Blood biomarkers confirm subjective cognitive decline (SCD) as a distinct molecular and clinical stage within the NIA-AA framework of Alzheimer´s disease

Abstract

Subjective cognitive decline (SCD) is proposed as an indicator of transitional disease stage 2 in the Alzheimer's disease (AD) continuum. However, molecular and particularly longitudinal fluid biomarker data for this stage are still limited. This study aimed to determine whether blood-based biomarkers in amyloid-positive individuals with SCD (A + SCD) support the notion of stage 2 as a distinct stage between stages 1 and 3 of AD and to identify those at high risk for clinical progression. In a prospective multicenter study (DELCODE) involving 457 participants across the AD continuum, we analyzed plasma phospho-tau 181 (p181) and neurofilament light chain (NfL) and assessed their association with longitudinal cognition, hippocampal atrophy, and AD clinical stage transition. The results showed that baseline plasma p181 levels were elevated and increased more rapidly in A + SCD individuals compared to amyloid-positive cognitively unimpaired (A + CU) individuals (stage 1). NfL levels rose across A + CU, A + SCD, and amyloid-positive mild cognitive impairment (A + MCI, stage 3). In A + SCD, but not in A + CU, higher p181 levels predicted cognitive decline (PACC5) and transition to MCI. In conclusion, plasma p181 provides molecular biomarker evidence supporting A + SCD as a pre-dementia AD stage (stage 2) distinct from A + CU (stage 1) and helps identify individuals at risk for cognitive decline early in the AD continuum.

Fig. 1. Plasma p181 and NfL are elevated in A+SCD.

CU (blue), SCD (red), and MCI (green) individuals were stratified by CSF-amyloid positivity (A+ vs A-), and their baseline plasma analyzed using Simoa assays to detect A p181 and B NfL. Plasma from AD patients (purple) was included as a reference for both biomarkers. The respective stage in the AD continuum, operationalized using clinical assessment combined with CSF amyloid-positivity, is indicated below the graph (I: A + CU, II: A + SCD, III: A + MCI, IV + : AD). In both graphs, each point represents an individual subject, and means ± SEM are indicated. Differences between groups were assessed using Welch-ANOVA followed by Dunnett’s post hoc test (for p181 data) or Kruskal Wallis H test followed by Dunn’s post hoc test (for NfL data) for the contrasts indicated. *p < 0.05, **p < 0.01, ***p < 0.001, n.s., non-significant. A Plasma p181 levels are elevated in A + SCD compared to A + CU and A-SCD, while levels do not differ between A + SCD and A + MCI. B Plasma NfL levels show a trend towards increased levels in A + SCD compared to A + CU, and are significantly increased in A + SCD compared to A-SCD. Plasma NfL levels are then further elevated in A + MCI vs A + SCD.

Fig. 2. Plasma p181 levels increase at a higher rate over time in A+SCD and A+MCI compared to A+CU, while plasma NfL levels rise at a similar rate in A+CU, A+SCD, and A+MCI.

Plasma p181 and NfL were measured in plasma samples collected at ~1 year intervals from A+D A + CU and A-CU, B+E A + SCD and A-SCD, and C+F A + MCI and A-MCI. A+B Plasma p181 levels in A + SCD, compared to each A + CU and A-SCD increase more steeply over time. C The rate of change is then kept in MCI. D–F Changes of plasma NfL levels over time are similar in A + CU, A + SCD, and A + MCI, which leads to elevated NfL in A + SCD and A + MCI compared to A + CU individuals. Estimated trajectories for CU (blue), SCD (red), and MCI (green) are drawn using mixed-effects modelling with an interaction term for time and amyloid-positivity, and adjusted for age at baseline, and sex. Shaded areas indicate 95% confidence intervals.

Fig. 3. Longitudinal cognitive decline in A+SCD is predicted by higher plasma p181 levels at baseline.

Longitudinal trajectories of the PACC5 score of A CU (blue), B SCD (red), and C MCI (green) individuals, stratified by CSF amyloid-positivity are displayed. Dashed black lines indicate the trajectories for the clinical groups (CU, SCD, MCI) irrespective of the CSF amyloid status. A–C The rate of cognitive deterioration over time, as measured by PACC5, is increased in SCD compared to CU, largely driven by the worse performance of A + SCD individuals. The observed cognitive trajectory in A + SCD is then accelerated further in A + MCI. In panel D–F, baseline (BL) plasma p181 levels of the A + CU, A + SCD, and A + MCI group, categorized into low (light grey), mid (medium grey), and high (dark grey) levels using 3-quantiles, are used to predict longitudinal performance on PACC5. D–F Future cognitive decline observed in the A + SCD group is associated with high p181 levels at baseline. This predictive association is not seen to the same extent in the A + CU group. Once this association is started in the A + SCD, it is then maintained in the A + MCI group. Trajectories were derived from linear mixed models with an interaction term for time and baseline p181 levels, and adjusted for age at baseline, sex, and years of education.

Fig. 4. A+SCD compared to A-SCD individuals have a higher risk for conversion to the MCI stage, which is further increased in the presence of higher baseline levels of p181.

Survival curves for progression from A SCD to MCI, and B MCI to dementia, stratified by CSF amyloid-positivity are indicated. A SCD and B MCI individuals have a higher risk of progression to MCI and AD, respectively, in the presence of amyloid deposition. In panel C, D, progression from C A + SCD to MCI, D and A + MCI to dementia among individuals with high (first and second quartile, in black) versus low (third and fourth quartile, in light grey) baseline plasma levels of p181 are shown. The x-axis shows the time of follow-up from diagnosis of SCD or MCI, while the y-axis is the fraction of patients free of MCI or dementia at given time-points. Values below each graph indicate the number of subjects free of MCI/dementia at 0, 1-, 2-, 3-, and 4-years follow-up from first detection of SCD/MCI. Higher baseline plasma p181 levels predict the conversion of C A + SCD to MCI, and D A + MCI to dementia.