Biochemically-defined pools of amyloid-β in sporadic Alzheimer's disease: correlation with amyloid PET.

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-beta remains associated with a lipid/membranous compartment. There is an exchange of amyloid-beta between the biochemical pools that was lost for the amyloid-beta(42) species in Alzheimer's disease, consistent with the peptide being irreversibly trapped in extracellular deposits. The quantitative amyloid-beta 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-beta 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 kg amyloid-beta/g of grey matter and the mean Alzheimer's disease dementia standard uptake value ratio level of 2.3 equates to 11.20 kg amyloid-beta/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 4.8mg of amyloid-beta between Alzheimer's disease and control brain allows for a first approximation of amyloid-beta accumulation of 28 ng/h. This equates to an estimated 2-5% of the total amyloid-beta production being deposited as insoluble plaques. Understanding these rates of amyloid-beta accumulation allows for a more quantitative approach in targeting the failure of amyloid-beta clearance in sporadic Alzheimer's disease.