Report Increased CSF Ab during the very early phase of cerebral Ab deposition in mouse models

Abnormalities in brains of Alzheimer’s disease (AD) patients are thought to start long before the first clinical symptoms emerge. The identification of affected individuals at this ‘preclinical AD’ stage relies on biomarkers such as decreased levels of the amyloid-b peptide (Ab) in the cerebrospinal fluid (CSF) and positive amyloid positron emission tomography scans. However, there is little infor-mation on the longitudinal dynamics of CSF biomarkers, especially in the earliest disease stages when therapeutic interventions are likely most effective. To this end, we have studied CSF Ab changes in three Ab precursor protein transgenic mouse models, focusing our analysis on the initial Ab deposition, which differs significantly among the models studied. Remarkably, while we confirmed the CSF Ab decrease during the extended course of brain Ab deposition, a 20–30 % increase in CSF Ab40 and Ab42 was found around the time of the first Ab plaque appearance in all models. The biphasic nature of this observed biomarker changes stresses the need for longitudinal biomarker studies in the clinical setting and the search for new ‘preclinical AD ’ biomarkers at even earlier disease stages, by using both mice and human samples. Ultimately, our findings may open new perspectives in identifying subjects at risk for AD significantly earlier, and in improving the stratification of patients for preventive treatment strategies