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Since 1993 the ε4 allele of apolipoprotein E (apoE) on chromosome 19 has been recognised as the major genetic risk factor for sporadic Alzheimer’s disease. Deposition of amyloid β protein (Aβ protein) in the cerebral cortex is a key feature of Alzheimer’s disease and may be of pathogenetic importance. Sporadic cerebral amyloid angiopathy often coexists with Alzheimer’s disease and involves the deposition of Aβ protein in leptomeningeal and cortical blood vessels. Both conditions may occur in Down’s syndrome, presumably because of the increased expression of β-amyloid precursor protein (APP) associated with trisomy 21, the chromosomal location of the APP gene.
Intracerebral haemorrhage is the principal, though uncommon clinical manifestation of cerebral amyloid angiopathy. Studies have suggested that the apoE ε2 allele and also the ε4 allele may occur more often in patients with cerebral amyloid angiopathy related haemorrhage.1 2 We report, to our knowledge, only the second case of cerebral amyloid angiopathy related haemorrhage in Down’s syndrome and suggest that the patient’s neuropathology and clinical manifestations were modulated by interacting influences of the APP and apoE genes.
A 46 year old man with Down’s syndrome was found dead in his bed. There were no suspicious circumstances. He had a long history of well controlled absence seizures on 800 mg sodium valproate a day. One month before his death he had had a left lower lobe pneumonia, from which he recovered well with intravenous antibiotic. He was cognitively impaired with some deterioration in behaviour in the last few years of his life, necessitating placement in care. There was no family history of dementia or intracerebral haemorrhage. He took no antiplatelet or anticoagulant medication and was not hypertensive. A necropsy was performed.
The patient had a typical Down’s syndrome facies. No head injury was apparent. There was evidence of bronchopneumonia in the left lung. There was no significant coronary atheroma and no evidence of congenital heart disease. Neuropathological examination disclosed a small brain (940 g) with a band of haemorrhage in the subarachnoid space overlying the frontal and parietal lobes of the right cerebral hemisphere. Coronal sections disclosed a large haematoma 7 cm×5.5 cm×5.5 cm lying superficially in the hemisphere beneath the subarachnoid haemorrhage. The middle third of the right cerebral hemisphere was expanded with a 5 mm shift of the midline structures and a supracallosal hernia to the left. There was extensive secondary haemorrhage into the tegmentum of the midbrain and upper pons, as a consequence of brainstem compression due to raised intracranial pressure.
Histological examination of sections of cerebral neocortex stained by silver impregnation (modified Bielschowsky’s stain) disclosed numerous non-neuritic plaques and sparse neuritic plaques. There were scanty neurofibrillary tangles. The age related neuritic plaque score and history of dementia gave a “definite” neuropathological diagnosis of Alzheimer’s disease according to the criteria of the Consortium to Establish a Registry for Alzheimer’s disease (CERAD). In sections from the haematoma wall there was extensive acute ischaemic necrosis in addition to the haemorrhage. Immunostaining for Aβ protein (Dako mouse monoclonal antibody raised to residues 8–17 of Aβ protein) confirmed the presence of multiple plaques within the cortical ribbon and showed severe amyloid deposition in many blood vessels within the cortex and overlying meninges. Some blood vessels had narrowed lumens and others displayed a “double barrel” appearance, typical findings in cerebral amyloid angiopathy associated vasculopathy. There was microscopical evidence of previous haemorrhage in the form of multiple small intracortical glial scars with haemosiderin pigment in macrophages. In the sections examined there was no evidence of fibrinoid necrosis.
The apoE genotype of the patient was ε2/ε4, determined by analysis of DNA extracted from formalin fixed paraffin embedded brain tissue as described previously.1
Only once before has a cerebral amyloid angiopathy related haemorrhage been reported in a patient with Down’s syndrome and Alzheimer’s disease.3 Indeed an analysis of death certificates listing Down’s syndrome as the underlying or a contributing cause of death did not document intracerebral haemorrhage among 793 cases examined from the United States during 1976.4 This seems surprising as Down’s syndrome is associated with both Alzheimer’s disease and cerebral amyloid angiopathy, the second predisposing to intracerebral haemorrhage. The studies on our patient may suggest some reasons why the expected quartet of findings is a rare but aetiologically related occurrence.
Patients with Down’s syndrome have a shorter life expectancy because of excess mortality from haemopoetic malignancies, congenital heart defects, and respiratory tract infections.4 Although there is “premature” Alzheimer’s disease in Down’s syndrome, predisposition to these other conditions can have an early fatal outcome.
Our patient was predisposed to Alzheimer’s disease not only because of his extra copy of the APP gene, but also because of his apoE ε4 allele. By the age of 40, virtually all patients with Down’s syndrome have neuropathological changes characteristic of Alzheimer’s disease. The increased dosage of the APP gene has been shown to produce increased serum concentrations of APP and the two major forms of Aβ protein—Aβ40 and Aβ42. The ε4 allele increases the risk of dementia in patients with Down’s syndrome. Indeed the combination of Down’s syndrome with the ε4 allele leads to very high deposition of Aβ protein in plaques.5 Possession of the ε4 allele also predisposes to deposition of Aβ protein in the cerebral leptomeningeal and cortical vasculature. Evidence currently suggests that the ε2 allele, although protective against Alzheimer’s disease, predisposes to haemorrhage due to cerebral amyloid angiopathy.1 2 We previously found more than a threefold overrepresentation of both the ε2 allele and the 2/4 genotype in patients with cerebral amyloid angiopathy related haemorrhage and speculated that whereas ε4 is a risk factor for deposition of Aβ protein in blood vessel walls, ε2 is a risk factor for haemorrhage from amyloid laden blood vessels.1 Although ε2 and ε4 alleles are neither necessary nor sufficient for cerebral amyloid angiopathy related haemorrhage, these apoE alleles seem to be major susceptibility polymorphisms for cerebral amyloid angiopathy (ε4) and cerebral amyloid angiopathy related haemorrhage (ε2). Because the ε2 allele is only 8% of the apoE alleles in the population, including the subgroup of patients with Down’s syndrome, it does not commonly coexist with the more closely related conditions of Alzheimer’s disease, cerebral amyloid angiopathy, and Down’s syndrome to produce cerebral haemorrhage.
In conclusion, we suggest that in this patient with Down’s syndrome, three copies of the APP gene, possession of the apoE ε4 allele, and age (46 years) predisposed to Alzheimer’s disease and cerebral amyloid angiopathy whereas the apoE ε2 allele predisposed to haemorrhage from the amyloid laden blood vessels.
MOMcC is supported by a Patrick Berthoud fellowship.
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