Cerebral spinal fluid synaptic biomarkers were altered early in the Alzheimer’s continuum

According to study results published in Neurology, cerebrospinal fluid synaptic biomarkers (CSF) increase in the early preclinical stages of Alzheimer’s disease (AD), even when there is little exposure to β-amyloid (Aβ) pathology.

Research to date on synaptic CSF biomarkers in preclinical AD is limited and unclear. In addition, research into preclinical AD is challenging because of the difficulty of recruiting participants in the early stages of the disease. The aim of the current study was to determine whether synaptic liquor biomarkers change in individuals in the preclinical stage of the AD continuum. The researchers also wanted to investigate how synaptic biomarkers differ from their association with AD risk factors and neurodegenerative biomarkers.

The cross-sectional study was carried out in a cohort of the Alzheimer’s and Families (ALFA) study with 2743 cognitively non-impaired persons aged 45 to 74 years with a family history of AD (47.4%) and APOE e4 sponsorship (32.5%) accomplished. The nested longitudinal study ALFA + comprised 450 participants aged 45 to 65 who were invited to participate based on their specific AD risk profile.

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A total of 384 participants (mean [SD] Age 61.1 [4.68] Years; 60.9% female; 54.4% APOE Ɛ4 carriers were finally included in the analysis and 64.8% (n = 249) were CSF-Aβ negative. For imaging purposes, 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.

CSF-neurogranin, SNAP-25, GAP-43 and synaptotagmin-1 increased significantly with age in the total cohort. CSF neurogranin was higher in female vs. male participants (P = 0.021), and CSF SNAP-25 was higher in APOE e4 carriers than in non-carriers (P = 0.020).

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

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

Increased levels of synaptic biomarkers in the CSF were significantly associated with increased p-tau in the CSF (CSF neurogranin: β = 0.94; CSF SNAP-25: β = 0.79; CSF GAP-43: β = 0.96 ; CSF synaptotagmin-1: β = 0.93; P <0.0001 for all analyzes). The synaptic biomarkers were also positively associated with the CSF neurofilament light chain (P <0.0001 for all associations), and the CSF or CSF / PET-Aβ status did not change these associations.

Regarding the neurodegenerative imaging results, CSF-neurogranin and GAP-43 were significantly and positively associated with brain metabolism in the FDG-PET-AD signature, and the CSF or CSF / PET-Aβ status did not change these associations.

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

“Overall, these results suggest that the four synaptic CSF biomarkers studied are elevated early in the preclinical stage of the Alzheimer’s continuum and may reflect various aspects of synaptic dysfunction at this stage that are differently associated with AD risk factors, pathology, and neurodegenerative outcomes . ”Explained the researchers. “These biomarkers should be considered in both observational and future interventional studies of preclinical AD.”

Disclosure: Several authors stated links with the pharmaceutical industry. For a full list of the details, see the original article.


Milà-Alomà M, Brinkmalm A, Ashton NJ, et al. Synaptic biomarkers in cerebrospinal fluid in the preclinical stage of Alzheimer’s disease and their relationship to MRI and PET: a cross-sectional study. Neurology. Published online 23 November 2021. doi: 10.1212 / WNL.0000000000012853

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