Dementia

Hereditary dementias differ markedly in their presenting features, age at onset and associated neurological signs.

typically presents with an amnestic syndrome and progressive impairment of episodic memory, language and visuospatial function, but the monogenic forms tend to begin at younger ages than common late-onset disease. The frontotemporal dementia spectrum presents instead with early changes in behaviour and personality (behavioural variant) or with progressive language impairment (primary progressive aphasia), and it overlaps clinically and genetically with amyotrophic lateral sclerosis and with parkinsonian syndromes. The C9orf72-associated form in particular can manifest as frontotemporal dementia, as amyotrophic lateral sclerosis, or as both in the same individual.

presents with recurrent subcortical ischaemic strokes, migraine with aura, mood disturbance and stepwise cognitive decline that can progress to vascular dementia. Genetic prion disease presents as a rapidly progressive dementia and encompasses genetic , fatal familial insomnia and , often with ataxia, myoclonus or sleep disturbance. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP, a CSF1R-related microglial encephalopathy) presents as a rapidly progressive dementia with prominent frontal, psychiatric and motor features on a background of white-matter disease.

Alzheimer disease is the most common form of dementia, and the overall burden of Alzheimer disease and other dementias is rising as populations age. Monogenic, autosomal dominant Alzheimer disease accounts for only a small proportion of all Alzheimer diseases. Among the other entities, the C9orf72 repeat expansion is a relatively frequent monogenic cause within its spectrum, accounting for approximately 10% of all amyotrophic lateral sclerosis and 10 to 15% of all frontotemporal dementia. CADASIL has an estimated prevalence in the range of 2 to 5 per 100,000, although typical cysteine-altering NOTCH3 variants are detected far more often than expected, in roughly 1 in 450 individuals in the general population. Genetic prion disease and CSF1R-related ALSP are individually rare causes of dementia.

The conditions covered by this panel arise through several different molecular mechanisms.

Early-onset familial Alzheimer disease is caused by autosomal dominant variants in APP, PSEN1 and PSEN2; in addition, the APOE ε4 allele acts as a major susceptibility factor that increases risk without being deterministic. The frontotemporal dementia and FTD-ALS spectrum is most often caused by variants in MAPT and GRN and by the C9orf72 repeat expansion, with further pathogenic genes including TARDBP, VCP and TBK1. The C9orf72 cause is a non-coding hexanucleotide repeat expansion that gives rise to frontotemporal dementia and/or amyotrophic lateral sclerosis. CADASIL, the most common hereditary cerebral small-vessel disease, is caused by cysteine-altering variants in NOTCH3; rarer monogenic small-vessel diseases involve other genes, such as HTRA1 and COL4A1. Genetic prion disease is caused by variants in PRNP. ALSP is caused by variants in CSF1R. Beyond APOE, rare variants in TREM2 are established risk factors that modify susceptibility to Alzheimer disease.

Inheritance varies by gene. Most of the monogenic dementias in this panel are inherited in an autosomal dominant manner, including familial Alzheimer disease (APP, PSEN1, PSEN2); frontotemporal dementia due to MAPT or GRN; CADASIL due to NOTCH3; genetic prion disease due to PRNP; and ALSP due to CSF1R. For an autosomal dominant condition, each child of an affected person has a 50% chance of inheriting the variant, although penetrance and the age at onset can vary. The C9orf72 cause is also inherited as an autosomal dominant trait, but it is a non-coding repeat expansion whose behaviour across generations differs from that of a conventional point variant. By contrast, the APOE ε4 allele and rare variants in TREM2 act as susceptibility factors that raise risk rather than determining disease, and they do not follow classic Mendelian transmission.

Assessment of a person with suspected dementia combines clinical history, cognitive testing, neuroimaging (typically MRI) and, where appropriate, cerebrospinal fluid or other biomarkers, supported by a detailed family history. Molecular genetic testing with a multigene panel can identify a causative variant and clarify which specific entity is present within this heterogeneous group; in frontotemporal dementia, broad panels detect pathogenic variants across multiple genes. Some causes require dedicated methods: the C9orf72 hexanucleotide repeat expansion is detected by a repeat-specific assay rather than by conventional sequencing, so whether C9orf72 testing is included in this panel should be confirmed with the laboratory and it may need to be requested as a separate test. In contrast, the cysteine-altering NOTCH3 variants underlying CADASIL are identified by sequence analysis.

The principal distinction is between an inherited monogenic dementia and the far more common sporadic, late-onset forms, which is informed by age at onset, associated neurological signs and family history. There is also substantial overlap within the spectrum itself: frontotemporal dementia and form a clinical and genetic continuum, and hereditary small-vessel disease can present with cognitive decline that overlaps with other causes of vascular dementia. Mixed pathology and potentially treatable contributors should be considered as part of the wider clinical work-up.

• Supports identification of the specific monogenic cause within a clinically and genetically heterogeneous group of dementias.
• Supports clarification of the diagnosis when clinical and imaging features overlap between subtypes.
• Supports informed genetic counselling for the individual and relatives, including discussion of predictive testing where appropriate.
• Supports reproductive decision-making and family-planning discussions.
• Supports assessment of eligibility for gene-specific research studies or clinical trials.
• Supports prognostic and surveillance discussions tailored to the identified entity.

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