Associations of CSF BACE1 with Amyloid Pathology, Neurodegeneration, and Cognition in Alzheimer’s Disease

Neurology Medical Laboratory Science Medicine Basic Medical Sciences Medical Imaging Life Sciences
Alzheimer’s disease BACE1 PET imaging neurodegeneration

Original Title: 《Associations of CSF BACE1 with Amyloid Pathology, Neurodegeneration, and Cognition in Alzheimer’s Disease》

Background and Research Purpose

Alzheimer’s Disease (AD) is a leading cause of dementia in the elderly, characterized by the accumulation of β-amyloid protein (Aβ) plaques in the brain. Beta-site APP cleaving enzyme 1 (BACE1) plays a crucial role in the production of Aβ. Previous studies have shown significantly increased BACE1 activity in the cortex of patients with mild cognitive impairment (MCI) and AD. Clinical trials of BACE1 inhibitors have shown side effects such as brain volume reduction and cognitive decline. Therefore, the exact role of BACE1 in the pathology of Alzheimer’s Disease remains not fully understood.

Research Institutions and Authors

This study was conducted by Feng Gao, Mengguo Zhang, Qiong Wang, and others, all from the School of Life Sciences at the University of Science and Technology of China, and multiple research centers related to neurodegenerative diseases. The research was published in the journal “Acta Neuropathologica,” with a received date of March 28, 2024, a revised date of May 21, 2024, and an acceptance date of June 4, 2024.

Research Methods

The study was based on the China Aging and Neurodegenerative Disease Initiative (CANDI) cohort, including individuals with normal cognition (CN), mild cognitive impairment (MCI), AD dementia, and non-AD dementia (Non-ADD). These participants were enrolled in the study starting in 2018 and provided detailed health information. The study mainly used CSF samples, various imaging techniques (such as MRI, PET), and multiple biomarkers to analyze the levels of BACE1 in different diagnostic groups and its association with AD pathology and cognitive function.

Specific Procedures

  1. Participant Selection and Exclusion Criteria: From the CANDI cohort, 419 subjects were selected (average age 62.11 years, balanced gender ratio). These subjects were classified according to the NIA-AA criteria (2011) into AD, MCI, CN, or Non-ADD.

  2. Biomarker Measurement: Multiple biomarkers in CSF and serum, including total tau (t-tau), Aβ40, and Aβ42, were measured using commercial Single Molecule Array (Simoa) technology. CSF BACE1 levels were measured using the Meso Scale Discovery (MSD) electrochemiluminescence platform, and SAPPβ levels were analyzed by enzyme-linked immunosorbent assay (ELISA).

  3. Imaging Detection: This included T1-weighted MRI detection on a GE Discover 750W 3.0T MRI scanner. MRI data were analyzed through the Freesurfer software automatic preprocessing pipeline, extracting indicators such as cortical thickness and subcortical nucleus volume. Additionally, 18F-Florbetapir (AV45) PET scans were used to assess brain amyloid load, and 18F-Fluorodeoxyglucose (FDG) PET scans were used to evaluate brain glucose metabolism.

  4. Statistical Analysis: Data analysis was performed using IBM SPSS 23.0, MATLAB (R2023a), and R (4.0.4). Differences in BACE1 and SAPPβ levels across diagnostic groups were compared using ANCOVA models, adjusting for covariates such as age, gender, and Apoe-ε4 carrier status. Multiple linear regression models analyzed the correlation between CSF BACE1 levels and other biomarkers, with multiple comparison correction by the False Discovery Rate (FDR) method.

Main Findings

  1. Changes in BACE1 and SAPPβ Levels: CSF BACE1 and SAPPβ levels were significantly elevated in the MCI and AD groups, showing a positive correlation with CSF Aβ40 and Aβ42 levels, but not with amyloid plaque deposition.

  2. Correlation of BACE1 with CSF Biomarkers: CSF BACE1 levels showed a significant correlation with CSF p-tau181 and t-tau levels. CSF BACE1 levels were also negatively correlated with the CSF Aβ42/Aβ40 ratio and serum GFAP in the A+ group.

  3. Correlation of BACE1 with Cognitive Function/Neurodegeneration: CSF BACE1 levels were significantly positively correlated with cortical thickness and Mini-Mental State Examination (MMSE) scores, indicating its possible role in protecting neural activity and function. Multiple linear regression analysis also indicated that CSF BACE1 and SAPPβ levels were positively correlated with brain glucose metabolism (FDG-PET) signals, affecting multiple prefrontal and superior temporal brain regions.

  4. Longitudinal Changes and Prognostic Analysis: Subjects with higher baseline CSF BACE1 levels experienced slower reductions in cortical thickness and cognitive decline during follow-up, particularly in the bilateral insula regions.

Research Conclusions and Significance

This study suggests that BACE1 not only plays a role in Aβ production but may also protect neurons by regulating cortical thickness and cognitive function. This implies that the physiological function of BACE1 might be crucial for maintaining neural function in the later stages of Alzheimer’s Disease. Future development of more specific drugs to inhibit BACE1 cleavage of APP while ensuring the normal physiological function of BACE1 is necessary.

Research Highlights

  1. Discovery of the Protective Role of BACE1: BACE1 not only promotes Aβ production but also shows a positive correlation with cortical thickness and cognitive function, indicating its potential key role in protecting neural function.

  2. Enriching Knowledge of AD Progression: Provides new insights into the complex role of BACE1 in various stages of Alzheimer’s Disease.

The findings of this study are crucial for further understanding the pathogenesis of Alzheimer’s Disease and developing more targeted treatment methods.