title: Biochemically-defined pools of amyloid-β in sporadic Alzheimer's disease: correlation with amyloid PET.
abstract: We fractionated frontal cortical grey matter from human Alzheimer's disease and control subjects into four biochemically defined pools that represent four distinct compartments: soluble/cytosolic, peripheral membrane/vesicular cargo, integral lipid/membranous pools and aggregated/insoluble debris. Most of the readily extractable amyloid-β remains associated with a lipid/membranous compartment. There is an exchange of amyloid-β between the biochemical pools that was lost for the amyloid-β42 species in Alzheimer's disease, consistent with the peptide being irreversibly trapped in extracellular deposits. The quantitative amyloid-β data, combined with magnetic resonance imaging volumetric analysis of the amount of cortical grey matter in brain, allowed us to estimate the total mass of amyloid-β in Alzheimer's disease (6.5 mg) and control (1.7 mg) brains. The threshold positron emission tomography standard uptake value ratio of 1.4 equates to 5.0 μg amyloid-β/g of grey matter and the mean Alzheimer's disease dementia standard uptake value ratio level of 2.3 equates to 11.20 μg amyloid-β/g of grey matter. It takes 19 years to accumulate amyloid from the threshold positron emission tomography standard uptake value ratio to the mean value observed for Alzheimer's disease dementia. This accumulation time window combined with the difference of 4.8 mg of amyloid-β between Alzheimer's disease and control brain allows for a first approximation of amyloid-β accumulation of 28 ng/h. This equates to an estimated 2-5% of the total amyloid-β production being deposited as insoluble plaques. Understanding these rates of amyloid-β accumulation allows for a more quantitative approach in targeting the failure of amyloid-β clearance in sporadic Alzheimer's disease.
authors.affiliation: The Florey Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Blaine R
authors.initials: BR
authors.lastname: Roberts
authors.affiliation: The Florey Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Monica
authors.initials: M
authors.lastname: Lind
authors.affiliation: The Florey Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Aaron Z
authors.initials: AZ
authors.lastname: Wagen
authors.affiliation: The Florey Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Alan
authors.initials: A
authors.lastname: Rembach
authors.affiliation: Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Tony
authors.initials: T
authors.lastname: Frugier
authors.affiliation: The Florey Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Qiao-Xin
authors.initials: QX
authors.lastname: Li
authors.affiliation: The Florey Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Ryan
authors.affiliation: The Florey Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.|Department of Anatomical Pathology, Alfred Hospital, Prahran, Victoria 3004, Australia.
authors.forename: Catriona A
authors.initials: CA
authors.lastname: McLean
authors.affiliation: CSIRO Health and Biosecurity/Australian e-Health Research Centre and Cooperative Research Centre of Mental Health, Brisbane, QLD, Australia.
authors.forename: James D
authors.initials: JD
authors.lastname: Doecke
authors.affiliation: The Florey Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.|Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Rowe
authors.affiliation: The Florey Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.|Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Victor L
authors.initials: VL
authors.lastname: Villemagne
authors.affiliation: The Florey Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016022:Case-Control Studies; D005625:Frontal Lobe / Q000378:metabolism* / Q000473:pathology; D066128:Gray Matter / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D059906:Neuroimaging; D058225:Plaque, Amyloid / Q000378:metabolism*; D049268:Positron-Emission Tomography; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides
keywords: Alzheimer’s disease; amyloid imaging; amyloid-β; biomarkers