Increased CSF Aß during the very early phase of cerebral Aß deposition in mouse models.

ABSTRACT

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-ß peptide (Aß) in the cerebrospinal fluid (CSF) and positive amyloid positron emission tomography scans. However, there is little information 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 Aß changes in three Aß precursor protein transgenic mouse models, focusing our analysis on the initial Aß deposition, which differs significantly among the models studied. Remarkably, while we confirmed the CSF Aß decrease during the extended course of brain Aß deposition, a 20-30% increase in CSF Aß40 and Aß42 was found around the time of the first Aß 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.