Dr Nayana Lahiri

Consultant in Clinical Genetics

& Honorary Senior Lecturer

Nayana.lahiri@nhs.net

Clinical Genetics & Dementia

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

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

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

72y

Case 1

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

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)

11% 56% Diabetes mellitus

9% 19% Coronary artery disease

24% 47% Asthma

7% 34% Rheumatoid arthritis

8% 38% Cleft lip and palate

5% 67% Manic depressive psychosis

Non-identical (DZ)

Identical (MZ)

Concordance

Both genetic and environmental factors important

Multifactorial disease

Alhzeimer’s Disease 55%

Genetic susceptibility to disease

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. 2016 May; 18(5): 421–430.

Genetic susceptibility to disease

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.

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%

Genetic Risk Variants

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, 1452–1458 (2013)

Direct to Consumer Testing

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

What is the point in finding them?

• Insight into pathogenic mechanisms

• Druggable targets

• Risk stratification in Clinical Trials?

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.

Case 2

?

?

Schizophrenia

onset 30’s

Died aged 72 -

dementia Dementia, 80’s

Psychotic episode, 57yrs

Now 68yrs in care home. Progressive

dementia with loss of ability to speak.

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

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

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

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

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%

Predictive testing – HD guidelines

• 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

• Initial visit – discuss FHx, reasons for wanting pre-symptomatic testing, implications of a positive test, insurance, mortgages.

• ?psychiatric assessment

• Cooling off period (40% drop out rate here)

Case 2

?

?

Schizophrenia

onset 30’s

Died aged 72 -

dementia Dementia, 80’s

C9orf72 expansion

Case 2

?

?

Schizophrenia

onset 30’s

Died aged 72 -

dementia Dementia, 80’s

C9orf72 expansion

Negative result

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

Online Resources

• https://www.southwestthamesgenetics.nhs.uk/

• https://www.youngdementiauk.org/

• https://www.alzheimers.org.uk/

• http://www.raredementiasupport.org/ftd/

• http://genfi.org.uk/