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Dementia: When to refer for diagnostic genetic testing

By Sarah Abdelhafeez, Sean O’Dowd, and Antoinette O’Connor - 01st Jan 2025


Reference: January 2025 | Issue 1 | Vol 11 | Page 38


Dementia represents a looming crisis for Irish society: Approximately 64,000 people in Ireland are living with dementia, and if current trends continue, prevalence is expected to more than double, increasing to 150,000 cases by 2045.1 Dementia is an umbrella term for multi-domain cognitive impairment leading to a decline in function and loss of independence.

Dementia has many different causes, with Alzheimer’s disease (AD) being the most common. However, other neurodegenerative conditions including frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), and vascular cognitive impairment can also lead to dementia. 

Dementia care is evolving and the need for timely diagnosis and accurate subtyping is more important than ever, especially given the advent of disease-modifying therapies which can slow AD in its early stages. Furthermore, increasing awareness and prevalence of dementia has led to a growing number of individuals being concerned about their own personal risk.

A small, but important number of neurodegenerative cases of dementia can be attributed to a genetic aetiology.2 The likelihood of a genetic diagnosis is influenced by age at onset, family history, and clinical syndrome.

A genetic diagnosis impacts on patients and their families, allowing access to more personalised management, informing prognosis, and potentially avoiding a protracted investigation process. It can also enable access to focused support groups, referrals to specialist clinics, and facilitate family members accessing genetic services for consideration of presymptomatic testing and reproductive planning.

Awareness of genetic risk is increasing and thus, there is an onus on clinicians to consider referring patients to appropriate services where genetic testing is available.

This summary of “Genetic testing in dementia” by O’Connor et al, 2024, will discuss when to suspect a genetic aetiology, which should prompt onward referral to specialist cognitive services for consideration of genetic testing.2

A genetic diagnosis can clarify the diagnosis, influence the treatment plan, support prognosis, and inform supports for patients and their families. Factors to consider when deciding who to refer to specialist cognitive services for consideration of genetic testing include the age of onset of symptoms and multi-generational family history alongside the patient’s clinical presentation. This article outlines a framework for when to consider a possible genetic cause for commonly diagnosed dementia types.

Family history

A detailed history of relatives extending over multiple generations should be taken, exploring all neurological or psychiatric presentations. The age of onset, initial presentation, and age of death of affected relatives should be documented in the referral. Any history of seizures, motor neuron disease or parkinsonism should be recorded.

Family history can be used to generate a Goldman score, which can inform the index of suspicion regarding a genetic cause. A score of one describes an autosomal dominant inheritance pattern where three people in two generations are affected with the same clinical syndrome as the patient, with at least one being a first degree relative.

A score of two reflects family aggregation where three relatives are affected, but do not satisfy criteria for autosomal dominance inheritance pattern. A score of three is given if a first-degree relative has the same clinical syndrome as the patient and the age of onset was less than 65 years, and a score of 3.5 if the age of onset was greater than 65.

A score of four denotes no contributory or an unknown family history.3 However, it is important to be aware that a negative family history or later age of onset (ie, >65 years) does not rule out a genetic diagnosis.3

Alzheimer’s disease

AD is the leading cause of dementia. Around 1 per cent of all AD cases, and up to 5 per cent of those with an onset before the age of 65, are genetic, ie, caused by mutations in genes associated with familial AD.4 Familial AD is inherited in an autosomal dominant fashion and the age of onset tends to be reasonably consistent across successive generations.5

The age of onset in familial AD is typically between the ages of 30 and 65 years.5 However, later age of onset and absence of a family history does not preclude a diagnosis of familial AD.6 In patients with AD, symptom onset prior to the age of 60 or those with a strong family history (Goldman score 1 or 2), should prompt referral to a specialist cognitive service that has experience in performing genetic testing.

In those with older onset and/or a less compelling family history, the decision to refer should be taken on a case by case basis. Some factors to consider include atypical presentations, limited family history, for example families where history is censored or unknown, in combination with patient and family wishes.

Most commonly, amnestic symptoms dominate in familial AD. However, there can be atypical presentations, including changes in behaviour and language-led presentations. Additionally, signs of pyramidal dysfunction occur in 20-25 per cent in certain familial AD genotypes.7,8 Myoclonus can also occur in up to 50 per cent of familial AD cases and can be a predictor of subsequent seizures.7,9

The apolipoprotein E ε4 (APOE4) allele is one of the most significant genetic risk factors for AD development and is present in 20 per cent of the general population.10 The presence of an APOE4 allele is not necessary or sufficient to cause symptomatic AD. Currently, there is no clinical role for APOE testing, but this will likely change with APOE4 status influencing eligibility for disease-modifying therapy.

Frontotemporal dementia

FTD refers to a group of diseases encompassing multiple clinical phenotypes, with heritability differing between phenotypes. Behavioural-variant FTD, where patients predominantly present with changes in behaviour and personality, is most frequently familial. However, certain language-led FTD and FTD overlap syndromes, especially FTD-motor neurone disease (FTD/MND) presentations, can also be genetic.

More than 90 per cent of genetic FTD cases are linked to either expansions in chromosome 9 open reading frame gene (C9ORF72) or pathogenic mutations in the progranulin (GRN) and microtubule-associated protein tau (MAPT) genes.11 The most common phenotype seen in these mutations is behavioural variant FTD, although presentations and age of onset can vary, even between members of the same family.

The range of ages at onset is broad for all three genetic groups, from 20 years to 90 years. At a group level, MAPT presents earlier than either C9ORF72 or GRN, with almost 100 per cent penetrance and reasonably consistent age of onset within MAPT families, whereas C9ORF72 and GRN can have incomplete penetrance.12

Consider referral to specialist services for consideration of genetic testing in all patients where a diagnosis of behavioural-variant FTD or FTD/MND is suspected, regardless of a contributory family history. In other phenotypes, consideration of genetic testing occurs on a case by case basis, for example, in those with a strongly positive family history.

Dementia with Lewy bodies

DLB cases are very rarely linked to pathogenic mutations. However various other autosomal dominant mutations can serve as mimics.13 Referral for consideration of genetic testing should be considered in patients with DLB with a convincing family history of cognitive disorders and/or parkinsonism.

Discussing genetic testing

It is important for clinicians who care for patients with neurodegeneration to understand the indications, benefits, risks, and limitations of genetic testing. Testing can provide diagnostic clarity and the potential for targeted treatment or enrolment in research trials. For at-risk family members, specialist genetic services can provide counselling and access to pre-symptomatic testing, which can help to inform reproductive decision-making.

However, from the family perspective, learning about the risk of developing future dementia can have a significant psychological impact. There are also potential insurance implications for family members if pathogenic mutations are discovered as this information will need to be disclosed as part of the family history.

The potential of genetic findings with unclear implications are important to be aware of. A genetic change is classified as a variant of unknown significance (VUS) when the evidence for causing disease is insufficient or conflicting.19

However, if new evidence comes to light, a VUS can be re-classified as pathogenic or benign.19 A VUS can have significant psychological impact for families given the lack of certainty surrounding the finding. In some cases, there may be potential for further testing and/or post-mortem brain donation as a means of providing diagnostic clarity to family members.

The limitations of genetic testing need to be understood: A negative test does not rule out genetic disease. Genetic tests cannot test for all possible mutations, and there is a chance that as yet unknown pathogenic mutations will be discovered in the future.

Discussing results

Clinicians should be mindful of the language used and its impact on patients and their families. When a disease-causing gene is identified, important points that should be discussed with families include the inheritance pattern and currently available treatment and management options.

Families should be given support and educational resources (www.raredementiasupport.org), in addition to being signposted to research opportunities and support groups. Families should be made aware of the potential for at-risk family members to access specialist genetic clinics for predictive testing.

It is important to be aware that if a pathogenic gene is not found it does not preclude a genetic diagnosis. With the evolution in genetic techniques, there is scope for the discovery of new pathogenic variants, and in certain cases it may be possible for samples to be reanalysed if new information becomes available in the future.19

Future

Although genetic testing is becoming more widely available, costs vary between countries, and it is bioinformatically challenging. With the advances in disease-modifying therapy and the potential for personalised medicine, effort must be made to address inequity in access to genetic testing.

Direct to consumer testing is becoming more prevalent, and challenges arise with managing results and providing post-test counselling and support in cases where it is limited or not provided. Whether genetic testing is pursued by a clinician or commercially by the patient, we must provide access to support, research opportunities, and targeted treatments to families with a pathogenic mutation. 

References

  1. About – HSE.ie.  www.hse.ie/eng/dementia-pathways/about/.
  2. O’Connor A, et al. Genetic testing in dementia. Pract Neurol pn-2024-004241 (2024) doi:10.1136/PN-2024-004241.
  3. Goldman JS, et al. Comparison of family histories in FTLD subtypes and related tauopathies. Neurology 65, 1817-1819 (2005).
  4. Arber C, et al. Familial Alzheimer’s disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta. Molecular Psychiatry 2019 25:11 25, 2919-2931 (2019).
  5. Ryan NS, et al. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: A case series. Lancet Neurol 15, 1326-1335 (2016).
  6. Ryman DC, et al. Symptom onset in autosomal dominant Alzheimer disease: A systematic review and meta-analysis. Neurology 83, 253-260 (2014).
  7. Ryan NS, et al. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: A case series. Lancet Neurol 15, 1326-1335 (2016).
  8. Tang M, et al. Neurological manifestations of autosomal dominant familial Alzheimer’s disease: A comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS). Lancet Neurol 15, 1317-1325 (2016).
  9. Zarea A, et al. Seizures in dominantly inherited Alzheimer disease. Neurology 87, 912-919 (2016).
  10. Gharbi-Meliani A, et al. The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study. Alzheimers Res Ther 13, 1-11 (2021).
  11. Greaves CV, Rohrer JD. An update on genetic frontotemporal dementia. J Neurol 266, 2075-2086 (2019).
  12. Moore KM, et al. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: An international retrospective cohort study. Lancet Neurol 19, 145-156 (2020).
  13. Orme T, Guerreiro R, Bras J. The genetics of dementia with Lewy bodies: Current understanding and future directions. Curr Neurol Neurosci Rep 18, (2018).
  14. Minguillón Pereiro, A. M. et al. PSEN2 mutations may mimic frontotemporal dementia: Two new case reports and a review. Biomedicines 2024, Vol 12, Page 1881 12, 1881 (2024).
  15. Ugbode C, West RJH. Lessons learned from CHMP2B, implications for frontotemporal dementia and amyotrophic lateral sclerosis. Neurobiol Dis 147, 105144 (2021).
  16. Wade C, Runeckles K, Chataway J, Houlden H, Lynch DS. CSF1R-related disorder: Prevalence of CSF1R variants and their clinical significance in the UK population. Neurol Genet 10, (2024).
  17. Li W, Gao H, Dong X, Zheng D. SQSTM1 variant in disorders of the frontotemporal dementia-amyotrophic lateral sclerosis spectrum: Identification of a novel heterozygous variant and a review of the literature. J Neurol 268, 1351-1357 (2021).
  18. Vacchiano V, et al. Frequency of Parkinson’s disease genes and role of PARK2 in amyotrophic lateral sclerosis: An NGS Study. Genes (Basel) 13, 1306 (2022).
  19. Koriath CAM, et al. Genetic testing in dementia – utility and clinical strategies. Nat Rev Neurol 17, 23–36 (2021).

Author Bios

Sarah Abdelhafeez, Department of Neurology, Tallaght University Hospital, Tallaght, Dublin; and Sean O’Dowd and Antoinette O’Connor, Department of Neurology, Tallaght University Hospital, Tallaght, Dublin, Tallaght Institute of Memory and Cognition, Tallaght University Hospital, Tallaght, Dublin, and Academic Unit of Neurology, Trinity College Dublin


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