In the present study, we found that discordant group was intermediate to concordant-negative and concordant-positive groups in terms of APOE ε4 positivity, CSF Aβ and p-tau levels at baseline, as well as the rates of cognitive decline reflected by cognitive scores and brain structures. Besides, the risk of cognitive progression increased from concordant-negative to discordant to concordant-positive. These longitudinal results were validated in A + T+, CN and MCI individuals, and were also validated by applying different cut-offs for neurodegenerative biomarkers. Altogether, our findings suggest that discordant neurodegenerative status denotes a stage of cognitive function which is intermediate between concordant-negative and concordant-positive.
Neurodegenerative pathology can be reliably measured in vivo with neuroimaging technology or CSF assessments, but substantial discordance exists when utilizing different methods to evaluate the “N” biomarkers in the same person . Several surrogate mechanisms were possibly helpful in explaining the discordant states. Firstly, discordant cases accounted for a large proportion in the whole study sample, and consequently differences might exist in the time point at which neurodegenerative changes were detected by CSF assessments, MRI or FDG-PET. Vemuri et al. reported that MRI could be closer correlated with cognitive development than CSF t-tau, since the latter might be more prone to diurnal physiologic variations, thus revealing transient rather than cumulative damage . However, this finding was inconsistent with our longitudinal results from discordant subjects. Thus, it's difficult to determine the sequence of “N” biomarker abnormality and find which specific “N” biomarker might indicate an earlier pathologic stage. Further research on this topic is needed. Secondly, the presence of the “N” biomarkers can be caused by several diseases, and therefore these biomarkers are not specific for neurodegenerative changes in AD. Also, in any individual, the proportion of neurodegenerative damage due to AD versus other probable comorbidities (most of which have no extant biomarker) remains unclear . Therefore, the “N” biomarker positivity measured by CSF assessments or neuroimaging could be caused by other situations rather than AD, such as cerebrovascular disease (white matter hyperintensity) and neuroinflammation [28–30]. The third explanation is the existence of analytical artifacts. CSF may be absorbed on the surface of the tube, and its decreased amount that's available for analysis probably affected the obtained concentration in CSF . However, neuroimaging technology is likely to bring false positive results in patients under comorbid conditions, and bring false negative results in patients with atypical forms of neurodegenerative pathology.
Since AD pathology has accumulated for decades before apparent clinical symptoms occur, the early identification of non-demented individuals at imminent risk of cognitive impairment would provide insights into intervention as well as new therapy approaches . And the heterogeneity in the definition of neuronal injury is vital to clinical trials using biomarkers for enrollment or as alternative endpoint measures. In the three profiles, the discordant group was intermediate to concordant-negative and concordant-positive groups in terms of cognitive performance, no matter in non-demented, or CN or MCI populations. Accordingly, concordant-negative, discordant and concordant-positive groups were likely to indicate meaningfully different stages of cognitive function. Regardless of any abnormality in neuroimaging signatures (patterns of gray matter atrophy on structural MRI or FDG-PET) or CSF t-tau measurements, the isolated "N" positivity indicated a relatively early stage that needed to implement interventions before any two biomarkers became abnormal. Previous studies have reported the correlations between neuronal injury factors, and it has been noted that the combination of these biomarkers might provide better prediction than either source of data alone [15, 19, 21, 22]. Vos et al. also suggested that individuals with both CSF Aβ deposition and neuronal injury showed an increased risk of disease progression . Nevertheless, due to the lack of evidence on whether and how discordant status influenced clinical outcomes, the feasibility and practicality of identifying discordant cases with cognitive disorders requires more research to confirm.
Our findings may have important implications for the diagnosis and treatment of AD, since they highlight the role of a discordant status in determining the therapeutic window before irreversible neuropathological changes. In the ATN system, “A” and “T” biomarkers reveal characteristic pathological changes that define AD, whereas neurodegenerative/neuronal injury biomarkers are nonspecific, which are applied only for staging of disease severity . Targeting A + T + patients, a recent study has compared the clinical outcomes of individuals having normal or abnormal single “N” biomarker and has found that all of the three “N” biomarkers were highly related to an increased risk of conversion to AD dementia . By combining these “N” biomarkers, our study revealed that the conversion risk in discordant group was intermediate between those of concordant-negative and concordant-positive groups. In another word, even among the patients who have developed into a stage which could be biologically defined as AD, early identification of the patients with abnormal “N” biomarkers may provide insights into disease-modifying therapeutics or interventions of modifiable risk factors, which thus might delay the occurrence of cognitive decline or disease progression. In addition, our work could be a complement to the original ATN framework for AD's biological definition.
We conducted a large prospective study with a relatively long follow-up duration, which well characterized the cognitive trajectories of discordant and concordant patients. An additional strength was that results were robust even after threshold modification, or in different populations. Nonetheless, some caveats should be emphasized. Firstly, dichotomizing each biomarker may mask a potential continuum. Compared with the condition employing only one single biomarker, the classification error rate increased when three distinct “N” biomarkers were utilized. Secondly, although the total sample size was large, the numbers of individuals in various groups were insufficient, especially when the discordant population was further categorized into different groups or when groups were stratified by clinical diagnosis, which may reduce the statistical power to detect longitudinal changes. Thirdly, the results targeting discordant subjects were inconsistent and it's difficult to conclude which “N” biomarker became abnormal first. Thus, further investigations targeting this topic were necessary.