Neurodegenerative and vascular diseases that present with or often cause dementia: patterns of inheritance and key neuropathological abnormalities
| Disease | Types of inheritance in familial forms/genetic associations | Distinctive neuropathological abnormalities |
|---|---|---|
| Alzheimer’s disease (AD) | Autosomal dominant in a minority of cases, due to mutations of: | Aβ plaques—diffuse and neuritic |
| APP (amyloid-β precursor protein gene) | Neurofibrillary tangles and neuropil threads | |
| PSEN1 (presenilin-1 gene) | Aβ amyloid angiopathy in >90% of patients | |
| PSEN2 (presenilin-2 gene) | ||
| Also has strong association with ε4 allele of APOE gene, and particularly in late onset cases, there is an association between AD and an increase in the number of mtDNA polymorphisms or the presence of mutations in complex I mtDNA. Several other genetic associations have been reported (see http://www.alzforum.org/res/com/gen/alzgene/) but not confirmed | ||
| Dementia with Lewy bodies and Parkinson’s disease dementia | Very rarely autosomal dominant, due to mutation (Park1) or triplication (Park4) of SNCA (α-synuclein gene) Also has associations with ε4 allele of APOE and ‘B’ allele of CYP2D6 gene (for debrisoquine 4-hydroxylase) | Lewy bodies, of both cortical and brain stem type Lewy neurites ∼75% of patients also have AD-type neuropathological abnormalities |
| Frontotemporal lobar degenerations (FTLDs): a pathologically and pathogenetically heterogeneous group of diseases characterised by the restriction of cerebral cortical degeneration to frontal and/or temporal regions | Several forms of autosomal dominant FTLD (FTDP-17 and some cases of Pick’s disease) are caused by mutations in MAPT, encoding the microtubule associated protein tau. Rarely FTLD-U or FTLD-MND/ALS is familial | Pick’s disease: Pick bodies, swollen/achromasic neurons (‘Pick cells’), predominance of 3-repeat tau |
| Frontotemporal lobar degeneration and parkinsonism linked to chromosome 17 (FTDP-17): tau immunopositive cytoplasmic inclusions (usually numerous) in neurons, astrocytes, and oligodendroglia; relative proportions of 3- and 4-repeat tau depend on mutation | ||
| FTLD-U: superficial cortical microvacuolation, ubiquitylated cytoplasmic and nuclear inclusions in small neurons in dentate gyrus and superficial cortex | ||
| FTLD-MND/ALS: changes of FTLD-U combined with those of motor neuron disease/amyotrophic lateral sclerosis | ||
| FTLD-NF: neurofilament immunopositive neuronal cytoplasmic inclusions | ||
| FTD: FTLD lacking demonstrable tau, ubiquitylated or neurofilament inclusions | ||
| Corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and argyrophilic grain disease (AGD) | CBD and PSP are associated with H1 haplotype of MAPT | All are associated with abnormal neuronal and glial accumulation of 4-repeat tau |
| CBD: nigral degeneration and superficial cortical microvacuolation, tau-immunopositive neuronal and glial inclusions in basal nuclei (especially nigra – ‘corticobasal inclusions’) and cortex and including cortical astrocytic plaques; swollen/achromasic cortical neurons | ||
| PSP: usually predominantly nigral and other subcortical degeneration with tau-immunopositive neuronal and glial inclusions but can involve cortex | ||
| AGD: grain-like tau immunopositive argyrophilic bodies in hippocampus, entorhinal cortex, and some subcortical nuclei; granular tau immunopositivity of neurons in these regions | ||
| Huntington’s disease | Autosomal dominant inheritance with anticipation; risk related to extent of CAG expansion in huntingtin gene | Striatal degeneration (particularly of putamen); mild cerebral cortical atrophy; nuclear inclusions (predominantly neuronal) that label for ubiquitin, polyglutamine, and huntingtin |
| Prion disease | Autosomal dominant forms of disease due to mutations in PRNP (prion protein gene) account for a minority of cases | Neuronal loss, microvacuolation of affected grey matter (spongiform degeneration), severe astrocytosis, accumulation of protease resistant prion protein PrPSc/PrPRes/PrPP |
| Cerebral amyloid angiopathy (CAA) | CAA is usually sporadic and often occurs in association with AD (either sporadic or familial—see above), but may be the predominant abnormality in several uncommon familial diseases including: hereditary cerebral haemorrhage with amyloidosis of Dutch type (HCHWA-D) due to mutation in APP; hereditary cerebral haemorrhage with amyloidosis of Icelandic type (HCHWA-I) due to mutation in cystatin C gene, CYST C; familial British and Danish dementias due to mutations in BRI2 gene | HCHWA-D: Aβ amyloid angiopathy mainly affecting cortical and overlying leptomeningeal blood vessels; diffuse Aβ plaques |
| HCHWA-I: cystatin C amyloid angiopathy mainly affecting cortical and overlying leptomeningeal blood vessels | ||
| Familial British and Danish dementias: severe, widespread CAA due to deposition of ABri or ADan, respectively; parenchymal ABri or ADan plaques, some associated with dystrophic neurites; tau-immunopositive neurofibrillary tangles and neuropil threads | ||
| Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) and rarer inherited arteriopathies | CADASIL is caused by mutations in NOTCH3. Another autosomal dominant disease, hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), is linked to 3p21.3-p21.1. Linkage has not yet been established for cerebral autosomal recessive arteriopathy with subcortical infarcts and leucoencephalopathy (CARASIL) in which patients also develop spinal disc disease and alopecia | CADASIL: predominantly subcortical infarcts and ischaemic damage; pronounced thickening of leptomeningeal and parenchymal arteries and arterioles with accumulation of deeply eosinophilic, highly electron dense granular material adjacent to smooth muscle cells in the tunical media |