Aβ oligomers peak in early stages of Alzheimer's disease preceding tau pathology

Abstract

Introduction: Soluble amyloid beta (Aβ) oligomers have been suggested as initiating Aβ related neuropathologic change in Alzheimer's disease (AD) but their quantitative distribution and chronological sequence within the AD continuum remain unclear.

Methods: A total of 526 participants in early clinical stages of AD and controls from a longitudinal cohort were neurobiologically classified for amyloid and tau pathology applying the AT(N) system. Aβ and tau oligomers in the quantified cerebrospinal fluid (CSF) were measured using surface-based fluorescence intensity distribution analysis (sFIDA) technology.

Results: Across groups, highest Aβ oligomer levels were found in A+ with subjective cognitive decline and mild cognitive impairment. Aβ oligomers were significantly higher in A+T- compared to A-T- and A+T+. APOE ε4 allele carriers showed significantly higher Aβ oligomer levels. No differences in tau oligomers were detected.

Discussion: The accumulation of Aβ oligomers in the CSF peaks early within the AD continuum, preceding tau pathology. Disease-modifying treatments targeting Aβ oligomers might have the highest therapeutic effect in these disease stages.

Highlights: Using surface-based fluorescence intensity distribution analysis (sFIDA) technology, we quantified Aβ oligomers in cerebrospinal fluid (CSF) samples of the DZNE-Longitudinal Cognitive Impairment and Dementia (DELCODE) cohortAβ oligomers were significantly elevated in mild cognitive impairment (MCI)Amyloid-positive subjects in the subjective cognitive decline (SCD) group increased compared to the amyloid-negative control groupInterestingly, levels of Aβ oligomers decrease at advanced stages of the disease (A+T+), which might be explained by altered clearing mechanisms.

Keywords: APOE; AT(N) classification; Alzheimer's disease; Aβ; cerebrospinal fluid; oligomers; preclinical; prodromal; sFIDA; tau.

FIGURE 1

Amyloid beta (Aβ) and tau oligomer pixel count based on amyloid pathology (A+/A−). (A) Aβ oligomer pixel counts in mild cognitive impairment (MCI) are significantly increased compared to the controls (p = .017). (B) By contrast, no significant changes were detected for tau oligomer pixel count. (C) After dividing groups along amyloid status, significantly higher levels in subjective cognitive decline (SCD) (A+) and MCI (A+) compared to controls (A−) were observed (p = .014 and p = .0028, respectively). Furthermore, SCD (A+) is significantly elevated compared to SCD (A−) (p = .048). (D) Tau oligomers in subgroups show no significant differences when divided in A+ and A−. Effect sizes for the significantly differing groups are provided in Table S3, while receiver operating characteristic curves and area under the curve scores are presented in Figure S4 and Table S5. Horizontal lines indicate the median; y‐axis scales are logarithmic. A two‐sided Mann–Whitney U‐test (confidence interval = .05) was carried out to investigate differences between the groups. Abbreviation: AD, Alzheimer's disease. *p ≤ .05, **p ≤ .01.

FIGURE 2

Amyloid beta (Aβ) oligomers in quantified cerebrospinal fluid (CSF) samples after AT (amyloid/tau) classification. Aβ oligomer pixel counts in CSF of A+T− patients are significantly increased compared to the reference group A−T− (p = 5.8 × 10⁻⁵) and to A+T+ (p = .0026). Effect sizes for the significantly differing groups are provided in Table S3, while receiver operating characteristic curves and area under the curve scores are presented in Figure S4 and Table S5. Horizontal lines indicate the median; y‐axis scale is logarithmic. A two‐sided Mann–Whitney U‐test (confidence interval = .05) was carried out to investigate differences between the groups. **p ≤ .01, ***p value ≤ .001.

FIGURE 3

Regression model for the interrelationship of amyloid beta (Aβ) oligomers pixel count, Aβ42, and phosphorylated tau (pTau) in cerebrospinal fluid (CSF). Based on Aβ42, pTau, and Aβ oligomer levels in CSF, regression models for prediction of Aβ oligomers pixel count were performed. Highest Aβ oligomer levels can be expected in patients with low Aβ42 while pTau is relatively low in (A) all patients, (B) apolipoprotein E (APOE) gene ε4 allele carriers, and (C) APOE ε4 noncarriers. Aβ42 oligomer levels in APOE ε4‐positive participants are overall higher and shifted toward higher pTau concentrations compared to those who were APOE ε4 negative.

FIGURE 4

Hypothetical model of amyloid beta (Aβ) oligomers in cerebrospinal fluid (CSF) within the Alzheimer's disease (AD) continuum. (A) Along the trajectory of biomarkers during AD progression from high Aβ42 and low pTau (A−T−) to lowered Aβ42 first (A+T−) followed by elevated pTau (A+T+), Aβ oligomers start to rise until a turning point is reached. Soon after pTau starts to increase, Aβ oligomer concentrations decrease. This panel is a zoomed‐in portion of Figure 3B. Data are represented in a binned form. (B) Hypothetical changes of Aβ oligomers during disease progression are transferred to the model of AD biomarker changes according to Jack et al. Apolipoprotein E (APOE) gene ε4 allele carriers show higher oligomer concentrations with a peak at a more advanced disease stage but still in the early stages of the disease. Due to the high age of the cohort (60+) and the absence of persons with advanced AD, it was not possible to cover the entire x‐axis with the curves. For validation of the model, Figure S5 shows a comparison between the measured oligomer level and the oligomer level determined by regression. Figure modified after Jack et al.

FIGURE 5

Proposed clearance mechanisms for amyloid beta (Aβ) oligomers and the influence on the use of Aβ oligomers as biomarker. Hypothetic scenario: Aβ monomer production at synapses is dependent on synaptic activity. At a certain time point, aggregation of Aβ monomers leads to the formation of toxic Aβ oligomers which can be cleared by different mechanisms. Aβ oligomers can be degraded by microglia (clearance mechanism #1), diffuse into cerebrospinal fluid (CSF), or be deposited into plaques (clearance mechanism #2) as soon as there are plaques. Formation of plaques in patients with amyloid pathology allows oligomers to be deposited there (clearance mechanism #2), which may well become the preferred fate of Aβ oligomers. Figure created with BioRender.com. APOE ε4, apolipoprotein E ε4 allele.