Context Blood-based analytes as indicators of pathological processes in Alzheimer's disease (AD). Objective Combined proteomic and neuroimaging approach to identify plasma proteins associated with AD pathology. Design Discovery-phase proteomic experiments to identify plasma proteins associated with correlates of AD pathology including evidence of atrophy using neuroimaging and more rapid clinical progression, followed by replication using quantitative immunoassay. Extension studies in older non-demented humans using 11C-PiB amyloid imaging and transgenic mice with amyloid pathology. Setting Multi-center European study, AddNeuroMed, and the Baltimore Longitudinal Study of Aging (BLSA) in United States. Participants AD patients, mild cognitive impairment (MCI) subjects and healthy controls with standardized clinical assessments and structural neuroimaging. Plasma samples from non-demented older BLSA participants with brain amyloid imaging by PET. Main outcome measures Association of plasma proteins with brain atrophy, disease severity and rate of clinical progression. Extension studies in man and transgenic mice tested association between plasma proteins and brain amyloid. Results Clusterin/apolipoprotein-J was associated with atrophy of the entorhinal cortex, baseline disease severity and rapid clinical progression in AD. Increased plasma concentration of clusterin was predictive of greater beta amyloid (Aβ) burden in the medial temporal lobe. Subjects with AD had increased clusterin mRNA in blood but there was no effect of SNPs in the gene encoding clusterin (CLU) with gene or protein expression. Finally, APP/PS1 transgenic mice showed increased plasma clusterin, age-dependent increase in brain clusterin and amyloid and clusterin co-localisation in plaques. Conclusions Clusterin/apolipoprotein-J is a known amyloid chaperone associated with Alzheimer's disease severity, pathology and progression. Increased plasma concentration of clusterin is also associated with greater burden of fibrillar Aβ in the brain. These results demonstrate an important role of clusterin in the pathogenesis of AD and suggest that alterations in amyloid chaperone proteins may be a biologically relevant peripheral signature of Alzheimer's disease.

IntroductionThe aim of this study was to determine whether years of schooling influences regional cortical thicknesses and volumes in Alzheimer’s disease (AD), mild cognitive impairment (MCI), and healthy age-matched controls.MethodsUsing an automated image analysis pipeline, 33 regional cortical thickness and 15 regional volumes measures from MRI images were determined in 121 subjects with MCI, 121 patients with AD, and 113 controls from AddNeuroMed study. Correlations with years of schooling were determined and more highly and less highly educated subjects compared, controlling for intracranial volume, age, gender, country of origin, cognitive status, and multiple testing.ResultsAfter controlling for confounding factors and multiple testing, in the control group, subjects with more education had larger regional cortical thickness in transverse temporal cortex, insula, and isthmus of cingulate cortex than subjects with less education. However, in the AD group, the subjects with more education had smaller regional cortical thickness in temporal gyrus, inferior and superior parietal gyri, and lateral occipital cortex than the subjects with less education. No significant difference was found in the MCI group.ConclusionEducation may increase regional cortical thickness in healthy controls, leading to increased brain reserve, as well as helping AD patients to cope better with the effects of brain atrophy by increasing cognitive reserve.

A framework for multi-centre MRI studies of Alzheimer's disease has been established consisting of a harmonized MRI acquisition protocol across centres, rigorous QC at both the sites and central data analysis hub and an automated image analysis pipeline. Early results demonstrate the high quality of the images acquired and the applicability of the automated image analysis techniques employed.

Here we describe the AddNeuroMed multicenter magnetic resonance imaging (MRI) study for longitudinal assessment in Alzheimer's disease (AD). The study is similar to a faux clinical trial and has been established to assess longitudinal MRI changes in AD, mild cognitive impairment (MCI), and healthy control subjects using an image acquisition protocol compatible with the Alzheimer's Disease Neuroimaging Initiative (ADNI). The approach consists of a harmonized MRI acquisition protocol across centers, rigorous quality control, a central data analysis hub, and an automated image analysis pipeline. Comprehensive quality control measures have been established throughout the study. An intelligent web-accessible database holds details on both the raw images and data processed using a sophisticated image analysis pipeline. A total of 378 subjects were recruited (130 AD, 131 MCI, 117 healthy controls) of which a high percentage (97.3%) of the T1-weighted volumes passed the quality control criteria. Measurements of normalized whole brain volume, whole brain cortical thickness, and point-by-point group-based cortical thickness measurements, demonstrating the power of the automated image analysis techniques employed, are reported.