James Lui

The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers.

The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)‐42, total‐tau (T‐tau), and phosphorylated‐tau (P‐tau) demonstrate good diagnostic accuracy for Alzheimers disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimers Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch‐to‐batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.

Plasma apolipoprotein E and Alzheimer disease risk: the AIBL study of aging.

Objective: There is mounting evidence for the contribution of apoE to the pathophysiology of Alzheimer disease (AD). Studies also indicate that plasma apoE levels may reflect disease status, suggesting that apoE is a potential AD biomarker. However, while some studies of apoE levels in plasma have presented correlations with AD pathology, others have not. Thus, there is a lack of consensus as to the suitability of plasma apoE as an AD biomarker. The major objective of this cross-sectional study was to investigate total plasma apoE as well as levels of the apoE4 form in a large, highly characterized cohort which included both healthy controls and participants with early-stage AD. Methods: Total apoE and apoE4 were measured in 1,079 individuals drawn from the highly characterized Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Total and isoform-specific plasma apoE levels were then compared with cerebral Aβ load, as assessed by PET using Pittsburgh compound B (PiB). Results: Total apoE and apoE4 levels were found to be significantly lower in patients with AD in the entire cohort, and decrease with Aβ load in the PiB-PET subset. ApoE levels were significantly lower among ϵ4 homozygous individuals. In APOE ϵ3/ϵ4 heterozygote carriers, apoE4 levels decrease, indicating that apoE3 levels increase with disease. Conclusion: Analysis of cross-sectional data from the AIBL study indicates that plasma apoE levels are altered in AD and correlate with AD pathology level. The significance of these findings will be determined in the AIBL longitudinal study of aging.

Plasma Amyloid-β as a Biomarker in Alzheimer's Disease: The AIBL Study of Aging

Amyloid-beta (Abeta) plays a central role in the pathogenesis of Alzheimers disease (AD) and has been postulated as a potential biomarker for AD. However, there is a lack of consensus as to its suitability as an AD biomarker. The objective of this study was to determine the significance of plasma Abeta as an AD biomarker and its relationship with Abeta load and to determine the effect of different assay methods on the interpretation of Abeta levels. Plasma Abeta1-40, Abeta1-42, and N-terminal cleaved fragments were measured using both a commercial multiplex assay and a well-documented ELISA in 1032 individuals drawn from the well-characterized Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Further, Abeta levels were compared to Abeta load derived from positron-emission tomography (PET) with the Pittsburgh compound B (PiB). Lower Abeta1-42 and Abeta1-42/1-40 ratio were observed in patients with AD and inversely correlated with PiB-PET derived Abeta load. However, assay methodology significantly impacted the interpretation of data. The cross-sectional analysis of plasma Abeta isoforms suggests that they may not be sufficient per se to diagnose AD. The value of their measurement in prognosis and monitoring of AD interventions needs further study, in addition to future longitudinal comparisons together with other predictors, which will determine whether plasma Abeta has diagnostic value in a panel of biomarkers.

Physical activity and amyloid-β plasma and brain levels: results from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing

Previous studies suggest physical activity improves cognition and lowers Alzheimers disease (AD) risk. However, key AD pathogenic factors that are thought to be influenced by physical activity, particularly plasma amyloid-β (Aβ) and Aβ brain load, have yet to be thoroughly investigated. The objective of this study was to determine if plasma Aβ and amyloid brain deposition are associated with physical activity levels, and whether these associations differed between carriers and non-carriers of the apolipoprotein E (APOE) ɛ4 allele. Five-hundred and forty six cognitively intact participants (aged 60–95 years) from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) were included in these analyses. Habitual physical activity levels were measured using the International Physical Activity Questionnaire (IPAQ). Serum insulin, glucose, cholesterol and plasma Aβ levels were measured in fasting blood samples. A subgroup (n=116) underwent 11C-Pittsburgh compound B (PiB) positron emission tomography (PET) scanning to quantify brain amyloid load. Higher levels of physical activity were associated with higher high density lipoprotein (HDL) (P=0.037), and lower insulin (P<0.001), triglycerides (P=0.019) and Aβ1−42/1−40 ratio (P=0.001). After stratification of the cohort based on APOE ɛ4 allele carriage, it was evident that only non-carriers received the benefit of reduced plasma Aβ from physical activity. Conversely, lower levels of PiB SUVR (standardised uptake value ratio) were observed in higher exercising APOE ɛ4 carriers. Lower plasma Aβ1−42/1−40 and brain amyloid was observed in those reporting higher levels of physical activity, consistent with the hypothesis that physical activity may be involved in the modulation of pathogenic changes associated with AD.

Association of plasma Aß peptides with blood pressure in the elderly

Background Aß peptides are often considered as catabolic by-products of the amyloid ß protein precursor (APP), with unknown physiological functions. However, several biological properties have been tentatively attributed to these peptides, including a role in vasomotion. We assess whether plasma Aß peptide levels might be associated with systolic and diastolic blood pressure values (SBP and DBP, respectively). Methodology/Principal Findings Plasma Aß1-40 and Aß1-42 levels were measured using an xMAP-based assay in 1,972 individuals (none of whom were taking antihypertensive drugs) from 3 independent studies: the French population-based 3C and MONA-LISA (Lille) studies (n = 627 and n = 769, respectively) and the Australian, longitudinal AIBL study (n = 576). In the combined sample, the Aß1-42/ Aß1-40 ratio was significantly and inversely associated with SBP (p = 0.03) and a similar trend was observed for DBP (p = 0.06). Using the median age (69) as a cut-off, the Aß1-42/Aß1-40 ratio was strongly associated with both SBP and DBP in elderly individuals (p = 0.002 and p = 0.03, respectively). Consistently, a high Aß1-42/ Aß1-40 ratio was associated with a lower risk of hypertension in both the combined whole sample (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.56-0.90) and (to an even greater extent) in the elderly subjects (OR, 0.53; 95% CI, 0.37–0.75). Lastly, all these associations appeared to be primarily driven by the level of plasma Aß1-40. Conclusion The plasma Aß1-42/Aß1-40 ratio is inversely associated with SBP, DBP and the risk of hypertension in elderly subjects, suggesting that Aß peptides affect blood pressure in vivo. These results may be particularly relevant in Alzheimers disease, in which a high Aß1-42/Aß1-40 plasma ratio is reportedly associated with a decreased risk of incident disease.

Association of plasma Amyloid Beta peptides with blood pressure in the elderly

P2-141 ASSOCIATION OF PLASMA AMYLOID BETA PEPTIDES WITH BLOOD PRESSURE IN THE ELDERLY Jean-Charles Lambert, Jean Dallongeville, Kathryn Ellis, Susanna Schraen-Maschke, James Lui, Simon Laws, Julie Dumont, Florence Richard, Dominique Cottel, Claudine Berr, David Ames, Colin Masters, Christopher Rowe, Cassandra Szoeke, Christophe Tzourio, Jean-Francois Dartigues, Luc Buee, RalphMartins, Philippe Amouyel, Institut Pasteur de Lille, Lille, France; Department of Psychiatry, Kew, Australia; Inserm U837, Lille, France; 5 Centre of excellence for Alzheimer’s disease research and care, Joondalup, Australia; 6 Inserm U88, Montpellier, France; 7 Department of Psychiatry, Victoria, Australia; Department of Psychiatry, Melbourne, VIC, Australia; Austin Hospital, Heidelberg, Melbourne, Australia; CSIRO, Victoria, Australia; 11 Inserm U708, Paris, France; 12 Inserm U593, Bordeaux, France; 13 Inserm U837 -Alzheimer & Tauopathies, Lille, France.