Plasma tau, neurofilament light chain and amyloid-β levels and risk of dementia; a population-based cohort study

Abstract

CSF biomarkers, including total-tau, neurofilament light chain (NfL) and amyloid-β, are increasingly being used to define and stage Alzheimer's disease. These biomarkers can be measured more quickly and less invasively in plasma and may provide important information for early diagnosis of Alzheimer's disease. We used stored plasma samples and clinical data obtained from 4444 non-demented participants in the Rotterdam study at baseline (between 2002 and 2005) and during follow-up until January 2016. Plasma concentrations of total-tau, NfL, amyloid-β40 and amyloid-β42 were measured using the Simoa NF-light® and N3PA assays. Associations between biomarker plasma levels and incident all-cause and Alzheimer's disease dementia during follow-up were assessed using Cox proportional-hazard regression models adjusted for age, sex, education, cardiovascular risk factors and APOE ε4 status. Moreover, biomarker plasma levels and rates of change over time of participants who developed Alzheimer's disease dementia during follow-up were compared with age and sex-matched dementia-free control subjects. During up to 14 years follow-up, 549 participants developed dementia, including 374 cases with Alzheimer's disease dementia. A log2 higher baseline amyloid-β42 plasma level was associated with a lower risk of developing all-cause or Alzheimer's disease dementia, adjusted hazard ratio (HR) 0.61 [95% confidence interval (CI), 0.47-0.78; P < 0.0001] and 0.59 (95% CI, 0.43-0.79; P = 0.0006), respectively. Conversely, a log2 higher baseline plasma NfL level was associated with a higher risk of all-cause dementia [adjusted HR 1.59 (95% CI, 1.38-1.83); P < 0.0001] or Alzheimer's disease [adjusted HR 1.50 (95% CI, 1.26-1.78); P < 0.0001]. Combining the lowest quartile group of amyloid-β42 with the highest of NfL resulted in a stronger association with all-cause dementia [adjusted HR 9.5 (95% CI, 2.3-40.4); P < 0.002] and with Alzheimer's disease [adjusted HR 15.7 (95% CI, 2.1-117.4); P < 0.0001], compared to the highest quartile group of amyloid-β42 and lowest of NfL. Total-tau and amyloid-β40 levels were not associated with all-cause or Alzheimer's disease dementia risk. Trajectory analyses of biomarkers revealed that mean NfL plasma levels increased 3.4 times faster in participants who developed Alzheimer's disease compared to those who remained dementia-free (P < 0.0001), plasma values for cases diverged from controls 9.6 years before Alzheimer's disease diagnosis. Amyloid-β42 levels began to decrease in Alzheimer's disease cases a few years before diagnosis, although the decline did not reach significance compared to dementia-free participants. In conclusion, our study shows that low amyloid-β42 and high NfL plasma levels are each independently and in combination strongly associated with risk of all-cause and Alzheimer's disease dementia. These data indicate that plasma NfL and amyloid-β42 levels can be used to assess the risk of developing dementia in a non-demented population. Plasma NfL levels, although not specific, may also be useful in monitoring progression of Alzheimer's disease dementia.

Keywords: Alzheimer’s disease; Aβ42; NfL; dementia; plasma biomarkers.

Figure 1

Correlation of plasma levels of total-tau, NfL, amyloid-β₄₀ and amyloid-β₄₂ with age. The correlation between individual plasma total-tau, NfL, amyloid-β₄₀ (Aβ40), and amyloid-β₄₂ (Aβ42) levels (pg/ml) with age are shown. The black line represents the mean obtained by regressing each biomarker on age. r = Pearson correlation coefficient; P-value for each biomarker <0.0001.

Figure 2

Association of plasma total-tau, NfL, amyloid-β₄₀ and amyloid-β₄₂ levels and amyloid-β₄₂/amyloid-β₄₀ ratio with all-cause dementia. (A) Forest plots showing hazard ratios for all-cause dementia and 95% CI per quartile of plasma levels (pg/ml) of total-tau, NfL, amyloid-β₄₀, amyloid-β₄₂, and amyloid-β₄₂/amyloid-β₄₀ ratio, with the lowest quartile (Q1) as reference group. Hazard ratios were obtained from the Cox proportional hazard models that were adjusted for age, sex, assay batch number, systolic blood pressure, total and HDL cholesterol, smoking status, highest level of education, body mass index, APOE ε4 status, history of diabetes, stroke and coronary heart disease. (B) Cause-specific incidence curves showing the incidence of all-cause dementia with current age for total-tau. P-value for test for equality of the cause-specific cumulative incidence curve between the five groups: total-tau (P = 0.3087), NfL (P = 0.0162), amyloid-β₄₀ (P = 0.0012), amyloid-β₄₂ (P < 0.0001) and amyloid-β₄₂/amyloid-β₄₀ ratio (P < 0.0001) (Klein and Moeschberger, 2003). Plasma levels are categorized into equally sized groups using quartiles (lowest group, Q1: black, Q2: brown, Q3: blue and Q4: green line). In total, 549 individuals had a diagnosis of all-cause dementia and 1229 individuals had death as a competing event. The remaining 2666 individuals were censored. Numbers represent the total number per quartile at risk for all-cause dementia at a given age.

Figure 3

Hazard ratios for all-cause and Alzheimer’s disease dementia per quartile of plasma amyloid-β₄₂ and NfL combined. Bars show the hazard ratios (HRs) for all-cause dementia (A) and for Alzheimer’s disease dementia (B) per quartile of plasma NfL and amyloid-β₄₂, with the combination of the highest quartile group (Q1) of amyloid-β₄₂ and the lowest quartile group (Q4) of NfL as reference group (HR = 1.0). Hazard ratios were obtained with the Cox proportional hazard model adjusted for age, sex, assay batch number, highest level of education, smoking status, systolic blood pressure, total and HDL cholesterol, body mass index, history of diabetes, stroke and coronary heart disease and APOE ε4 status. There were no significant interactions between amyloid-β₄₂ and NfL for all-cause dementia (P = 0.15) and for Alzheimer’s disease dementia (P = 0.32), suggesting that the association between amyloid-β₄₂, NfL and the risk of dementia are independent of each other.

Figure 4

Longitudinal changes of plasma NfL and amyloid-β₄₂ levels and their rates of change over time before and after Alzheimer’s disease dementia diagnosis. (A) Trajectories of plasma NfL levels on a population-level are shown for Alzheimer’s disease (AD) dementia cases and dementia-free control subjects. (B) Trajectories of plasma amyloid-β₄₂ levels are shown for Alzheimer’s disease dementia cases and dementia-free control subjects. The yellow and blue lines depict estimated means of plasma levels based on repeatedly measured biomarkers for 374 cases with Alzheimer’s disease dementia and their age- and sex-matched controls, respectively. Dotted lines represent 95% CI. Background shaded dots are coloured accordingly and denote single measurements corresponding to data where models were fit upon. (C) Rate of change of plasma NfL at the individual level for cases with Alzheimer’s disease dementia compared to dementia-free control subjects. (D) Rate of change of plasma amyloid-β₄₂ at the individual level for cases with Alzheimer’s disease dementia compared to dementia-free control subjects. For these analyses, a log₂-transformed rate of change was estimated for those participants that had two or more biomarker measurements. One datapoint reflects the rate of change for each of these individuals, anchored at the time since disease diagnosis relative to first biomarker measurement. Analyses with linear mixed effect models were adjusted for age at baseline, sex, APOE ε4 status, time between baseline measurement and disease onset and the interaction with case or control status. Rates of change derived from the population level (A and B) are different compared to those derived from the individual level analysis presented in C and D, as population level analyses are based on the entire sample, and individual level analysis required multiple measurements and were therefore only carried out among those participants that contributed two or three measurements.