Association of CSF, Plasma, and Imaging Markers of Neurodegeneration With Clinical Progression in People With Subjective Cognitive Decline

Abstract

Background and objectives: Multiple biomarkers have been suggested to measure neurodegeneration (N) in the AT(N) framework, leading to inconsistencies between studies. We investigated the association of 5 N biomarkers with clinical progression and cognitive decline in individuals with subjective cognitive decline (SCD).

Methods: We included individuals with SCD from the Amsterdam Dementia Cohort and SCIENCe project, a longitudinal cohort study (follow-up 4±3 years). We used the following N biomarkers: CSF total tau (t-tau), medial temporal atrophy visual rating on MRI, hippocampal volume (HV), serum neurofilament light (NfL), and serum glial fibrillary acidic protein (GFAP). We determined correlations between biomarkers. We assessed associations between N biomarkers and clinical progression to mild cognitive impairment or dementia (Cox regression) and Mini-Mental State Examination (MMSE) over time (linear mixed models). Models included age, sex, CSF β-amyloid (Aβ) (A), and CSF p-tau (T) as covariates, in addition to the N biomarker.

Result: We included 401 individuals (61±9 years, 42% female, MMSE 28 ± 2, vascular comorbidities 8%-19%). N biomarkers were modestly to moderately correlated (range r -0.28 - 0.58). Serum NfL and GFAP correlated most strongly (r 0.58, p < 0.01). T-tau was strongly correlated with p-tau (r 0.89, p < 0.01), although these biomarkers supposedly represent separate biomarker groups. All N biomarkers individually predicted clinical progression, but only HV, NfL, and GFAP added predictive value beyond Aβ and p-tau (hazard ratio 1.52 [95% CI 1.11-2.09]; 1.51 [1.05-2.17]; 1.50 [1.04-2.15]). T-tau, HV, and GFAP individually predicted MMSE slope (range β -0.17 to -0.11, p < 0.05), but only HV remained associated beyond Aβ and p-tau (β -0.13 [SE 0.04]; p < 0.05).

Discussion: In cognitively unimpaired older adults, correlations between different N biomarkers were only moderate, indicating they reflect different aspects of neurodegeneration and should not be used interchangeably. T-tau was strongly associated with p-tau (T), which makes it less desirable to use as a measure for N. HV, NfL, and GFAP predicted clinical progression beyond A and T. Our results do not allow to choose one most suitable biomarker for N, but illustrate the added prognostic value of N beyond A and T.

Classification of evidence: This study provides Class II evidence that HV, NfL, and GFAP predicted clinical progression beyond A and T in individuals with SCD.

Figure 1. Correlations Between N Biomarkers

Heatmaps showing correlations between different biomarkers. (A) Correlation coefficients (Pearson). (B) Correlation coefficients (partial correlation, adjusted for age and sex). Phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were log-transformed. HV = hippocampal volume; MTA = medial temporal atrophy.

Figure 2. Distribution of AT(N) Profiles According to Different Definitions of Neurodegeneration

Distribution of AT(N) profiles for different definitions of neurodegeneration. GFAP 75 = glial fibrillary acidic protein, threshold 75th percentile; GFAP 90 = glial fibrillary acidic protein, threshold 90th percentile; HV 10 = hippocampal volume, threshold 10th percentile; HV 25 = hippocampal volume, threshold 25th percentile; MTA = medial temporal atrophy; NfL 75 = neurofilament light, threshold 75th percentile; NfL 90 = neurofilament light, threshold 90th percentile; t-tau = total tau.

Figure 3. Kaplan-Meier Curves Visualizing Clinical Progression Within a Classification

Kaplan-Meier curves visualizing clinical progression to mild cognitive impairment or dementia for different definitions of neurodegeneration (A, total tau [t-tau]; B, medial temporal atrophy [MTA]; C, hippocampal volume, threshold 25th percentile [HV 25]; D, neurofilament light, threshold 75th percentile [NFL 75]; E, glial fibrillary acidic protein, threshold 75th percentile [GFAP 75]). Survival is visualized by constructing a 4-level variable of dichotomous amyloid and neurodegeneration status (A–N–, A–N+, A+N–, A+N+).