In:
Alzheimer's & Dementia, Wiley, Vol. 16, No. S4 ( 2020-12)
Abstract:
Alzheimer’s disease (AD) comprises a preclinical stage characterized by pathophysiological changes that occur decades before symptoms arise. Despite the importance of this stage, the biological pathways involved are not yet well understood. The main aim of this study is to define the pathophysiological processes, as measured by CSF biomarkers changes, that occur in the preclinical stage of the Alzheimer’s continuum in a finely‐characterized cohort of cognitively unimpaired individuals. Methods We measured a comprehensive set of CSF biomarkers that reflect different pathophysiological processes in 381 cognitively unimpaired participants aged between 49 and 73 years of the ALFA+ study (61% women; 53% APOE‐ε4 carriers; 34% Aβ positive). Specifically, we measured CSF biomarkers related to amyloid‐β (Aβ42, Aβ40) or tau (p‐tau, t‐tau) metabolism, neuronal and axonal damage (NfL), synaptic dysfunction (neurogranin), neuroinflammation (IL6, MCP1), micro‐ and astroglial markers (sTREM2, YKL40, GFAP, S100), vascular injury (sVCAM1, sICAM1), and total α‐synuclein. Measurements were performed using MSD, NeuroToolKit and Elecsys ® immunoassays. Results We found that CSF tau‐related (p‐tau and t‐tau) and synaptic dysfunction (neurogranin) biomarkers increase throughout ageing only in Aβ‐positive individuals. In contrast, neuronal injury (NfL), micro‐ and astroglial (sTREM2, YKL40, GFAP) and vascular (sVCAM1, sICAM1) CSF biomarkers increase with ageing both in Aβ‐positive and ‐negative individuals (Fig.1). We modelled the changes in CSF biomarkers as a function of CSF Aβ42/40 ratio, p‐tau and p‐tau/Aβ42, which were used as proxies of disease progression. We observed that the first change that occurs in the Alzheimer’s continuum is a decrease in the Aβ42/40 ratio. Shortly after this ratio becomes positive, there is a steep increase in CSF p‐tau, t‐tau, neurogranin and, to lesser extent, in CSF NfL and glial biomarkers (Fig. 2). Conclusion Our results show that multiple biological pathways are altered very early in the Alzheimer’s continuum, but differ in their association with Aβ pathology. Whereas CSF tau‐related and synaptic dysfunction biomarkers change promptly and specifically when there is underlying Aβ pathology, CSF NfL and glial biomarkers have a less pronounced and specific increase. Altogether, our results suggest that different biological pathways could be targeted during the preclinical stage of the Alzheimer’s continuum.
Type of Medium:
Online Resource
ISSN:
1552-5260
,
1552-5279
Language:
English
Publisher:
Wiley
Publication Date:
2020
detail.hit.zdb_id:
2201940-6
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