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

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 beta-amyloid (A beta) (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 A beta 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 beta -0.17 to -0.11, p < 0.05), but only HV remained associated beyond A beta and p-tau (beta -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.