Distinct cerebrospinal fluid profile of amyloid-β peptides for cerebral amyloid angiopathy or Alzheimer’s disease

5 March 2024

Accumulation of amyloid-β (Aβ) peptides of 40 or 42 amino acids long are recognized as main neuropathological hallmarks in cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD), respectively. The significance of alternative Aβ peptide species in the pathogenesis and differentiation between both diseases remains understudied.

In a recent publication titled 'Profiling amyloid-β peptides as biomarkers for cerebral amyloid angiopathy', Emma van den Berg (PhD candidate in Marcel Verbeek’s neurochemistry research group) explored the biomarker potential of various amyloid-β (Aβ) isoforms to distinguish between cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD) pathology. Using liquid chromatography and tandem mass spectrometry, concentrations of six different Aβ peptides (Aβ_1-34, Aβ_1‑37, Aβ_1-38, Aβ_1-39, Aβ_1-40, and Aβ_1‑42) could simultaneously be quantified in cerebrospinal fluid (CSF). The findings were recently published in the Journal of Neurochemistry.

Decreased levels of all Aβ peptides were found in CAA patients compared with controls. Moreover, when comparing Aβ peptides levels of CAA patients to subjects with a CSF profile indicative of AD pathology (i.e., AD-like subjects), all peptides, except for Aβ_1‑42, were decreased in CAA. Notably, these findings suggest distinct pathological mechanisms between vascular and parenchymal Aβ aggregation, reflected by decreased CSF levels of shorter Aβ peptides specifically in CAA, but not in AD-like subjects.

Importantly, the study highlights the potential use of this panel of Aβ peptides to aid in detecting the presence of CAA in AD patients. Currently, it is insufficiently possible to identify people with CAA, by using magnetic resonance imaging. These CSF biomarkers may aid to exclude AD patients with CAA from anti-Aβ immunotherapy trials. Namely, AD patients with comorbid CAA who participated in these trials are at an increased risk of developing so-called ‘amyloid-related imaging abnormalities’, characterized by hemorrhagic or edematous swelling of the brain, which may result in neurological side-effects instead of providing beneficial treatment effects.

In conclusion, the study's findings underscore the importance of considering alternative Aβ peptide species in distinguishing between CAA and AD pathology, offering potential implications for diagnostic strategies and treatment decisions. Moving forward, further research is needed to validate these findings in larger cohorts and explore the broader implications for clinical practice, especially in selecting individuals for therapy.

Read the full study here: https://onlinelibrary.wiley.com/doi/10.1111/jnc.16074