Clarifying the association of CSF Aβ, tau, BACE1, and neurogranin with AT(N) stages in Alzheimer disease

Abstract

Background: Current AT(N) stratification for Alzheimer's disease (AD) accounts for complex combinations of amyloid (A), tau proteinopathy (T) and neurodegeneration (N) signatures. Understanding the transition between these different stages is a major challenge, especially in view of the recent development of disease modifying therapy.

Methods: This is an observational study, CSF levels of Tau, pTau181, pTau217, Aβ38/40/42, sAPPα/β, BACE1 and neurogranin were measured in the BALTAZAR cohort of cognitively impaired patients and in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Biomarkers levels were related to the AT(N) framework. (A) and (T) were defined in BALTAZAR with CSF Aβ42/40 ratio and pTau217 respectively, and in ADNI with amyloid and tau PET. (N) was defined using total CSF tau in both cohorts.

Results: As expected, CSF Aβ42 decreased progressively with the AD continuum going from the A-T-N- to the A + T + N + profile. On the other hand, Tau and pTau181 increased progressively with the disease. The final transition from A + T + N- to A + T + N + led to a sharp increase in Aβ38, Aβ42 and sAPP levels. Synaptic CSF biomarkers BACE1 and neurogranin, were lowest in the initial A + T-N- stage and increased with T + and N + . CSF pTau181 and total tau were closely related in both cohorts.

Conclusions: The early transition to an A + phenotype (A + T-N-) primarily impacts synaptic function. The appearance of T + and then N + is associated with a significant and progressive increase in pathological Alzheimer's disease biomarkers. Our main finding is that CSF pTau181 is an indicator of N + rather than T + , and that N + is associated with elevated levels of BACE1 protein and beta-amyloid peptides. This increase may potentially fuel the amyloid cascade in a positive feedback loop. Overall, our data provide further insights into understanding the interconnected pathological processes of amyloid, tau, and neurodegeneration underlying Alzheimer's disease.

Keywords: Alzheimer’s disease; Amyloid; BACE1; Cerebrospinal fluid; Neurodegeneration; Neurogranin; Tau proteinopathy.

Fig. 1

CSF biomarker levels in the AT(N) framework. Violin plot distribution of Aβ40 and Aβ42 CSF levels in the BALTAZAR (A, C) and the ADNI (B, D) cohorts, stratified by AT(N) classification showing median and quartiles. Aβ40 levels were statistically different between A-T-N- vs. A + T-N- and between A + T + N- vs. A + T + N + . Aβ38 levels (F) showed also an statistically significant increase with the presence of N + . Aβ42 levels as well as Aβ42/40 ratio (E) is used for A + stratification were much lower in A + T-N- compared to A-T-N-. sAPPs distribution (G, H) are similar to that of Aβ40. Ng (I), as a synaptic biomarker, is decreased in isolated A + T-N- and increased in T + and N + . BACE1 (H) is also decreased in isolated A + T-N-, increased a little in T + and more in N + . P values of Wilcoxson test < 0.001 are indicated with ***, < 0.01 with ** and < 0.05, with *

Fig. 2

Unsupervised clustering of AT(N) status and CSF biomarkers in the BALTAZAR cohort. "In this representation, the individual biomarkers in each row are ordered based on their Euclidean distance, also illustrated by the dendrograms. Each column is ordered similarly and represents the A, T, N positive and negative situations (see supplementary Table 2). CSF biomarkers formed three distinct clusters. The first cluster grouped Aβ42 and Aβ42/40. The second cluster grouped Ng with Tau, pTau181, and pTau217. The third cluster grouped BACE1, Aβ40, Aβ38, sAPPα, and sAPPβ. ATN situations are also separated into positive and negative situations, with T and N closer together. The legend and the color gradient represent the variation of the biomarkers from low (blue) to high levels (red) in the different ATN subgroups