Plasma apolipoprotein E levels in longitudinally followed patients with mild cognitive impairment and Alzheimer's disease

Abstract

Background: Low levels of plasma apolipoprotein E (apoE) and presence of the APOE ε4 allele are associated with an increased risk of Alzheimer's disease (AD). Although the increased risk of AD in APOE ε4-carriers is well-established, the protein levels have received limited attention.

Methods: We here report the total plasma apoE and apoE isoform levels at baseline from a longitudinally (24 months) followed cohort including controls (n = 39), patients with stable amnestic mild cognitive impairment during 24 months follow up (MCI-MCI, n = 30), patients with amnestic MCI (aMCI) that during follow-up were clinically diagnosed with AD with dementia (ADD) (MCI-ADD, n = 28), and patients with AD with dementia (ADD) at baseline (ADD, n = 28). We furthermore assessed associations between plasma apoE levels with cerebrospinal fluid (CSF) AD biomarkers and α-synuclein, as well as both CSF and plasma neurofilament light chain (NfL), YKL-40 and kallikrein 6.

Results: Irrespective of clinical diagnosis, the highest versus the lowest apoE levels were found in APOE ε2/ε3 versus APOE ε4/ε4 subjects, with the most prominent differences exhibited in females. Total plasma apoE levels were 32% and 21% higher in the controls versus MCI-ADD and ADD patients, respectively. Interestingly, MCI-ADD patients exhibited a 30% reduction in plasma apoE compared to MCI-MCI patients. This decrease appeared to be associated with brain amyloid-β (Aβ₄₂) pathology regardless of disease status as assessed using the Amyloid, Tau, and Neurodegeneration (A/T/N) classification. In addition to the association between low plasma apoE and low levels of CSF Aβ₄₂, lower apoE levels were also related to higher levels of CSF total tau (t-tau) and tau phosphorylated at Threonine 181 residue (p-tau) and NfL as well as a worse performance on the mini-mental-state-examination. In MCI-ADD patients, low levels of plasma apoE were associated with higher levels of CSF α-synuclein and kallikrein 6. No significant correlations between plasma apoE and the astrocytic inflammatory marker YKL40 were observed.

Conclusions: Our results demonstrate important associations between low plasma apoE levels, Aβ pathology, and progression from aMCI to a clinical ADD diagnosis.

Keywords: APOE ε4; Alzheimer’s disease; Apolipoprotein E; Mass spectrometry; Plasma.

Fig. 1

Levels of plasma apoE in subjects with different APOE genotypes. Plasma apoE levels as assessed in subjects grouped based on their APOE genotype (a), APOE ε4 status (b), and in males and females with different APOE genotype (c). Data are shown as median (minimum–maximum). Group comparisons were done using the Kruskal–Wallis test followed by Dunn’s test (a, b) before/after Bonferroni correction for multiple comparisons or ANOVA with Tukey HSD as post hoc test (c)

Fig. 2

Total plasma apoE isoform distribution in APOE heterozygous individuals. Percentage (%) (a) and actual concentrations (b) of apoE2, apoE3, and apoE4 isoforms of total plasma apoE in APOE ε2/ε3, APOE ε2/ε4, and APOE ε3/ε4 subjects. Data are presented as average (a) or median (minimum–maximum) (b). p-values for APOE ε2/ε3 (black dots for apoE2, black triangles for apoE3), for APOE ε2/ε4 (black dots for apoE2, black squares for apoE4) and APOE ε3/ε4 (black triangles for apoE3, black squares for apoE4) were acquired using the Student’s t-test

Fig. 3

Plasma apoE levels per diagnostic group. Plasma apoE levels in controls, MCI-MCI, MCI-ADD and ADD patients (a) and in groups based on the A/T/N classification (b) and the Aβ_1-42 status (c). Data is presented as median (minimum–maximum). Group differences were assessed using ANOVA (Tukey HSD post hoc) (a), the Kruskal–Wallis test followed by the Dunn’s test uncorrected/corrected for multiple comparisons using Bonferroni correction (b), or Mann–Whitney U test (c). Star marked p-values obtained after accounting for the APOE genotype of the studied subjects. The A-/T-/N + and A + /T + /N- groups were excluded from the statistical analysis due to low n-numbers (n = 2, in each group)