Blood biomarkers of neurodegeneration associate differently with amyloid deposition, medial temporal atrophy, and cerebrovascular changes in APOE ε4-enriched cognitively unimpaired elderly

Abstract

Background: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tau tangles, and neurodegeneration in the brain parenchyma. Here, we aimed to (i) assess differences in blood and imaging biomarkers used to evaluate neurodegeneration among cognitively unimpaired APOE ε4 homozygotes, heterozygotes, and non-carriers with varying risk for sporadic AD, and (ii) to determine how different cerebral pathologies (i.e., Aβ deposition, medial temporal atrophy, and cerebrovascular pathology) contribute to blood biomarker concentrations in this sample.

Methods: Sixty APOE ε4 homozygotes (n = 19), heterozygotes (n = 21), and non-carriers (n = 20) ranging from 60 to 75 years, were recruited in collaboration with Auria biobank (Turku, Finland). Participants underwent Aβ-PET ([¹¹C]PiB), structural brain MRI including T1-weighted and T2-FLAIR sequences, and blood sampling for measuring serum neurofilament light chain (NfL), plasma total tau (t-tau), plasma N-terminal tau fragments (NTA-tau) and plasma glial fibrillary acidic protein (GFAP). [¹¹C]PiB standardized uptake value ratio was calculated for regions typical for Aβ accumulation in AD. MRI images were analysed for regional volumes, atrophy scores, and volumes of white matter hyperintensities. Differences in biomarker levels and associations between blood and imaging biomarkers were tested using uni- and multivariable linear models (unadjusted and adjusted for age and sex).

Results: Serum NfL concentration was increased in APOE ε4 homozygotes compared with non-carriers (mean 21.4 pg/ml (SD 9.5) vs. 15.5 pg/ml (3.8), p = 0.013), whereas other blood biomarkers did not differ between the groups (p > 0.077 for all). From imaging biomarkers, hippocampal volume was significantly decreased in APOE ε4 homozygotes compared with non-carriers (6.71 ml (0.86) vs. 7.2 ml (0.7), p = 0.029). In the whole sample, blood biomarker levels were differently predicted by the three measured cerebral pathologies; serum NfL concentration was associated with cerebrovascular pathology and medial temporal atrophy, while plasma NTA-tau associated with medial temporal atrophy. Plasma GFAP showed significant association with both medial temporal atrophy and Aβ pathology. Plasma t-tau concentration did not associate with any of the measured pathologies.

Conclusions: Only increased serum NfL concentrations and decreased hippocampal volume was observed in cognitively unimpaired APOEε4 homozygotes compared to non-carriers. In the whole population the concentrations of blood biomarkers were affected in distinct ways by different pathologies.

Keywords: Alzheimer’s disease; Blood biomarkers; PET imaging.

Fig. 1

Serum NfL, plasma NTA-tau and plasma t-tau concentrations in cognitively unimpaired APOE ε4 homozygotes (ε4ε4), heterozygotes (ε4ε3) and noncarriers (ε3ε3). Raw concentrations, median, first and third quartile and range are presented by the box plot, p values are further adjusted for age and sex. P-values below the figures presents overall difference between groups

Fig. 2

Hippocampal volume, medial temporal and global atrophy scores in cognitively unimpaired APOE ε4 homozygotes (ε4ε4), heterozygotes (ε4ε3) and noncarriers (ε3ε3). Raw concentrations, median, first and third quartile and range are presented by the box plot, p values are further adjusted for age and sex. P-values below the figures presents overall difference between groups

Fig. 3

Significant MRI voxel based morphometry results. (A) ε4ε4 < ε4ε3 (B) ε4ε4 < ε3ε3

Fig. 4

Voxel wise correlations between (A) serum NfL, (B) plasma GFAP and smaller grey matter volume. FDR corrected p < 0.001 in green colour. FWE corrected p < 0.05 in blue colour