Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects

Abstract

In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-β1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-β1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-β amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal fluid amyloid-β1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE ε4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-β1-42 values and APOE ε2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-β1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-β1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology.

Keywords: Alzheimer’s disease; biomarkers; cognitive ageing; dementia; imaging.

In a large multicentre study, Toledo et al. examine core Alzheimer’s disease CSF biomarkers in 1233 cognitively normal subjects aged 40–85 years. Alzheimer disease-like changes in Aβ1-42 are seen as early as middle age, while APOE genotype strongly modifies age-related effects on both Aβ1–42 and phosphorylated/total tau.

Figure 1

CSF amyloid-β_1-42, total tau and phosphorylated tau₁₈₁ levels in association with ageing in healthy controls stratified by APOE genotype. Dashed lines represent the cut-off points for the biomarkers.

Figure 2

Estimated frequency of pathological amyloid-β (A) and neurodegeneration (N) categories according to age of the subjects. Plots represent all subjects and subjects stratified by gender and APOE genotype. Due to smaller sample size subjects with ε2 alleles were not stratified by gender. Shaded areas represent 95% CI.

Figure 3

Frequency of A+, N+, A+N− and A+N+ stratified by APOE-defined groups.

Figure 4

Differences in the frequency of the four biomarker groups in subjects with APOE ε3/ ε3 genotype compared subjects who are ε2 or ε4 allele carriers. The lines above the black dashed line indicate that the plotted group has a higher frequency of the studied biomarker category. For the gender plots values above the 0 represent a higher frequency for females, whereas values below 0 represent a higher frequency in males. Shaded areas represent 95% CI.