Cerebrospinal fluid levels of synaptic and neuronal integrity correlate with gray matter volume and amyloid load in the precuneus of cognitively intact older adults

Abstract

The main pathophysiological alterations of Alzheimer's disease (AD) include loss of neuronal and synaptic integrity, amyloidogenic processing, and neuroinflammation. Similar alterations can, however, also be observed in cognitively intact older subjects and may prelude the clinical manifestation of AD. The objectives of this prospective cross‐sectional study in a cohort of 38 cognitively intact older adults were twofold: (i) to investigate the latent relationship among cerebrospinal fluid (CSF) biomarkers reflecting the main pathophysiological processes of AD, and (ii) to assess the correlation between these biomarkers and gray matter volume as well as amyloid load. All subjects underwent extensive neuropsychological examinations, CSF sampling, [18F]‐flutemetamol amyloid positron emission tomography, and T1‐weighted magnetic resonance imaging. A factor analysis revealed one factor that explained most of the variance in the CSF biomarker dataset clustering t‐tau, α‐synuclein, p‐tau181, neurogranin, BACE1, visinin‐like protein 1, chitinase‐3‐like protein 1 (YKL‐40), Aβ1–40 and Aβ1–38. Higher scores on this factor correlated with lower gray matter volume and with higher amyloid load in the precuneus. At the level of individual CSF biomarkers, levels of visinin‐like protein 1, neurogranin, BACE1, Aβ1–40, Aβ1–38, and YKL‐40 all correlated inversely with gray matter volume of the precuneus. These findings demonstrate that in cognitively intact older subjects, CSF levels of synaptic and neuronal integrity biomarkers, amyloidogenic processing and measures of innate immunity (YKL‐40) display a latent structure of common variance, which is associated with loss of structural integrity of brain regions implicated in the earliest stages of AD. Open Science Badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript, and for *Preregistration* because the study was pre‐registered at https://osf.io/7qm9t/. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Synaptic biomarkers in CSF aid in diagnosis, correlate with cognition and predict progression in MCI and Alzheimer's disease

“…A cluster of CSF biomarkers, namely Tau, neurogranin, SNAP25 in this study, and also alpha‐synuclein, Visinin‐like protein‐1 (VILIP‐1), GAP43 and Beta‐secretase 1 (BACE‐1) levels are increased in MCI and AD and correlate highly with one another [6,9,36,37]. Even in cognitively normal individuals, these markers clustered with structural brain measures (MRI) in a factor analysis [38]. The strong correlation between CSF markers of cytosolic (Tau), presynaptic (SNAP25) and dendritic (neurogranin) proteins suggests that they may represent a coordinated aspect of neurodegeneration.…”

β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualification

“…A recent study investigated a broad set of candidate biomarkers tracking distinct pathophysiological processes in patients with AD and reported a positive cross-sectional correlation between BACE1 CSF concentrations and NGR [20]. Interestingly, another group reported that the CSF NGR/BACE1 ratio, along with core AD biomarkers, displays good accuracy to distinguish between depression with cognitive impairment and AD dementia [29].…”

“…Studies investigating CSF BACE1 biomarkers and indicators of brain accumulation of Aβ, including CSF 42-amino acid forms of amyloid-β protein (Aβ42) and Aβ positron emission tomography (Aβ-AΒ-PET), do not show consistent results, as some studies did not find any significant association [ 10 , 14 , 16 , 17 ], while other studies showed significant correlations [ 18 – 20 ].…”

“…A significant association was found in studies that stratified the whole study population according to the clinical diagnosis, reporting positive correlations only in HC individuals and patients with ADDs [ 18 – 20 ], but not in individuals with MCI [ 18 ]. There is no clear biological explanation for the variation of results across different studies but rather a potential methodological issues related to employing different study designs, populations, and assays.…”

“…Evidence indicating an association between BACE1 and neurodegeneration can be derived from studies reporting positive correlations between CSF BACE1 biomarkers and CSF total tau protein [ 9 – 12 , 14 – 20 , 26 ], a surrogate marker of axonal damage and neuronal loss. It is conceivable that BACE1 is released into CSF by degenerating neurons and that the concentrations may correlate with the severity of neurodegeneration and the progression of synaptopathy and neuronal loss.…”