Correlations between plasma and PET beta-amyloid levels in individuals with subjective cognitive decline: the Fundació ACE Healthy Brain Initiative (FACEHBI)

Abstract

BackgroundPeripheral biomarkers that identify individuals at risk of developing Alzheimer’s disease (AD) or predicting high amyloid beta (Aβ) brain burden would be highly valuable. To facilitate clinical trials of disease-modifying therapies, plasma concentrations of Aβ species are good candidates for peripheral AD biomarkers, but studies to date have generated conflicting results.MethodsThe Fundació ACE Healthy Brain Initiative (FACEHBI) study uses a convenience sample of 200 individuals diagnosed with subjective cognitive decline (SCD) at the Fundació ACE (Barcelona, Spain) who underwent amyloid florbetaben(18F) (FBB) positron emission tomography (PET) brain imaging. Baseline plasma samples from FACEHBI subjects (aged 65.9 ± 7.2 years) were analyzed using the ABtest (Araclon Biotech). This test directly determines the free plasma (FP) and total plasma (TP) levels of Aβ40 and Aβ42 peptides. The association between Aβ40 and Aβ42 plasma levels and FBB-PET global standardized uptake value ratio (SUVR) was determined using correlations and linear regression-based methods. The effect of the APOE genotype on plasma Aβ levels and FBB-PET was also assessed. Finally, various models including different combinations of demographics, genetics, and Aβ plasma levels were constructed using logistic regression and area under the receiver operating characteristic curve (AUROC) analyses to evaluate their ability for discriminating which subjects presented brain amyloidosis.ResultsFBB-PET global SUVR correlated weakly but significantly with Aβ42/40 plasma ratios. For TP42/40, this observation persisted after controlling for age and APOE ε4 allele carrier status (R2 = 0.193, p = 1.01E-09). The ROC curve demonstrated that plasma Aβ measurements are not superior to APOE and age in combination in predicting brain amyloidosis. It is noteworthy that using a simple preselection tool (the TP42/40 ratio with an empirical cut-off value of 0.08) optimizes the sensitivity and reduces the number of individuals subjected to Aβ FBB-PET scanners to 52.8%. No significant dependency was observed between APOE genotype and plasma Aβ measurements (p value for interaction = 0.105).ConclusionBrain and plasma Aβ levels are partially correlated in individuals diagnosed with SCD. Aβ plasma measurements, particularly the TP42/40 ratio, could generate a new recruitment strategy independent of the APOE genotype that would improve identification of SCD subjects with brain amyloidosis and reduce the rate of screening failures in preclinical AD studies. Independent replication of these findings is warranted.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0444-1) contains supplementary material, which is available to authorized users.

Total Aβ 42 /Aβ 40 ratio in plasma predicts amyloid-PET status, independent of clinical AD diagnosis

“…These results are consistent with our previous findings showing an inverse association between the Aβ42/40 plasma ratios, particularly TP42/40, and cortical Aβ burden in an AIBL subcohort of cognitively normal controls 3 and other independent cohorts. 10,32 In agreement with this, it has previously been reported that the plasma Aβ42/40 ratio correlated directly with Aβ 42 CSF levels and inversely with Aβ-PET SUVR. [4][5][6][7][8][9] Moreover, our present results support previous community-based studies in healthy people reporting an association between lower plasma Aβ42/40 ratio and greater cognitive decline 12 or increased risk of developing AD dementia at follow-up.…”

Plasma Amyloid Concentration in Alzheimer’s Disease: Performance of a High-Throughput Amyloid Assay in Distinguishing Alzheimer’s Disease Cases from Controls

“…To our knowledge, we provide the first application of a novel, highthroughput technique for plasma A␤ analysis [43] to a research study that was run independently of the manufacturer. The assay had previously been used in four studies [28,45,47,48] of which one [47] used a subsample of an earlier investigation [45]. In sum, the studies found correlations of plasma A␤ 42/40 with CSF A␤ 42/40 [45], as well as associations of low plasma A␤ with presence of [28,45,47,48] and an increased 3-year accumulation of A␤ burden on PET [28].…”

Plasma amyloid beta levels are associated with cerebral amyloid and tau deposition

“…In addition, all samples were processed blinded to the diagnostic group or amyloid status. We analyzed two ratios, free plasma Aβ42 to free Aβ40 (Aβ F42:F40) and total plasma Aβ42 to total Aβ40 (Aβ T42:T40), as they had been previously shown to correlate with amyloid positivity [5,13,16,36].…”

“…In addition, all samples were processed blinded to the diagnostic group or amyloid status. We analyzed two ratios, free plasma Ab42 to free Ab40 (Ab F42:F40) and total plasma Ab42 to total Ab40 (Ab T42:T40), as they had been previously shown to correlate with amyloid positivity [5,13,16,36]. After a 90-minute uptake period, PET data were acquired for 20 minutes (90-110 minutes) using continuous list mode acquisition on a Siemens mCT.…”

“…Reduced plasma Ab has also been linked to poorer cognition [6,7,19,21,[27][28][29][30]. In addition, some studies have suggested that plasma levels of Ab42 and Ab40 are associated with the levels of cerebral Ab on positron emission tomography (PET), cerebrospinal fluid levels of Ab and tau, and AD-like brain atrophy [4,7,8,11,16,17,24,[31][32][33][34][35][36][37][38], while others have not seen such an association [25,39,40]. These conflicting results may be due to the type of plasma markers measured and the methodologies used to extract these values.…”