Cerebrospinal Fluid Profiles of Amyloid β-Related Biomarkers in Alzheimer’s Disease
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The amyloid cascade hypothesis on the pathogenesis of Alzheimer’s disease (AD) states that amyloid β (Aβ) accumulation in the brain is a key factor that initiates the neurodegenerative process. Aβ is generated from amyloid precursor protein (APP) through sequential cleavages by BACE1 (the major β-secretase in the brain) and γ-secretase. The purpose of this study was to characterize APP metabolism in vivo in AD patients versus cognitively healthy subjects by examining alterations in cerebrospinal fluid (CSF) biomarkers. We measured BACE1 activity and concentrations of α- and β-cleaved soluble APP (sAPPα and sAPPβ, respectively) and Aβ40 in CSF, biomarkers that all reflect the metabolism of APP, in 75 AD patients and 65 cognitively healthy controls. These analytes were also applied in a multivariate model to determine whether they provided any added diagnostic value to the core CSF AD biomarkers Aβ42, T-tau, and P-tau. We found no significant differences in BACE1 activity or sAPPα, sAPPβ, and Aβ40 concentrations between AD patients and controls. A multivariate model created with all analytes did not improve the separation of AD patients from controls compared with using the core AD biomarkers alone, highlighting the strong diagnostic performance of Aβ42, T-tau, and P-tau for AD. However, AD patients in advanced clinical stage, as determined by low MMSE score (≤20), had lower BACE1 activity and sAPPα, sAPPβ, and Aβ40 concentrations than patients with higher MMSE score, suggesting that these markers may be related to the severity of the disease.
KeywordsAlzheimer APP Biomarkers Amyloid β Cerebrospinal fluid BACE1
We thank Åsa Källén, Monica Christiansson, Sara Hullberg, and Dzemila Secic for excellent technical assistance. This study was supported by grants from the Swedish Research Council, the Söderberg Foundation, Alzheimer’s Association, Swedish Brain Power, Swedish State Support for Clinical Research, the Lundbeck Foundation, Stiftelsen Psykiatriska Forskningsfonden, Stiftelsen Gamla Tjänarinnor, Uppsala Universitets Medicinska Fakultets stiftelse för psykiatrisk och neurologisk forskning, Alzheimerfonden, Hjärnfonden, the Göteborg Medical Society, Thuréus stiftelse, Pfannenstills stiftelse, and Demensfonden.
Conflict of interest
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