Table 2.

Autosomal dominant primary dementia syndromes

	Gene	Chromosome	Onset age (years)	Clinical features	MRI features	Pathological changes
Alzheimer's disease	PSEN1 >150 mutations	14	Usually <60; typically 35–55	~70% of familial Alzheimer's disease; usually resembles sporadic Alzheimer's disease; can have behavioural presentation; variants associated with spastic paraparesis and ataxia	Disproportionate symmetrical hippocampal atrophy; can have white matter change	Often prominent tau pathology; mutations above residue 200 associated with increased Aβ deposition; exon 8 and 9 mutations associated with ‘cotton wool’ plaques; can have associated Lewy bodies
	PSEN2	1	Variable, usually 45–65	Very rare (association with Volga German ancestry)	Limited information	Can have associated Lewy bodies
	APP	21	Usually <65; typically 45–60	~10–15% of familial Alzheimer's disease; APP duplications recently recognised, associated with early seizures	Disproportionate symmetrical hippocampal atrophy; often prominent white matter change	APP duplications associated with increased Aβ deposition
Prion disease	PRNP	20	Highly variable	Rarely presents with an amnestic phenotype resembling Alzheimer's disease; can have rapid course; can be associated with familial fatal insomnia, GSS, or CJD phenotypes	Variable; can have cerebellar atrophy, altered basal ganglia signal on FLAIR	Deposition of amyloid-containing abnormal prion protein; Alzheimer's disease-like phenotype associated with prominent vascular involvement
Behavioural variant FTLD, CBS, PSP	MAPT >40 mutations	17	25–65	5–15% of FTLD; presentation can be cognitive, parkinsonian disorder, or combination; phenotypic variation within families; can have semantic impairment	Frontotemporal atrophy; can have relatively symmetrical anterior mesial temporal lobe atrophy	Tau-positive inclusions in neurons and glia
Behavioural variant FTLD, PA, CBS	GRN >50 mutations	17	35–90	5–15% of FTLD; wide phenotypic variation within families, often prominent parietal signs; shorter duration of disease than for MAPT mutations	Frontal, temporal, and parietal atrophy on MRI: often strikingly asymmetric	TARDBP-positive inclusions in neurons
Behavioural variant FTLD	VCP	9	20–65	Very rare; association with inclusion body myopathy and Paget's disease, which can precede cognitive complaints; can have sphincteric disturbance, semantic impairment	Frontal or temporal atrophy (can be asymmetric), can have prominent white matter change	TARDBP-positive intranuclear inclusions in neurons
Behavioural variant FTLD	TARDBP (encodes TARDBP)	1	50–75	Very rare (French families); associated with MND; can have semantic impairment	Unclear (frontotemporal hypoperfusion on SPECT)	Not described (anticipated to have TARDBP-positive inclusions)
Behavioural variant FTLD	Not known	9	40–70	Rare; associated with MND	Frontal atrophy	TARDBP inclusions (MND type) in neurons and glia
Behavioural variant FTLD	CHMP2B	3	>50	Very rare (Danish family); can have extrapyramidal features, MND	Generalised atrophy	Ubiquitin-positive, TARDBP-negative cytoplasmic inclusions in neurons

Key features of the major familial dementias with autosomal dominant inheritance are summarised. Cognitive dysfunction is generally the hallmark of these diseases at presentation; however, other neurological features can supervene during the course of the disease. CBS=corticobasal syndrome. CJD=Creutzfeldt-Jakob disease. FLAIR=fluid-attenuated-inversion-recovery sequence. FTLD=frontotemporal lobar degeneration. GSS=Gerstmann-Straussler-Scheinker syndrome. MND=motor neuron disease. PA=progressive aphasia. PSP=progressive supranuclear palsy. SPECT=single-photon emission computed tomography. APP=amyloid precursor protein. PSEN=presenilin. PRNP=prion protein. MAPT=microtubule-associated protein tau. GRN=granulin. VCP=valosin-containing protein. TARDBP=TAR-DNA binding protein (also known as TDP-43). CHMP=chromatin-modifying protein. Aβ=amyloid β.