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-β peptide (Aβ) 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 Aβ changes in three Aβ precursor protein transgenic mouse models, focusing our analysis on the initial Aβ deposition, which differs significantly among the models studied. Remarkably, while we confirmed the CSF Aβ decrease during the extended course of brain Aβ deposition, a 20–30% increase in CSF Aβ40 and Aβ42 was found around the time of the first Aβ 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.
Highlights
Alzheimer’s disease (AD) abnormalities in the brain occur at least 10–20 years before the onset of the first symptoms in both sporadic and familial AD patients (Holtzman et al, 2011b; Bateman et al, 2012; Buchhave et al, 2012)
cerebrospinal fluid (CSF) Ab40 and Ab42 exhibit a biphasic profile in Ab precursor protein (APP) transgenic mouse models
In the APP24 model, the peak in CSF amyloidb peptide (Ab) occurred at 3–4 months, while in APP51 mice, CSF Ab was increased at 15 months of age
Summary
Alzheimer’s disease (AD) abnormalities in the brain occur at least 10–20 years before the onset of the first symptoms in both sporadic and familial AD patients (Holtzman et al, 2011b; Bateman et al, 2012; Buchhave et al, 2012). We previously reported a 50–80% age-related decline in Ab42, and to a lesser extent in Ab40 in the CSF of APP transgenic mice (Maia et al, 2013) The levels of both peptides were inversely correlated with Ab deposition in brain, an observation virtually identical to that reported in AD patients (Maia et al, 2013). While we confirmed the CSF Ab decrease during the later course of brain Ab deposition, we consistently found a 20–30% increase in CSF Ab40 and Ab42 around the time of the appearance of the first Ab plaques in all three models
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