Recently, MDS-Oaβ values have been utilized as a biomarker reflecting the pathophysiology of AD. This study compared MDS-Oaβ values between patients with and those without POD, in patients aged ≥ 70 years who underwent general anesthesia surgery. The research findings revealed a significantly higher MDS-Oaβ value in patients with POD compared to those without. Additionally, there was a significant positive correlation between the MDS-Oaβ value and the severity of delirium in patients with POD. Considering the epidemiological findings that POD in the elderly is associated with an increased risk of AD, it is highly likely that POD is linked to the pathophysiology of AD in this group. Therefore, to further explore this possibility, numerous studies have investigated the connection between POD and AD biomarkers.
According to a recent meta-analysis, there is a negative correlation between the levels of Aβ42 in CSF and the occurrence of POD. Conversely, no significant associations were found with other CSF biomarkers: Aβ40, total tau (T-tau), phosphorylated tau (P-tau), and the Aβ42/T-tau ratio[28]. Studies investigating plasma Aβ or the Aβ40/42 ratio have largely reported non-significant results regarding their association with POD[29–32]. Recently, Payne et al. examined the relationship between plasma Aβ levels and Aβ ratio (AβR) in 100 elderly individuals, both before and after surgery, to determine their association with POD[29]. They observed a postoperative increase in AβR compared to preoperative levels in surgical patients. However, this rise in AβR, or in individual plasma Aβ values, did not correlate significantly with the frequency or severity of delirium. The authors concluded that their findings do not support a connection between plasma amyloid and POD[29, 33].
In contrast to these studies, our findings revealed significantly higher MDS-Oaβ values in patients with POD compared to those without POD. Furthermore, a significant positive correlation was observed between MDS-Oaβ values and delirium severity in patients with POD, suggesting a clear link between amyloid pathology and POD. These results differed from previous findings, prompting the question: what factors could underlie this discrepancy?
The key difference between our study and previous ones lies in the selection of the amyloid biomarker. Unlike prior studies that employed amyloid monomers like plasma Aβ40 and Aβ42, we utilized the MDS-Oaβ test to specifically evaluate amyloid beta oligomers (AβOs). Initially recognized as intermediate substances in amyloid plaque formation, AβOs are now understood to be more neurotoxic than other amyloid peptides. Additionally, unlike static markers such as amyloid plaques, AβOs exhibit phasic behavior, varying with disease progression or state. This biomarker has the potential to manifest in the pathophysiology of AD from a very early stage, potentially earlier than other conventionally used biomarkers.
Studies have shown that ApoE purified from AD patient brains enhances Aβ oligomerization in an isoform-dependent manner, with the strongest effect observed for the E4 isoform[35]. In particular, individuals with two copies of the E4 isoform form more brain Aβ than E3 homozygotes[36] and be cleared more slowly from the body[37]. A study tracking long-term cerebrospinal fluid changes before the transition from normal cognition to mild cognitive impairment (MCI) in ApoE4 carriers revealed a lower Aβ42/Aβ40 ratio compared to non-carriers, suggesting amyloidopathy prior to symptom onset[38]. Our study showed significantly higher MDS-Oaβ values and an increased number of ApoE4 alleles in patients with POD. While regression analysis revealed no significant association between the number of ApoE4 alleles and POD occurrence, it did significantly influence MDS-Oaβ values in patients without POD. These findings suggest that the ApoE4 allele may have indirectly influenced the results of this study. Therefore, this study presents two sets of results: one from the overall study population and the other from a propensity score matching analysis conducted after reconstructing the study population based on the ApoE4 allele.
The observed elevation in MDS-Oβ values among patients with POD compared to those without POD in this study suggests two potential explanations. Firstly, POD delirium might arise from a post-surgical increase in Aβ, potentially triggering pathophysiological processes like neuroinflammation or synaptic dysfunction, ultimately contributing to the delirium pathology. This hypothesis finds support in the established ability of commonly used inhaled anesthetics, such as isoflurane, to promote Aβ oligomerization and accumulation in both in vitro and in vivo models. Isoflurane induces a time-dependent increase in Aβ oligomerization and accumulation in the brain. Moreover, evidence suggests that various anesthetics can alter amyloid metabolism through diverse pathways, leading to amyloidopathy. These findings raise concerns about the potential acceleration of AD progression in individuals exposed to these agents[39]. The second possibility is that even in patients who appear clinically normal, if they already have long-standing Aβ plaques (indicating ongoing AD pathology), the elevated Aβ levels during the surgical process could accelerate silent brain pathology. This acceleration could contribute to the development of both delirium and increase the risk of AD onset. However, due to the cross-sectional design of our study, it is not possible to determine which possibility is more likely. It merely indicates an association between POD and AβOs in some way. A prospective study, measuring MDS-Oβ values before surgery and comparing those with and without POD afterwards, is needed to definitively understand the relationship between MDS-Oβ values and POD.
This study has several limitations. First, the relatively short study duration limited the sample size. Second, the impact of general anesthetic surgery on MDS-Oaβ values in elderly patients aged 70 and above remains unclear. If, hypothetically, MDS-Oaβ values increase immediately after surgery and gradually decrease over time, the difference in sampling times could potentially influence the results. Patients with POD had immediate assessments at delirium onset, while the control group was assessed three days after surgery(Table 1, Table 3). This difference in sampling timing could potentially influence the results. Lastly, as previously mentioned, the cross-sectional design precludes establishing causation between delirium and AβOs.
This study, however, revealed a statistically significant association between POD and amyloid status. Among patients aged 70 or above undergoing general anesthesia surgery, those with POD exhibited significantly higher MDS-Oaβ values compared to those without delirium. Additionally, a positive correlation was found between MDS-Oaβ values and delirium severity, suggesting a link between elevated AβOs and the severity of delirium. Future research with larger and prospective cohorts is necessary to confirm these findings and explore potential preventive or therapeutic strategies for POD based on these observations.