title: Microvasculature changes and cerebral amyloid angiopathy in Alzheimer's disease and their potential impact on therapy.
abstract: The introduction of immunotherapy and its ultimate success will require re-evaluation of the pathogenesis of Alzheimer's disease particularly with regard to the role of the ageing microvasculature and the effects of APOE genotype. Arteries in the brain have two major functions (a) delivery of blood and (b) elimination of interstitial fluid and solutes, including amyloid-beta (Abeta), along perivascular pathways (lymphatic drainage). Both these functions fail with age and particularly severely in Alzheimer's disease and vascular dementia. Accumulation of Abeta as plaques in brain parenchyma and artery walls as cerebral amyloid angiopathy (CAA) is associated with failure of perivascular elimination of Abeta from the brain in the elderly and in Alzheimer's disease. High levels of soluble Abeta in the brain correlate with cognitive decline in Alzheimer's disease and reflect the failure of perivascular drainage of solutes from the brain and loss of homeostasis of the neuronal environment. Clinically and pathologically, there is a spectrum of disease related to functional failure of the ageing microvasculature with "pure" Alzheimer's disease at one end of the spectrum and vascular dementia at the other end. Changes in the cerebral microvasculature with age have a potential impact on therapy with cholinesterase inhibitors and especially on immunotherapy that removes Abeta from plaques in the brain, but results in an increase in severity of CAA and no clear improvement in cognition. Drainage of Abeta along perivascular pathways in ageing artery walls may need to be improved to maximise the potential for improvement of cognitive function with immunotherapy.
authors.affiliation: Clinical Neurosciences, University of Southampton School of Medicine, LD74, South Laboratory & Pathology Block, Southampton General Hospital, Southampton SO166YD, UK. row@soton.ac.uk
authors.forename: Roy O
authors.initials: RO
authors.lastname: Weller
authors.forename: Delphine
authors.initials: D
authors.lastname: Boche
authors.forename: James A R
authors.initials: JA
authors.lastname: Nicoll
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D016657:Cerebral Amyloid Angiopathy / Q000150:complications / Q000473:pathology*; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use; D015140:Dementia, Vascular / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D055806:Microvessels / Q000473:pathology* / Q000503:physiopathology
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors