Plasma NfL levels were higher in CN participants with AD CSF biomarker profile as compared to CN with non-AD biomarker profile while plasma p-tau181 levels were higher in the CI patients with AD CSF profile. Plasma levels beyond 9,68 pg/ml were associated with higher occurrence of AD and adding them to a reference model improved the prediction of AD in CI participants. Plasma NfL levels were associated with CDRSoB changes over time in CN and CI patients while plasma p-tau181 levels were associated with changes in both CDRSoB and MMSE in CI. Adding plasma p-tau181 levels to a reference model improved the predictive performance of decline in global cognition in CI participants.
Both plasma biomarkers were associated with the presence of cerebral AD pathology as defined by a high CSF p-tau181/Aβ1–42 ratio. Previous studies have reported higher plasma NfL levels to be associated with AD dementia (3, 5, 4, 6). These studies defined AD using clinical assessment only (23) and did not consider CSF biomarkers for AD diagnosis. Accordingly, patients presenting clinically as AD dementia, but having cognitive impairment due to other cerebral pathologies may have been misdiagnosed and included, whereas our approach considers cerebral pathology as measured by CSF biomarkers. Additionally, we considered in our reference model known diagnosis covariates, including APOE ε4 status. We found that while plasma NfL is associated with AD it does not have an independent effect on the prediction of AD when considering covariates. These results along with the correlations between NfL and CSF tau, but not CSF Aβ1–42 and CSF Aβ42/Aβ40 ratio reinforce the role of NfL as a marker for neuronal injury (2), although not in an AD specific fashion as, in line with previous work, NfL appears independent of amyloid pathology (24).
Previous studies found associations of elevated plasma p-tau181 with amyloid positivity in participants with normal cognition or with cognitive impairment 8,12 11. A study found that combining plasma p-tau181 levels with either CSF tau or p-tau181 increases the predictive performance of clinically defined AD (25) Another study that defined AD considering both amyloid pathology and tau pathology reported results in line to ours, i.e. elevated p-tau181 levels in AD and predictive power in MCI and dementia participants (10). The addition of plasma p-tau181 levels to a reference model including age, sex, years of education and APOE ε4 status significantly improved the prediction performance for AD in CI patients. We observed a significant contribution of plasma p-tau181 independently of APOE ε4 in this model. Previous studies investigating the association of plasma p-tau181 with AD, either did not consider the APOE genotype (13, 12); or they did not consider the effects of this factor independently of p-tau181 (10, 9). Considering the APOE ε4 genotype as a covariate, we found that plasma p-tau181 additionally contributes to improve the prediction of AD in patients with cognitive impairment. This finding suggests that combining APOE ε4 genotype and plasma p-tau181 with clinical variables is superior to considering APOE ε4 genotype alone for the diagnosis of AD in memory clinic patients with cognitive impairment.
Together, our results indicate that plasma NfL levels can be used to identify participants with normal cognition at increased risk of having cerebral AD pathology, and contributes to identifying neurodegeneration irrespective of the underlying cause. However, plasma NfL does not seem suitable to improve differential diagnosis of AD in memory clinic patients with cognitive impairment. On the other hand, plasma p-tau181 levels have an independent and significant contribution to the prediction of the presence of cerebral AD pathology and appear to be more specific than plasma NfL levels for AD pathology. Therefore, plasma p-tau181 may be more appropriate for differential diagnosis in memory clinic patients presenting with cognitive impairment.
The non-specificity of the association of plasma NfL with AD is further shown by correlations of plasma NfL with CSF tau levels, independently of cognitive status, while only a weak correlation with CSF p-tau181 in CN, and no correlation with CSF markers other than CSF tau were present in CI. In a previous study, plasma NfL was not associated with any CSF biomarker in CN participants and AD dementia patients, but in MCI participants it was associated with CSF Aβ1–42 and CSF tau (3). Plasma NfL levels have been previously correlated to amyloid load assessed by PET scan in cognitively normal participants (26). This suggests AD pathology might be the main cause of neuronal injury and therefore NfL increase in CN participants, while in a majority of patients in the CI group neuronal injury might be caused by other pathologies, rendering NfL inefficient for differential diagnosis in this later group. Conversely, plasma p-tau181 levels correlated with CSF p-tau181 in CN participants and with all CSF biomarkers in CI participants, reinforcing its role as a biomarker candidate useful for differential diagnosis of AD.
In both CN and CI groups, higher plasma NfL baseline levels were associated with more rapid increase in disease severity as indicated by CDRSoB change at follow-up. After controlling for possible confounders only the association of plasma NfL levels with CDRSoB changes in CN participants remained significant. Previous studies have reported plasma NfL levels to correlate with baseline cognition (7, 4–6, 3). Of these studies, only two considered both CDR and MMSE scores (7, 4), and a single study reported a correlation of plasma NfL levels with longitudinal MMSE change in cognitively impaired participants (3). In line with previous reports (6, 4, 5), in CI patients higher NfL was associated with more marked increase in clinical disease severity over time, When added to a reference model based on clinical variables and the APOE ε4 status, plasma NfL did not significantly improve the prediction of severity progression at follow-up visit, however. Since NfL can be associated with neuronal injury of multiple aetiologies rather than with a specific pathological mechanism, elevated levels are indicative of multiple potential outcomes, rendering it inappropriate for modelling. Overall, our results suggest plasma NfL may be useful as a blood-based marker to identify individuals at high risk of cognitive decline among cognitively normal individuals.
We found higher plasma p-tau181 levels to be associated with more rapid increase in disease severity as well as with more marked decline in global cognition as assessed by changes in MMSE. Adding plasma p-tau181 levels to a reference model including age, sex, years of education, APOE ε4 status, baseline MMSE, and time to follow-up, significantly improved the prediction of decline in global cognition in CI participants. While the association of high levels of plasma p-tau181 with cognitive decline has been previously observed in MCI patients (13), we show here the added value of this plasma marker to predict cognitive decline when combined with other non-invasive measures. While these findings remain to be confirmed in an independent cohort, they suggest the utility of plasma p-tau181 in clinical practice as a blood-based prognostic biomarker for cognitive decline, in particular in patients with cognitive impairment.