The current cross-sectional analysis, which used the ADNI cohort, found that P-tau181 plasma levels were correlated with microstructural changes and NFL levels in the brains of AD and MCI patients. We investigated the correlation between plasma P-tau181 and participant demographic variables, including age, sex, education period, MMSE scores, APOE genotype, and brain regional glucose uptake between and within the groups. We used a partial correlation model controlled for age, APOE and sex to investigate the relation between plasma P-tau181 level and changes in WM microstructure. We provided evidence that baseline plasma P-tau181 levels are linked to extensive WM changes in all participants in the disease's pathological signature regions, including the hippocampal cingulum, splenium of corpus callosum, tapatum, posterior corona radiate, sagittal stratum, uncinate fasciculus, retrolenticular part of the internal capsule, cerebellar peduncles, and Medial lemniscus.
Due to the growing AD population and the associated social costs, as well as the fact that AD pathogenesis manifests several years before clinical signs occur, a reliable biomarker with sufficient sensitivity and specificity is needed (16). CSF biomarkers can be identified several years before the onset of AD symptoms, with Aβ and Tau being the most significant ones (36). Many studies have emphasized the diagnostic role of total tau (T-tau) and P-tau in CSF and suggesting that they can predict dementia progression (37-40). On the other hand, some studies present contradictory results (41, 42). Regardless, in terms of specificity and sensitivity, P-tau is preferred in predicting AD over the other biomarkers (36). Blood-based biomarkers have been studied in recent years as a noninvasive and accessible marker for tracking people at risk of developing AD. Beside T-tau, plasma P-tau181 levels have a high diagnostic value, according to evidence, and their levels are far higher in AD patients than in MCI and healthy controls (43). P-tau181 has been identified as a highly specific marker for AD development and tauopathy than T-tau in both CSF and blood (23, 24). Plasma P-tau181 act better than plasma T-tau for detecting pathological brain changes since it is more brain-specific, whereas T-tau can potentially be developed outside the CNS (44). On the other hand, other studies have found much weaker correlations between plasma T-tau and CSF T-tau levels than those found in P-tau181 (45). According to the findings of the largest plasma P-tau181 analysis in the diagnosis of AD, which included the results of four independent cohorts, plasma P-tau181 level has a high performance in determining the clinical stage of AD patients with significant correlation with Aβ deposition in the brain, and also distinguishing AD from other neurodegenerative disorders (19). In line with these findings our results showed that plasma P-tau181 levels were significantly higher in AD and MCI patients than in healthy individuals. It was also linked to a lower MMSE score and lower brain glucose uptake in the angular, temporal, and posterior cingulate regions, implying poor cognitive function and hypometabolism.
DTI is a sensitive tool for detecting WM microstructural changes, such as demyelination and axonal damage. There is also evidence that WM disturbance found by DTI can be seen in preclinical stages of AD and is linked to changes in cognitive performance in several domains, including memory and executive function (12, 46). Results of studies investigated WM damage in AD development were promising and revealed that changes in WM integrity in the temporal limbic and medial parietal is significantly related to NFTs pathology (47). Besides that, WM changes could be used to classify AD and MCI patients, as well as monitor CSF biomarkers in the early stages of the disease. (48, 49).
Although previous studies have reported a significant correlation between DTI metrics and CSF biomarkers including Aβ, T-tau, and P-tau, the association between blood-based biomarkers and WM damage is not clearly understood (50, 51)(). Besides that, little attention has been paid to the relationship between plasma P-tau181 and WM changes. WM degeneration can be determined by a decrease in FA and an increase in MD variables (52), as observed in the current study. In light of this, our findings mostly demonstrated WM neurodegeneration in relation to the level of plasma P-tau181. Coupled with our results, X Li et al. indicated that pathological levels of CSF Aβ1-42 and T-tau in AD patients with cognitive impairments was correlated with decreased FA and increased MD in the WM (53).
In the onset of dementia and cognitive decline, changes may extend to a wide variety of regions. When comparing AD patients to healthy individuals without cognitive impairment, DTI results revealed a significant WM damage in the internal capsule, corona radiates, uncinate fasciculus, cerebellar peduncles, medial lemniscus, and hippocampal cingulum (54). Our findings are in line with previous studies investigating WM microstructural changes related to AD (55, 56).
Interestingly, plasma P-tau181 was found to be correlated with microstructural changes in the left hippocampal cingulum in our study, highlighting the role of the cingulum in the pathological progression of the disease (57). The cingulum bundle links the frontal, parietal, and medial temporal lobes, connecting the subcortical nucleus to the cingulate gyrus and extending into the hippocampal and parahippocampal regions. As a result, damage in the cingulum near the hippocampus leads to cognitive problems in a variety of domains, including language, memory, and executive function (58). There is also evidence of a correlation between CSF P-tau and Aβ and a change in MD in the cingulum region, which could be detected using plasma P-tau 181 measurements as a reliable reflection of CSF levels (59). Furthermore, Nakata et al. presented convincing evidence of the posterior cingulum's involvement in cognitive functions, and neurodegeneration in this region appears to contribute to the development of AD (60).
CSF Aβ and tau have previously been discovered to be a predictor of changes in the uncinate fasciculus (61), which is involved in language processing and damage to this area can result in language impairments (62). According to our findings, there is a significant correlation between plasma P-tau181 and WM integrity changes in uncinate fasciculus as part of AD development process. Similarly, the parahippocampal WM, uncinate fasciculus, superior longitudinal fasciculus, cingulum, fornix, genu, and splenium of the corpus callosum all showed decreased FA in AD patients (63). Furthermore, our results indicated that level of plasma P-tau181 levels were significantly correlated with DTI values in other regions including internal capsule, corona radiates, cerebellar peduncles, corpus callosum and medial lemniscus which have previously been linked to cognitive function in AD and MCI patients (63). Previously, several studies were reported significant association of CSF Aβ, tau, and P-tau biomarkers with WM damage in variety of brain regions, including the internal capsule, corona radiates, cerebellar peduncles and corpus callosum, which was close to our findings for plasma P-tau181 (64, 65).
In conclusion, our study provide evidence regarding the association between plasma P-tau181 levels and neurodegeneration in brain WM regions of AD patients, demonstrating the biomarker's diagnostic potential and support the application of blood-based biomarkers as an early indicator for WM damages. Due to the increasing AD population and the resulting social costs and considering that AD pathogenesis appears several years before the emerging of the clinical signs, achieving a reliable biomarker with adequate sensitivity and specificity is necessary. Despite the fact that plasma P-tau181 outperforms CSF biomarkers and imaging techniques in terms of availability, low cost, and non-invasiveness, further research remains to be done to standardize biomarker measurement and establish pathological thresholds. Longitudinal studies are also needed to demonstrate the biomarker's efficacy in predicting structural changes.