The primary objective of this study was to compare plasma Aβ40, Aβ42 and t-tau examined by Simoa immunoassay in a continuum of cognitive decline including NC, SCD, Obj-SCD, MCI and AD. Consistent with the previous reports(6, 11, 12), concentration of plasma Aβ42 and ratio of Aβ42/Aβ40 were significantly lower in AD patients, while plasma Aβ40 was less distinct. Plasma t-tau showed no significant difference among the diagnostic groups, which was in agreement with the findings in the cohort of BioFINDER(34). It is worth noting that levels of plasma Aβ40 and Aβ42 were obviously higher in our groups of SCD and Obj-SCD, and showed a significant trend of initially increasing from NC to SCD and Obj-SCD, and then decreasing from SCD and Obj-SCD to MCI and AD. To a great extent, this change was similar to the findings that levels of plasma Aβ isoforms manifested as a bidirectional character over the course of cognitive decline, which was more likely to increase in the early stages of cognitive impairment and decrease prior to clinical AD onset(16–18). As in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, plasma Aβ40 and Aβ42 levels measured by double sandwich ELISA tended to be higher for MCI than both NC and AD, though were statistically less significant (16). However, with more detailed grouping criteria for cognitive decline, our results indicated that plasma Aβ42 and Aβ40 were significantly higher in SCD and Obj-SCD but not MCI. This may be partly due to the diagnosis of MCI in this study were based on an actuarial method with comprehensive neuropsychological tests, which may lead to less false positive and greater percentage of progression to dementia compared to conventional MCI diagnostic criteria(29). Compared to the marginal significance in AIBL, significant differences of plasma Aβ40 and Aβ42 between diagnostic groups in this study may also attribute to the ultrasensitive performance of SIMOA platform we used. On the other hand, given the bidirectional character of plasma Aβ40 and Aβ42 during the progression of cognitive decline in our study, no significant difference of plasma Aβ40 and Aβ42 between the groups of NC and MCI was not surprising, as observed in this study and previous report(35). In contrast, this study showed no biphasic evolution of Aβ42/Aβ40 ratio across the cognitive decline but significantly lower Aβ42/Aβ40 ratio in AD than all other groups. At this point, though the relative ratio of Aβ42 and Aβ40 may normalize the pre-analytical variability and eliminate the inter-individual differences for total Aβ concentrations(36, 37), as plasma Aβ42 and Aβ40 showed synchronous changes in SCD and Obj-SCD, the change of Aβ42/Aβ40 ratio would inevitably be weakened.
Previous studies demonstrated that plasma amyloid-β examined using the Simoa immunoassay could be useful as a potential surrogate for brain Aβ pathology, though the performances were not sufficient and discrepancies remained(6, 7, 9, 38, 39). In the present study, relationships between plasma amyloid-β and 18F-florbetapir SUVR were assessed not only in all the subjects with Aβ-PET scan, but also in subjects with different Aβ-PET status. As a result, both plasma Aβ42 and Aβ42/Aβ40 ratio were significantly corelated with 18F-florbetapir SUVR in all the subjects, though the correlation became weak in the subgroup of Aβ-PET-positive, and no significant relationship was found in the subgroup of Aβ-PET-negative. We therefore speculate that significant correlation between plasma amyloid-β and 18F-florbetapir SUVR in all the subjects may due to their marked alteration between the subgroups of cerebral Aβ positive and negative. In view of the bidirectional character of amyloid-β with cognitive decline in our study, we further compared the levels of plasma biomarkers between different cerebral Aβ burden subgroups but not the simple status of positive or negative via visual interpretation of Aβ-PET. As a result, similar to their bidirectional character in the progression of cognitive decline, the levels of plasma Aβ42 and Aβ40 showed an increasing trend from low SUVR to moderate SUVR and decreasing from moderate SUVR to high SUVR, though only the decreasing of plasma Aβ42 in the subgroup of high 18F-florbetapir SUVR had statistical significance. Taken together, as transportation of Aβ across blood–brain barrier (BBB) plays a major role in Aβ clearance(40), the bidirectional trend of plasma amyloid-β along with cognitive decline and cerebral Aβ burden may be associated with the alteration of equilibrium between amyloid-β production and clearance in AD continuum. A higher level of amyloid-β in peripheral blood may be attributed to the compensatory increased transportation of amyloid-β across blood–brain-barrier. At this point, though it is typically considered that decreased Aβ clearance contribute to the predominant pathogenesis of late-onset AD (LOAD)(41), the elevated plasma Aβ40 and Aβ42 in SCD and Obj-SCD, or not decreased plasma Aβ40 and Aβ42 in the group of moderate Aβ-PET SUVR indicated that amyloid‑β clearance from brain by the BBB was not initially impaired, at least in preclinical AD. However, plasma amyloid-β showed significantly decreased with disease progression, consistent with the change in CSF. This may, at least in part, be due to the dysfunction of clearance systems for removing Aβ from brain, such as BBB clearance, Interstitial fluid bulk-flow clearance and CSF absorption clearance(40). In addition, this can also be explained by the acceleration of Aβ aggregation in brain(42), rather than an intrinsic defect of clearance system. On the other hand, whether the initially elevated level of plasma Aβ in SCD and Obj-SCD represents more soluble forms of amyloid-β in brain and be a potential window period for anti-Aβ immunotherapy still need more studies to confirm. Either way, the ratio of Aβ42/Aβ40 showed a gradually decreasing but not bidirectional trend with the increasing of SUVR. This may contribute to the fact that Aβ42 is more likely to form hard-to-clear aggregates than Aβ40 in the progression of cerebral amyloid deposition according to their structural characteristics(43).
Owning to the invasive procedure of CSF and high cost of PET image, blood-based assessments with comparable accuracy in predicting cerebral pathology of AD are urgently needed, especially in population screening. In our current study, a lower ratio of plasma Aβ42/Aβ40 demonstrated acceptable value (AUC = 0.762) in identifying high brain Aβ burden. This was similar to the study in which amyloid-PET positivity was defined by composite SUVR (AUC = 0.79)(38), and higher than the study in which amyloid-PET positivity was defined by visually read (AUC = 0.68)(7). In any case, with the ultrasensitive technology of Simoa, plasma amyloid-β may be a potential surrogate in predicting cerebral Aβ deposition and could undoubtedly serve as a prescreening method to reduce the need of invasive or expensive methods such as lumbar puncture or PET scanning. In our whole cohort regardless the underlying Aβ pathology, both plasma Aβ42 and Aβ42/Aβ40 ratio showed potential ability in discriminating the diagnosis of AD from non-AD. Furthermore, in the subset of AD continuum with Aβ positive determined by 18F-florbetapir PET, both plasma Aβ42 and Aβ42/Aβ40 ratio showed even higher diagnostic accuracy in identifying AD. Thus, it can be seen that, even Aβ deposition reaches the threshold of positivity in PET imaging, plasma amyloid-β may continue to change along with cerebral Aβ deposition during the natural course of AD.
Several limitations should be noted in this study. First, only parts of our participants underwent 18F-florbetapir PET scan, which may have led to the non-significant differences of plasma amyloid-β between the groups of low and moderate 18F-florbetapir SUVR. By expanding the sample size of our cohort, we would like to re-assess the changes of plasma amyloid-β between different cerebral Aβ burdens or different distributions of Aβ in brain regions. In addition, the NC subgroup had relatively lower prevalence of Aβ-PET positivity in our study than previous reports, though this could contribute to the fact that SCD and Obj-SCD may be regarded as normal controls in previous studies. Second, as another primary neuropathological hallmarks of AD, phosphorylated tau in blood was not measured in this study. Plasma p-tau181 examination and cerebral tau PET scan will be carried out in our future studies to further increase our understanding of cerebral and peripheral biomarkers of AD. Third, designed as a cross sectional study, longitudinal data are needed to confirm the evolution of plasma biomarkers along with cognitive decline within our findings.