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APOE ɛ4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of Aβ protein
Author(s) -
Chalmers K.,
Wilcock G. K.,
Love S.
Publication year - 2003
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1046/j.1365-2990.2003.00457.x
Subject(s) - cerebral amyloid angiopathy , apolipoprotein e , pathology , parenchyma , pathological , alzheimer's disease , medicine , autopsy , amyloid beta , degenerative disease , dementia , angiopathy , vascular disease , beta (programming language) , disease , central nervous system disease , endocrinology , diabetes mellitus , computer science , programming language
The relative amounts of amyloid β‐protein (Aβ) in cerebral blood vessels and parenchyma vary considerably amongst patients with Alzheimer's disease (AD). Although several mechanisms have been proposed to explain this variability, the underlying genetic and environmental determinants are still unclear, as are the functional consequences. Polymorphisms in APOE , the gene for apolipoprotein E (ApoE), influence the risk of developing AD and of deposition of Aβ within the brain. We examined the relationship between the APOE genotype and the relative extent of accumulation of Aβ as plaques within the cerebral parenchyma and in cortical blood vessels in the form of cerebral amyloid angiopathy (CAA), in autopsy brain tissue from 125 AD cases and from 53 elderly, neurologically normal controls of which 19 had CAA without other neuropathological features of AD. In the AD cases, we also assessed whether the severity of CAA was related to the age of onset and duration of dementia, risk factors for atherosclerotic vascular disease, and histologically demonstrable cerebral in‐farcts or foci of haemorrhage. The APOE genotype was determined by a standard polymerase chain reaction‐based method. Paraffin sections of frontal, temporal and parietal lobes were immunolabelled for Aβ and the parenchymal Aβ load (total Aβ minus vessel‐associated Aβ) was quantified by computer‐assisted image analysis. CAA severity was scored for cortical and leptomeningeal vessels. The relevant clinical data were obtained from the database of the South West Brain Bank. In AD, we found the severity of CAA to be strongly associated with the number of ɛ4 alleles ( P < 0.0001) but the parenchymal Aβ load to be independent of APOE genotype. Cases with severe CAA had a lower parenchymal Aβ load than had those with moderate CAA ( P = 0.003). Neither the severity of CAA nor the parenchymal Aβ load correlated with age of onset, duration of disease or age at death, and the severity of CAA also did not correlate with the presence of cerebral infarcts or foci of haemorrhage. These findings indicate that possession of the APOE ɛ4 allele favours vascular over parenchymal accumulation of Aβ in AD. This may influence the pathogenesis of neurodegeneration in ɛ4‐associated AD.