Presentation: Adult with suspected genetic young-onset Alzheimer’s disease

A 47-year-old man attends the memory clinic with his wife and daughter. They are concerned that he has become more forgetful over the past six months. He works as an accountant and acknowledges that he is struggling with his workload, having to write everything down so he does not miss tasks. Cognitive testing reveals deficits, predominantly in working memory. Other organic causes of cognitive change are excluded and an MRI head shows mild temporal lobe and hippocampal atrophy.

• The greatest risk factor for Alzheimer’s disease is age.
• Less than 1% of Alzheimer’s disease is attributable to a causative single gene variant.
• In the context of a likely diagnosis of Alzheimer’s disease, the offer of genomic testing should be considered if either or both of the following are true:
  • onset of presentation is below 55 years of age; and/or
  • there is a family history highly suggestive of a monogenic cause for Alzheimer’s disease, for example, one or more first- or second-degree relatives with Alzheimer’s disease onset before 65 years of age where the type of dementia is the same as the individual presenting to clinic.
• Assessment of the family history should include related neurological conditions, such as motor neurone disease and Parkinson’s disease, as this can be important for interpretation of genomic variants.
• Patients should be counselled that, even where a family history of Alzheimer’s disease is present, the chance of finding a causative variant in an Alzheimer’s disease-related gene is relatively low.
• Genomic testing can potentially be utilised early in the diagnostic process to accelerate definitive diagnosis. Early diagnosis of Alzheimer’s disease is becoming increasingly important with the licensing of disease-modifying therapies on the horizon.
• Identifying a genomic cause of Alzheimer’s disease within a family can have a profound effect. It may influence the decision that ‘at risk’ family members make, in terms of financial and family planning.
• Genomic counselling and, potentially, predictive (presymtomatic) testing for at-risk relatives can be accessed via the local clinical genetics service.

• Take a family history. This should include a history of at least three generations (including children, siblings, parents and grandparents), any dementias or other neurological conditions in those individuals, as well as subtypes and age of presentation.
• Discuss with patients and their families the possibility of a genomic cause of dementia, the availability of testing and the implications of different outcomes, including incidental findings and the identification of alternative dementia syndromes from genomic testing.
• Check phenotype/presentation and consider alternative conditions if not typical of Alzheimer’s disease. Seek further advice from clinical genetics for next steps in this instance.
• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria document for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource. However, there is only one gene panel currently available for ‘Adult onset neurodegenerative disorders’.
• R58 covers all known causative genes for Alzheimer’s disease. This panel looks at more than 120 genes known to cause adult-onset neurodegenerative conditions, including Parkinsonism and motor neurone disease, as well as dementia syndromes.
  • The test uses whole genome sequencing (WGS), though only genes known to cause adult-onset neurodegenerative conditions are analysed.
  • It also includes short tandem repeat (STR) testing for a number of conditions, including Huntington disease, spinal and bulbar muscular atrophy (also known as Kennedy disease), C9orf72-related frontotemporal dementia and motor neurone disease.
• As R58 is undertaken using WGS, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband) and their parents where available, including details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number (see How to complete a test order form for WGS for support);
  • complete an NHS GMS record of discussion (RoD) form for each person being tested – (see How to complete a RoD form for support); and
  • obtain a consultee form signed by an appropriate relative or advocate if an adult patient does not have capacity to consent to genomic testing.
• For all the tests outlined above, an EDTA sample (typically purple-topped tube) is required.
• Information about patient eligibility and test indications were correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• GeneReviews: Alzheimer Disease Overview
• Genomics England: NHS Genomic Medicine Service (GMS) signed off panels resource
• NHS England: National Genomic Test Directory
• Practical Neurology: Genetics of Dementia

For patients

• Alzheimer’s Society: Young-onset dementia
• Dementia UK: Young onset dementia
• Rare Dementia Support