Genetic testing for dementia

The genetic landscape

Dementia is mostly sporadic, with risk influenced by many genetic and environmental factors. A small minority (around 1 to 2 per cent of all dementia) is caused by single-gene mutations inherited in an autosomal dominant pattern. The risk genes vary by dementia type:

• Alzheimer's Disease: PSEN1, PSEN2, APP (autosomal dominant; usually Early-Onset). APOE4 is a risk factor, not a single-gene cause.
• Frontotemporal Dementia: C9orf72, GRN, MAPT (about 10 to 30 per cent of FTD).
• Huntington's Disease: the HTT gene; autosomal dominant with full penetrance above a certain CAG repeat threshold.
• Familial Prion Disease: PRNP mutations.
• CADASIL (vascular): NOTCH3 mutations.

When genetic testing is offered

UK NHS Regional Genetics Services offer testing in selected cases:

• Young-onset dementia (under 65) with a strong family history;
• Multiple affected family members in successive generations;
• Specific clinical syndromes pointing to a known gene (for example, FTD with motor neuron disease);
• Where the result will inform treatment, family planning, or eligibility for genetic clinical trials.

Genetic counselling

Genetic counselling, by a trained clinical genetics service, is essential before testing. The counselling covers:

• What the test can and cannot tell you;
• What a positive, negative or uncertain result would mean for you and your family;
• Implications for insurance, employment and life planning;
• Family discussion and informed consent for cascade testing;
• Psychological support before, during and after the result.

For predictive testing in healthy at-risk relatives, the counselling is more involved and is delivered over several appointments before any test is offered.

APOE testing

APOE is the gene that produces apolipoprotein E. The APOE4 variant increases Alzheimer's risk but does not cause it: many people with APOE4 do not develop Alzheimer's, and many people without APOE4 do. NICE NG97 1.2.18 explicitly recommends against using APOE testing to diagnose Alzheimer's Disease. APOE testing may, however, become more relevant where anti-amyloid antibody therapies are considered, because APOE4 homozygotes have higher risk of ARIA.

Practical implications

Insurance

Under the UK Genetic Testing Code of Practice (Concordat 2018, extended), insurers cannot ask about or use predictive genetic test results for most insurance products, with the exception of Huntington's Disease for life cover above a high threshold. This protects most people who consider genetic testing.

Family planning

Preimplantation genetic testing is available in the UK for confirmed autosomal dominant dementia mutations. The Human Fertilisation and Embryology Authority must licence each indication.

Predictive testing in relatives

Once a familial mutation is identified, healthy at-risk relatives may choose predictive testing or may choose not to know. Both choices are respected; counselling is offered either way.

UK Genetics Services

NHS Regional Genetics Services across the UK provide genetic counselling and testing. Referral is via memory clinic or neurology. Waiting times vary by region; typically 3 to 9 months from referral to first appointment.

Private clinical genetics is also available; a specialist consultation typically costs £400 to £800, with testing fees additional.

Future directions

Polygenic risk scores (combining many small genetic effects into an overall risk estimate) are emerging as research tools. They may have a role in future risk stratification for prevention trials but are not yet in routine clinical use.