Presentation: Patient with Alzheimer’s disease and a family history suggestive of a genetic form

A 70-year-old man has received a clinical diagnosis of Alzheimer’s disease. He misplaces things more often at home and his family report that he is more repetitive. He is worried because his sister had Alzheimer’s disease (age 69, passed away age 75). His older brother (age 72) has a diagnosis of motor neurone disease and his father died with Alzheimer’s. He remembers that his grandfather lived in a nursing home later in life.

• The largest risk factor for Alzheimer’s disease is age.
• Less than 1% of Alzheimer’s disease is attributable to a monogenic cause.
• In the context of a likely diagnosis of Alzheimer’s disease, genomic testing should be considered if any of the following is true:
  • onset of symptoms is <55 years of age;
  • first- or second-degree relative with motor neurone disease/amyotrophic lateral sclerosis; and/or
  • 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 <65 years of age where the type of dementia is the same as the individual presenting to clinic.
    • Note: A family history of dementia of uncertain or mixed type and/or where onset is predominantly >65 years of age is unlikely to represent a monogenic disorder.
• Frontotemporal dementia (FTD) symptomatology can overlap with Alzheimer’s disease and is more likely to have a genomic cause.
• Some genetic forms of dementia like FTD are associated with other neurological disorders, such as motor neurone disease and atypical Parkinsonism. Assessment of the family history should therefore include neurological disorders, as this can be important when considering whether genomic testing is appropriate.
• Genomic testing can potentially be used 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.
• Patients should also 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.
• Identifying a genomic cause of Alzheimer’s disease within a family can have a profound effect. For instance, it may influence the decision that at-risk family members make in terms of financial and family planning.
• Where a genomic cause has been identified in an affected individual, genomic counselling and, potentially, predictive (presymtomatic) testing for at-risk relatives can be accessed via the local clinical genetics service.

• An appropriate family history should be taken, including a history of at least three generations (including children, siblings, parents and grandparents), any dementias or other neurological disorders in those individuals, as well as subtypes and age of presentation.
• Discuss with patient and their family the possibility of a genomic cause of dementia, the availability of testing and the implications of different outcomes including incidental findings and the possible identification of alternative dementia syndromes from genomic testing.
• 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.
• 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.
  • This 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)
  • 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 (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

• AlzForum: Mutations
• 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 Research UK: Genes and dementia (booklet)
• Alzheimer’s Society: Genetics of Dementia (factsheet)
• Rare Dementia Support