Dementia and its genes

Abstract

Dementia is a collective term for a range of conditions that lead to a progressive deterioration in cognitive function. Together they are a major cause of disability, and it is estimated that 10 000 000 new cases are diagnosed every year, worldwide. Studies suggest that 1-in-20 individuals develop symptoms below the age of 65 years. Although non-genetic causes must be considered, a young age of onset or a strong family history could be due to the presence of a particularly strong genetic factor; a highly penetrant pathogenic variant. This article aims to provide GPs with an introduction to inherited forms of adult-onset dementia, their presenting features and clues to look out for in the family history.

The RCGP curriculum and dementia and its genes

The role of the GP in the genomic medicine clinical topic guide requires GPs to:

Take and consider family histories in order to identify families with or at risk of genetic conditions (including autosomal and X-linked disorders) and familial clusters of common conditions such as cancer, cardiovascular disease, diabetes

Identify patients and families who would benefit from being referred to appropriate specialist services

Manage the day-to-day care of patients with genetic conditions, even if the patient is also under specialist care

Coordinate care across services, including transitions from paediatric to adult services

Communicate information about genetics and genomics, including discussing results from antenatal and new-born screening programmes

Understand how genomic information is used within the context of routine clinical practice

The role of the GP in the Neurodevelopmental disorders, intellectual and social disability clinical topic guide requires GPs to:

Recognise that neurological conditions are common causes of serious disability and have a major, but often unrecognised, impact on health and social services

Adopt approaches to assess and manage common but non-specific presentations such as headache, which can present diagnostic challenges and may have serious consequences if misdiagnosed. Managing the associated uncertainty should be carefully balanced with cost-effective use of resources

Understand that, increasingly, care for patients with long term neurological disease is coordinated in primary care with access to specialist clinical networks. GPs have to deal with disability, comorbidity (which includes depression), and inequalities in available resources

Diagnose acute neurological emergencies, cognitive difficulties, and epilepsy, which will usually present in primary care

For each problem or disease, the GP should consider the following areas within the general context of primary care:

Typical and atypical presentations

Diagnostic features and differential diagnosis

Management including self-care, initial, emergency and continuing care, chronic disease monitoring, and end-of-life care

Patient information and education including self-care

The heritability of dementia

Genetic factors exert their influence on all aspects of our health. Common conditions, such as dementia in older age, type 2 diabetes and heart disease, develop secondary to a complex interplay between environmental factors (the non-heritable components) and multiple genetic factors (the heritable components). Each individual risk factor has a small effect (see Fig. 1 later in this article). Many of these factors may be shared between family members. As age is a significant risk factor, and people are living longer, dementia is increasing in prevalence. Therefore, a family where a number of members have developed dementia is not uncommon. How then do we distinguish those individuals or families where a single pathogenic variant is the overwhelming risk factor? Offering genetic testing for ‘high-risk’ dementia genes to all individuals with dementia is neither necessary, nor helpful, nor feasible. However, clues in the clinical history and family history may direct clinicians to consider a genetic cause.

Figure 1.

Multifactorial vs monogenic (single gene) inheritance.

Age of onset

It is important to clarify some of the terms that are used in relation to inherited dementia. The terms ‘early-onset dementia’ (EOD) or ‘young-onset dementia’ are generally used where symptoms begin below the age of 65 years. In the UK, it is estimated that over 42 000 people have EOD.

Non-genetic causes in this age group include alcoholism, head injury, drug toxicity, vasculitis and AIDS. Individuals with sleep apnoea or limbic encephalitis can also present with dementia-like symptoms. As some of these causes are treatable, they must be considered when taking a history.

The three most common causes of EOD are Alzheimer’s disease, frontotemporal dementia and vascular dementia. The latter is frequently associated with vascular risk factors, although there are rare genetic causes such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Alzheimer’s disease and frontotemporal dementia are discussed below, as inherited causes for these are relatively common in the under-65-year age group.

Although it does depend on the genetic condition in question, not everyone with a high-risk pathogenic variant will necessarily develop dementia below the age of 65 years. Therefore, age of onset can be an indicator of an inherited cause, but this must be viewed within the context of the clinical features and the wider family history.

Family history

This article focuses on conditions with a Mendelian (single gene) pattern of inheritance (Fig. 1) and, in the case of dementia, these are usually autosomal dominant (Fig. 2). Autosomal dominant conditions affect both males and females equally. Each child of a person with the pathogenic variant will have a 50% chance of inheriting it.

Figure 2.

Autosomal dominant inheritance.

It is not uncommon for individuals not to know the specifics of their family history, especially if they are distantly related or estranged. Individuals can have misconceptions about the heritability of a condition, such as ‘it only affects females’, if it happens that women tend to be more affected in their family (or the converse). Varying clinical presentations within a family may also mean it takes time for a unifying cause to be considered. Therefore, a family history has its limitations and lack of a clear ‘familial’ picture should not lead to a genetic diagnosis being entirely discounted. Box 1 provides some tips on how to take a family history and some of the pitfalls.

Box 1.

Taking a family history.

• Document at least three generations of the family, more if the information is available

• Ask if siblings are full or half siblings or if anyone in the family has been adopted

• Identify which individuals developed dementia, the cause/specific type (if known) and the age of onset. Also document the age and cause of death

• Be aware that some individuals may not have been recognised or formally diagnosed as having dementia. Therefore, make note of anyone in the family with a psychiatric or neurological condition

Other points to consider:

• Some inherited forms of dementia can be associated with unusual clinical features (see Table 1)

• The smaller the family, the less obvious an inherited cause will be, as there are fewer individuals who can develop the disease

• Inherited forms of dementia show ‘age-related penetrance’, which means that the likelihood of clinical manifestation increases with age

• This also means that the age of onset may differ between individuals in a family. If a parent developed dementia at age 50 years and their child has no symptoms at age 60 years, the ‘child’ may still be at some risk and develop the condition later on

• Genes do not ‘skip’ generations. If there is a high-risk gene alteration in a parent, the child will either inherit it or they will not. However, someone who has inherited the gene alteration may reach old age and never develop the condition. This is known as ‘incomplete penetrance’. Penetrance varies depending on the gene and the condition

• Note the ages of unaffected relatives in the family who have died, particularly those who are closely related to individuals who have developed dementia. If they were young, they may have died before developing symptoms of dementia

The most common causes of inherited dementia

Alzheimer’s disease

Over 500 000 people in the UK have Alzheimer’s disease. It is estimated that 5% develop early-onset disease and that 20% of these individuals will have a pathogenic variant in one of the three main associated genes: presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP). If there is a family history of early-onset Alzheimer’s disease that appears to be following an autosomal dominant pattern of inheritance, the chance of identifying a gene mutation is higher.

As with presentation in the elderly, memory loss is a key clinical feature. However, atypical features are more common, particularly in familial early-onset Alzheimer’s. Myoclonus, seizures, pyramidal signs, behavioural change, psychiatric symptoms, and language problems have all been reported. Clinical symptoms tend to start earlier for those with PSEN1 pathogenic variants compared with PSEN2 or APP mutations, and the penetrance is almost 100%.

There has been much interest in the Apolipoprotein E gene (APOE) and its association with an increased risk of developing late-onset Alzheimer’s disease. A certain form of the gene (APO E4) is a known risk factor for the development of Alzheimer’s disease in some white population groups, but it is not associated with the high level of dementia risk that is seen with pathogenic variants in PSEN1, PSEN2, and APP. As the predictive value of the APOE E4 allele is limited, it is not recommended that testing for this should be used either in diagnosis or in an attempt at risk ‘prediction’.

Frontotemporal dementia

Due to degeneration of the frontal and temporal lobes, frontotemporal dementia (FTD) is associated with language problems, behavioural change and motor deficits. Clinically, FTD can be divided into different clinical subtypes after careful assessment by a Neurologist or Neuropsychiatrist. Clinical features seen in FTD include:

Personality change: Apathy and disinhibition

Language deficits: Verbal stereotypies, non-fluent aphasia or fluent aphasia with loss of word meaning (known as semantic dementia)

Psychiatric features: Depression, anxiety, obsessive behaviour, psychosis and hallucinations

Motor disorders: Ataxia, chorea and stereotypies

The heritability of FTD is complex; in some individuals it is genetic, whereas in others it arises as a sporadic condition. Pathogenic variants may be identified in isolated cases of FTD, but the presence of a family history increases the chance of identifying a genetic cause. Many different genes are associated with Mendelian types of FTD. Depending on the gene in question, the clinical and magnetic resonance imaging (MRI) features vary, as does the penetrance. For example, C9ORF72 can be associated with motor neurone disease (MND) as well as FTD. Within a family, the clinical phenotypes seen may be pure MND, pure FTD or a combination of FTD and MND. Penetrance with C9ORF72 is incomplete and age-dependent.

The time from recognition of symptoms to diagnosis of FTD often takes up to 5 years, but can be significantly longer. Due to the varied symptoms and lack of awareness of FTD, it is often misdiagnosed as a psychiatric condition, Alzheimer’s disease, Huntington’s disease, or another neurological condition.

Rarer causes of inherited dementia

There are many rare causes of inherited dementia. Cognitive dysfunction may not be the presenting feature, but may develop as the condition progresses. Table 1 lists those conditions that are mainly seen in adults with inherited forms of dementia. However, it is important to be aware that those adults who develop dementia under the age of 35 years frequently have inherited metabolic conditions that overlap with childhood-onset forms of inherited dementia.

Table 1.

Rare causes of adult-onset inherited dementia and their common features.

Autosomal dominant conditions	Features
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy	Migraines, psychiatric symptoms, recurrent transient ischaemic attacks and strokes
Huntington’s disease	Personality change, abnormal eye movements and chorea
Dentatorubral-pallidoluysian atrophy	Ataxia, choreoathetosis and seizures
Hereditary diffuse leucoencephalopathy with spheroids	Psychiatric symptoms and movement disorders
Inherited prion disease	Psychiatric symptoms, seizures, myoclonus and autonomic disturbance
X-linked conditions	Features
Fabry disease	Peripheral neuropathy, skin lesions, cardiomyopathy and renal impairment
Fragile X-associated tremor and ataxia syndrome	Ataxia, tremor and bradykinesia. Although more common in men, women can also be affected and may experience early menopause
Mitochondrial conditions	Features
Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes	Stroke-like episodes, that can leave residual deficits, in the context of fatigue, weakness, visual symptoms and sometimes headaches, vomiting and/or seizures

Presentation in primary care

Individuals with clinical features suggestive of dementia should be referred to a memory clinic or neurologist for detailed clinical assessment. Informing the neurologist about any relevant family history will be a useful prompt for them to consider an inherited cause to the person’s presentation, although a genetic diagnosis may still be considered, even where there is no family history. Mainstreaming of genomic testing means that Neurologists can arrange appropriate genetic testing if they feel that an inherited cause is likely.

Unaffected family members will often present to their GP asking for advice about their family history, or because a relative has been diagnosed with an inherited form of dementia. Where there is a pathogenic variant in the family, at-risk individuals can be referred to their local clinical genetics service if they have questions about their risk or wish to consider predictive genetic testing or reproductive options.

Case study: Part 1.

Leanne is 48 years old and has recently received a diagnosis of FTD. Her family first became concerned about her 4 years ago and she was initially treated for depression, as she seemed less interested in things generally. She became quieter at home and did not want to socialise. Anti-depressants did not have an effect and, when a close friend from Leanne’s workplace commented to Leanne’s husband that she seemed to be struggling with tasks at work, the family became concerned.

Leanne reluctantly visited her GP with her husband. The GP asked about her mood, general health, interests and work. Leanne did not feel there was a need for concern, as she felt fine. She denied any issues with her mood or stress. Leanne was quiet, somewhat distant and kept reorganising the contents of her bag throughout the appointment. She occasionally used a (subtly) incorrect word and her husband then corrected her. Leanne’s memory appeared to be intact. The GP felt there was something unusual about Leanne’s presentation and took a brief family history (Fig. 3). Leanne’s maternal uncle died of MND 15 years ago but there is no other family history of note.

Figure 3.

Leanne’s family tree.

The GP performed some baseline investigations including a full blood count, urea, creatinine, electrolytes, liver function test, HbA1c or glucose, thyroid function tests, B12 and folate. These came back as normal, and after discussion with Leanne, she was referred to a Neurologist. After neurological assessment, which included a full examination, cognitive testing and an MRI brain scan, the neurologist explained that Leanne appeared to have FTD. Diagnostic genetic testing confirmed that Leanne has a pathogenic variant in the C9ORF72 gene, which confirms that she has a genetic form of FTD.

The cognitive decline in individuals with FTD is often gradual, and it may initially be difficult for family members to notice. Many relatives find it hard to describe what has changed, and frequently attribute the changes to some other problem, such as depression, stress or other life events. Memory deficits may be present but not prominent. Although affected individuals frequently have a lack of insight into their difficulties, they also learn to compensate in the early stages, and they and their families can often explain away things that seem out of character. However, as the condition progresses, it begins to have more impact on work, relationships, household tasks and money management. As affected individuals are young, they often have children at home who are dependent on them. Caregivers have described that it can feel like living with a stranger as their relative loses the interests and skills they once had. A general ‘failure to cope’, or a sudden crisis of coping, may trigger concerns by family, friends or others, especially if the affected person is living alone or has learning difficulties.

Leanne’s uncle dying of MND may not seem to be of relevance, but is in fact a very useful piece of information. MND and FTD are part of a clinical spectrum, and pathogenic variants in the C9ORF72 gene are associated with both phenotypes. Indeed, some individuals have features of both conditions. As her uncle has passed away, testing to confirm whether he also had the pathogenic variant cannot be done unless a sample of his DNA has been stored. However, his two children are likely to be at 50% risk of inheriting the C9ORF72 pathogenic variant and can be offered predictive genetic testing for the variant found in Leanne. Other at-risk individuals include Leanne’s two children, who each have a 50% risk of inheriting the pathogenic variant, and also her brother.

Leanne’s mother died at age 65 years from breast cancer. Based on her brother having had MND and her daughter having FTD, and if we assume that she had the pathogenic variant, why did she not develop MND or FTD? It is possible that she had early cognitive features that were not recognised, or she might have gone on to develop symptoms later in life if she had lived. The age of onset of the symptoms associated with variants in C9ORF72 is wide and a few individuals can live into their 80 s and 90 s without any obvious clinical features. The other possibility is that Leanne’s mother did not carry the pathogenic variant, with her uncle’s diagnosis of MND being a complete coincidence, perhaps having arisen as a sporadic case in Leanne.

Case Study: Part 2.

Leanne’s daughter, Jade, made an appointment with her GP, as she wanted to discuss having genetic testing for the C9ORF72 pathogenic variant. She was not sure that she wanted a test, but wants to get more information before making a decision. The GP referred Jade to clinical genetics.

Jade attended two appointments with clinical genetics where she had a detailed discussion about the genetics underlying her mother’s condition, her reasons for and against having testing, and how she felt knowing her genetic status may influence her life decisions. Jade was aware that there is no treatment that prevents or slows the progression of FTD/MND, and that even if she had the pathogenic variant, no one could predict when or if she would ever develop symptoms. Jade decided not to have predictive genetic testing at that stage. Five years later, when she is thinking about starting a family with her partner, she begins to think again about testing. She wants to know what her reproductive options are and her GP re-refers her to clinical genetics.

Understandably, Jade has concerns about what her mother’s result may mean for her and for any future children she may have. Other family members may feel equally concerned, but not feel that testing is the right decision for them. It is estimated that 70–80% of persons at-risk of developing FTD decide against predictive testing. Studies in relation to Huntington’s disease show similar figures. The role of clinical genetics is not solely to arrange testing. It is to inform and counsel people to help them make the decision with which they can best live, whether this is to be tested or not at that time. Not testing at one stage of life does not stop a person deciding to go ahead with testing a few years later. As these are complex discussions, they usually take place over a series of appointments, so that individuals who want testing are as sure as possible that they wish to know their genetic status.

For those who decide to undergo predictive genetic testing, reproductive decision making is a common driver. There are a number of reproductive options that may be available for someone who has inherited a pathogenic variant and they can be discussed in the genetics clinic.
Accepting the 50% risk to each child that she has, and not opting for any intervention

Choosing not to have children

Adoption

Pregnancy through In vitro fertilisation using a donor egg

Natural conception with invasive prenatal genetic testing in early pregnancy - an option which is usually chosen if a couple plan to end a pregnancy that has inherited the pathogenic variant

Pre-implantation genetic diagnosis (Fig. 4)

Figure 4.
Preimplantation genetic diagnosis.

The testing options mentioned above are usually performed to detect the pathogenic variant that causes the condition. However, it is sometimes possible to test a pregnancy without knowing or discovering whether the at-risk parent has inherited the pathogenic variant (i.e. where the fetus is at 25% rather than at 50% risk). Such ‘prenatal exclusion testing’ involves some complexities and has some distinct disadvantages, but it infers the risk to the fetus by determining the grandparent of origin of the gene transmitted by the at-risk parent to the fetus. If a couple wishes to look into this, a referral for genetic counselling would be essential.

Complex situations

When genetic testing to confirm a diagnosis cannot be performed

The initial test in a family is undertaken in an affected person, as they are the ones who are most likely to carry a high-risk pathogenic variant. If a cause is found, at-risk relatives can then be offered predictive genetic testing. However, there are situations where predictive genetic testing cannot be offered, as a genetic cause has not been identified in an affected family member.

If genetic testing was performed, but this has not identified a pathogenic variant in an affected person, this could be because:
They have a high-risk pathogenic variant in an unknown gene. In time, as more genes are discovered, further genetic testing may be arranged if appropriate

The test performed has missed the pathogenic variant. The clinician ordering the genetic test needs to understand the limitations of the test, and decide whether further tests could or should be arranged

The person tested does not have a high-risk pathogenic variant as the cause of their dementia. When there is a family history of dementia, it will be important to test the most appropriate person as a way of identifying the family’s pathogenic variant, if there is one. Clinical genetics can decide if further testing of other affected relatives would be appropriate

In practice, distinguishing between these possibilities is not always possible. If the person tested is the youngest to have been affected in the family, then further genetic testing in the family may be unlikely to be productive.

Where all affected individuals in a family have passed away before genetic testing was possible, and there is no DNA stored that can be used for testing, refining the risk for at-risk family members is problematic. Although not routine, in certain families genetic testing can be offered to asymptomatic at-risk individuals to try and identify a pathogenic variant. This test for unaffected individuals is considered after genetic counselling, and only where the family history strongly suggests an inherited cause.

Requests for childhood testing in adult-onset conditions

The conditions highlighted in this article are, in the vast majority of cases, adult-onset conditions where there is no treatment or cure. Therefore, predictive testing in childhood is not offered, as the identification of the pathogenic variant will not change medical management. Requests to clinical genetics for testing in childhood from parents are handled with careful acknowledgement of their worries, and discussion about the reasons for not offering testing.

In some genetic conditions that cause dementia, it is (rarely) possible for there to be disease onset in childhood. This can occur with Huntington’s disease and Dentatorubral-pallidoluysian atrophy, although the clinical presentation may be rather different in children from that usual in adults. Genetic testing may then be appropriate in childhood, but only after detailed assessments by those experienced in such problems, typically involving both a neurologist and a clinical geneticist.

Long term support and ongoing research in treatments

The case study of Leanne and her family is fictional, but serves as a template upon which to consider the impact of a diagnosis of inherited dementia in such a (relatively) young person. Leanne is in the prime of her life with a job, with young adult children, and a social life. Leanne and her partner have full, active lives which will now change in a way for which they had not planned.

In order to help patients to achieve the best quality of life, and to support them and their families in adapting to, and planning for, the future, primary health care has much to offer. Most regions provide young-onset dementia services, specialist dementia nurses, social groups, carers’ groups, art and music groups and respite services (Box 2). There are also a number of national charities, including ‘Young Onset Dementia UK’, that specialise in supporting affected individuals and families. Their aims are to provide information as well as help people to deal with challenges such as:
Diagnosis and feelings of anger, frustration, guilt, fear and sadness

Self-care and general health

Working and job planning

Driving and travel

Finances, pensions, wills and insurance

Children and childcare

Relationships with partners

Adaptations to the home

Support for carers, who may also be looking after children and/or older relatives

Friendships and social groups

Hobbies and interests

Communication, understanding of the world and independence

Planning for care in the future

Box 2.
Useful websites and support services.

• Dementia UK: www.dementiauk.org

• Alzheimer’s Society: www.alzheimers.org.uk

• Young Dementia UK: www.youngdementiauk.org

• www.youngdementiauk.org/young-onset-dementia-resources. Provides a decision-making guide for GPs, pathways and a personal checklist that can be given to patients

• Rare Dementia Support: www.raredementiasupport.org

• CADASIL: www.cambridgestroke.com/cadasil.php

• Huntington’s Disease Association: www.hda.org.uk

• University College London, Dementia Research Centre: www.ucl.ac.uk/drc

The genomics era is bringing forward new potential treatments for many genetic conditions. High profile studies for Huntington’s disease, Alzheimer’s disease and FTD are all in progress, some already involving treatment trials in human patients. Whether an at-risk individual chooses to have predictive genetic testing is influenced by many factors, including the fact that there are no curative treatments.

It is likely that the emergence of definitive treatments for some conditions will change whether or not people choose to have predictive genetic testing, particularly if treatment prior to symptom onset is deemed beneficial. The availability of future treatments may also change how many individuals with dementia are offered genetic testing in the first place, as identification of those with a high-risk pathogenic variant may lead to a particular treatment path being offered or participation in research and clinical trials. Regardless of whether treatments may be available in the future, there is much that can be done in the primary care setting to aid early diagnosis and provide long term support.

KEY POINTS

Dementia is becoming more prevalent, but the majority of cases are not due to the presence of a high-risk pathogenic variant

Family history, age of onset and clinical features must all be taken into account when considering whether a genetic cause for dementia is possible

In some families, Alzheimer’s disease is an autosomal dominant condition with high penetrance

FTD is frequently misdiagnosed or diagnosis is delayed due to its complex clinical features

Predictive genetic testing and discussion about reproductive options is available through clinical genetics services for those who are at-risk of inheriting a pathogenic variant

Support for individuals with dementia at a younger age should be holistic and acknowledge the different challenges faced when compared with those who develop dementia at older ages

Footnotes

ORCID iD

Dr Vani Jain

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