Differential effects of neurodegeneration biomarkers on subclinical cognitive decline

Abstract

Introduction Neurodegeneration appears to be the biological mechanism most proximate to cognitive decline in Alzheimer's disease. We test whether t-tau and alternative biomarkers of neurodegeneration—neurogranin and neurofilament light protein (NFL)—add value in predicting subclinical cognitive decline. Methods One hundred fifty cognitively unimpaired participants received a lumbar puncture for cerebrospinal fluid and at least two neuropsychological examinations (mean age at first visit = 59.3 ± 6.3 years; 67% female). Linear mixed effects models were used with cognitive composite scores as outcomes. Neurodegeneration interactions terms were the primary predictors of interest: age × NFL or age × neurogranin or age × t-tau. Models were compared using likelihood ratio tests. Results Age × NFL accounted for a significant amount of variation in longitudinal change on preclinical Alzheimer's cognitive composite scores, memory composite scores, and learning scores, whereas age × neurogranin and age × t-tau did not. Discussion These data suggest that NFL may be more sensitive to subclinical cognitive decline compared to other proposed biomarkers for neurodegeneration.

New fluid biomarkers tracking non-amyloid-β and non-tau pathology in Alzheimer’s disease

“…However, NFL levels were significantly associated with cognitive decline and brain atrophy in all patients, regardless of amyloid pathology, while neurogranin levels were significantly associated with cognitive decline and brain atrophy only in patients with amyloid pathology 20 . When both biomarkers were compared directly, NFL levels were superior to neurogranin as a prognostic biomarker in MCI patients with positive Aβ biomarker results 94 and in normal elderly individuals (mean age, 59.3 ± 6.3 years) 95 .…”

“…For N, which relies on CSF tTau levels (which can be affected by tau pathology), the identification of new biomarkers of neurodegeneration, such as CSF NFL and neurogranin levels, may now be imminent. In many studies, CSF NFL better reflected clinical severity and predicted future cognitive decline more accurately than Aβ and tau proteins 22,94,95 . Therefore, CSF NFL could improve our ability to track disease progression.…”

Cognition at age 70

“…6 Several variations of the PACC have been tested. [6][7][8][19][20][21][22] We replaced the FCSRT with the 12-item Face-Name test (FNAME-12), 23 to avoid potential overlap with a similar wordlearning memory test administered to the NSHD cohort at multiple time-points throughout adulthood. 24 FNAME-12 is similar to FCSRT in terms of being an episodic memory test of immediate and delayed recall, is moderately correlated with FCSRT free recall scores 23 and is also relatively challenging for cognitively normal populations.…”

Elevated neurofilament light chain in plasma is associated with reduced right hippocampal and amygdala volume in Alzheimer's patients

“…NfL is an important cytoarchitectural protein present primarily in large-caliber myelinated axons 31 ,and increased NfL in CSF will indicate damage or degeneration of these axons. This protein appears to be relatively independent of tau and amyloid levels, and might correlate with symptomology, progression, and survival 32 . Now NfL has been considered as an especially promising biomarker for neurodegeneration because it can be measurable in plasma 33 .…”