 Take Home Messages Genetic testing and advising on dementia risk remains challenging despite advances in genomic technology. Rapidly advancing genomic technologies are helping develop treatments for dementia. If early-onset dementia with/without a family history consider referral to Specialist Cognitive Neurology Clinic for phenotyping. If in doubt and if practicable, store a DNA sample. Do refer for children/family members to Genetics - but we can t offer predictive testing unless there is an established genetic diagnosis in an affected individual

34 Online Resources