Cerebrospinal Fluid Synaptic Biomarkers Altered Early in Alzheimer Disease Continuum

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In a cross-sectional study, researchers determined whether CSF synaptic biomarkers are altered in individuals during the preclinical stage of Alzheimer continuum.

Cerebrospinal fluid (CSF) synaptic biomarkers increase in the early preclinical stages of Alzheimer disease (AD) even when a low burden of β-amyloid (Aβ) pathology is present, according to study findings published in Neurology.

Previous research on CSF synaptic biomarkers in preclinical AD is limited and unclear. Moreover, research on preclinical AD is challenging due to the difficulty of recruiting participants during early disease stage. The objective of the current study was to determine whether CSF synaptic biomarkers change in individuals at the preclinical stage of AD continuum. Also, the researchers sought to investigate how synaptic biomarkers differ from their association with AD risk factors and neurodegeneration biomarkers.

The cross-sectional study was conducted in a cohort from the Alzheimer’s and Families (ALFA) study of 2743 cognitively unimpaired individuals aged 45 to 74 years with a family history of AD (47.4%) and APOE e4 carriership (32.5%). The nested longitudinal ALFA+ study included 450 participants aged 45 to 65 years who were invited to participate based on their specific AD risk profile.

A total of 384 participants (mean [SD] age 61.1 [4.68] years; 60.9% female; 54.4% APOE Ɛ4 carriers) were ultimately included in the analysis, and 64.8% (n=249) were CSF Aβ-negative. Regarding imaging, 327 (85.2%) participants had Aβ and fluorodeoxyglucose positron emission tomography (FDG PET), and 365 (95.1%) had structural magnetic resonance imaging (MRI) with automatic segmentation available.

CSF neurogranin, SNAP-25, GAP-43, and synaptotagmin-1 significantly increased with age in the overall cohort. CSF neurogranin was higher in female vs male participants (P =.021), and CSF SNAP-25 was higher in APOE e4 carriers vs noncarriers (P =.020).

Increased levels of the 4 CSF synaptic biomarkers were significantly associated with higher Aβ pathology (lower CSF Aβ42/40). The biomarkers also significantly increased as a function of Aβ PET Centiloids.

The researchers also assessed biomarker levels in the participants with a low burden of Aβ pathology to determine whether the biomarkers are altered early in the Alzheimer continuum. The 4 biomarkers were all significantly increased in the low-burden group (n =89) and in the CSF/PET Aβ-positive group (n =26) vs the CSF/PET Aβ-negative group (n =212).

Increased levels of CSF synaptic biomarkers were significantly associated with increased CSF p-tau (CSF neurogranin: β = 0.94; CSF SNAP-25: β = 0.79; CSF GAP-43: β = 0.96; CSF synaptotagmin-1: β = 0.93; P <.0001 for all analyses). The synaptic biomarkers were also positively associated with CSF neurofilament light chain (P <.0001 for all associations), and CSF or CSF/PET Aβ status did not modify these associations.

Regarding neuroimaging neurodegeneration outcomes, CSF neurogranin and GAP-43 were significantly and positively associated with brain metabolism in the FDG PET AD signature, and CSF or CSF/PET Aβ status did not modify these associations.

Study limitations include the cross-sectional design, other CSF synaptic biomarkers were not included, and PET measures of tau pathology or synaptic density were not available.

“Overall, these results suggest that the 4 CSF synaptic biomarkers studied are increased early in the preclinical stage of the Alzheimer continuum and might reflect different aspects of synaptic dysfunction at this stage, differentially associating with AD risk factors, pathology, and neurodegeneration outcomes,” stated the researchers. “These biomarkers should be considered in both observational and interventional future studies in preclinical AD.”

Disclosure: Multiple authors declared affiliations with the pharmaceutical industry. Please refer to the original article for a full list of disclosures.


Milà-Alomà M, Brinkmalm A, Ashton NJ, et al. CSF synaptic biomarkers in the preclinical stage of Alzheimer disease and their association with MRI and PET: a cross-sectional study. Neurology. Published online November 23, 2021. doi: 10.1212/WNL.0000000000012853