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BackgroundIn Alzheimer’s disease, plasma Aβ1-42 and p-tau predict high amyloid status from Aβ-PET, however the extent to which combination of both plasma assays predict remains unknown.MethodsPrototype Simoa assays were used to measure plasma samples from cognitively normal (CN) and symptomatic adults in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.ResultsThe p-tau181/Aβ1-42 ratio showed the best prediction of Aβ-PET across all participants (AUC=0.905, 95%CI:0.86-0.95) and in CN (AUC=0.873; 0.80–0.94), and symptomatic (AUC=0.908; 0.82–1.00) adults. Plasma p-tau181/Aβ1-42 ratio correlated with CSF-p-tau181 (Elecsys®, Spearman’s ρ=0.74, P1-42 ratio also predicted future rates of cognitive decline assessed by AIBL PACC or CDR-SOB (PDiscussionPlasma p-tau181/Aβ1-42 ratio predicted both Aβ-PET status and cognitive decline, demonstrating potential as both a diagnostic aid and as a screening and prognostic assay for preclinical Alzheimer’s disease trials.

INTRODUCTIONWe evaluated a new Simoa plasma assay for phosphorylated tau at aa217 enhanced by additional ptau sites (p217+tau).METHODSPlasma p217+tau levels were compared to 18F-NAV4694 amyloid-beta (Aβ) PET and 18F-MK6240 tau PET in 174 cognitively impaired (CI) and 223 cognitively unimpaired (CU) participants.RESULTSCompared to Aβ-CU, the plasma levels of p217+tau increased two-fold in Aβ+ CU and 3.5-fold in Aβ+ CI. In Aβ-the p217+tau levels did not significantly differ between CU, MCI or dementia. P217+tau correlated with Aβ centiloids ρ=0.67 (CI 0.64; CU 0.45) and tau SUVRMT ρ=0.63 (CI 0.69; CU 0.34). Area under curve (AUC) for AD vs Aβ-CU was 0.94, for AD vs other dementia was 0.93, for Aβ+ vs Aβ– PET was 0.89 and for tau+ vs tau-PET was 0.89.DISCUSSIONPlasma p217+tau levels elevate early in the AD continuum and correlate well with Aβ and tau PET.Research in ContextSystematic review: The authors reviewed the literature using PubMed, meeting abstracts and presentations. Plasma phospho-tau measures compare well to PET and post-mortem across the continuum of AD but accuracy varies across ptau target sites and assay methods. There are no reports comparing PET to plasma assays targeting multiple sites of tau phosphorylation as typically found in AD. The p217+tau assay targets p217 with binding enhanced by phosphorylation at additional sites such as aa212.Interpretation: Plasma p217+tau elevates early and correlates with both Aβ and tau as measured by PET indicating that tau phosphorylation is an early event in AD and occurs with Aβ deposition. Plasma p217+tau measurement should assist both selection for trials and diagnosis of AD.Future directions: Further validation studies, head-to-head comparison to other assays, assessing the influence of co-morbidities and the ability to measure change in brain Aβ and tau levels are required.

BackgroundOngoing research seeks to identify blood-based biomarkers able to predict the onset and progression of Alzheimer’s disease (AD). A potential biomarker is the unfolded conformational variant of p53, previously observed in individuals in the prodromal and clinical AD stages. In this retrospective study, we compare diagnostic and prognostic performances of measures of the amyloid β load with those of a conformational variant of U-p53 in plasma samples from individuals participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) cohort.MethodsImmunoprecipitation (IP) followed by liquid chromatography (LC) tandem mass spectrometry (MS/MS) and protein sequencing in plasma samples from the AIBL study identified the clinically relevant AZ 284®peptide, representing a measure of the U-p53 conformational variant (U-p53AZ). Based on U-p53AZquantification via IP/LC electrospray ionisation-coupled MS/MS (AlzoSure®Predict test) on 515 samples from 482 individuals from the AIBL cohort, the predictive performance of U-p53AZwas assessed and compared with amyloid load as measured by amyloid β-positron emission tomography (Aβ-PET). Its predictive performance was determined at 36, 54, 72 and 90 months following baseline assessment.ResultsU-p53AZwas able to identify individuals with AD dementia with an area under the receiver operating characteristic curve (AUC) of 99%. U-p53AZoutperformed the conventional Aβ-PET measures in predicting the onset of AD dementia both from preclinical (AUC=98%) and prodromal stages (AUC=89%), even 90 months prior to onset (AUC=99%). Additionally, the estimated predictive performance of U-p53AZwas superior (AUC ≥98%) to other risk factors (i.e., gender, Aβ-PET andAPOEε4 allele status) in identifying individuals at high risk for progression to AD.ConclusionThese findings support use of U-p53AZas blood-based biomarker predicting if individuals, at both asymptomatic and MCI stages, would progress to AD at least six years prior to the onset of clinical AD dementia.

The Australian Imaging and Biomarker Lifestyle (AIBL) study of aging is designed to aid the discovery of biomarkers. The current study aimed to discover differentially expressed plasma proteins that could yield a blood-based screening tool for Alzheimer’s disease. To search for biomarkers and elucidate mechanisms of AD, we immuno-depleted the most abundant plasma proteins and pre-fractionated the remaining proteins by HPLC, prior to two-dimensional gel electrophoresis. The relative levels of approximately 3,400 protein species resolved on the 2D gels were compared using in-gel differential analysis with spectrally resolved fluorescent protein detection dyes (Zdyes™). Here we report on analysis of pooled plasma samples from an initial screen of a sex-matched cohort of 72 probable AD patients and 72 healthy controls from the baseline time point of AIBL. We report significant changes in variants of apolipoprotein E, haptoglobin, α1 anti-trypsin, inter-α trypsin inhibitor, histidine-rich glycoprotein, and a protein of unknown identity. α1 anti-trypsin and α1 anti-chymotrypsin demonstrated plasma concentrations that were dependent onAPOEε4 allele dose. Our analysis also identified an association with the level of Vitamin D binding protein fragments and complement factor I with sex. We then conducted a validation study on individual samples using a targeted LC-MS/MS assay. This study indicates that a peripheral protein signature has potential to aid in the characterization of AD. We also found significant associations of protein levels with APOE genotype, indicating that differences in genotype influence the circulating abundances of proteins other than ApoE.

Higher cardiorespiratory fitness has been associated with enhanced cognitive function in older adults; yet, this relationship demonstrates a degree of variability. Thus, it is hypothesised that variation in genetic factors may influence the relationship between fitness and cognitive health. In this study we evaluate whether the BDNF Val66Met polymorphism moderates the relationship between cardiorespiratory fitness and verbal and visuospatial memory. Data from ninety-nine cognitively normal men and women aged 60 – 80 years were used. Fitness was assessed by peak oxygen consumption, and verbal and visuospatial memory were evaluated using well-validated measures. Participants were categorised into: lower-fit Met carriers, higher-fit Met carriers, lower-fit Val/Val, or higher-fit Val/Val. A significant interaction was observed between BDNF Val66Met and fitness on visuospatial memory performance; whereby lower-fit Met carriers performed 1SD lower than higher-fit Met carriers (p=0.04). We observed higher levels of fitness mitigated the deleterious effect of BDNF Met allele carriage on visuospatial memory. Future intervention studies should evaluate the effect of structured exercise on cognitive health between BDNF Val66Met carriers and Val/Val homozygotes.