Prediction of Alzheimer’s disease in subjects with Mild Cognitive Impairment using biomarkers

Abstract: Background: Alzheimer’s disease (AD) is the most common cause of dementia. In order to have effect of future disease-modifying therapies for AD, the disease must be identified early, before the patients have developed dementia. Many patients with Mild Cognitive Impairment (MCI) have prodromal AD, but other causes for the syndrome are common. No diagnostic method can identify AD in patients with MCI with sufficient accuracy. Aim: Evaluation of biomarkers in cerebrospinal fluid (CSF) and plasma for identifying prodromal AD in patients with MCI. Settings: At baseline 137 subjects with MCI and successful lumbar puncture were included. CSF from baseline was analyzed for phosphorylated tau (P-tau), total tau (T- tau) and amyloidβ1-42 (Aβ42). Furthermore, the levels of soluble receptors for Tumor Necrosis Factor-α (sTNFR) 1 and 2, as well as soluble CD40 (sCD40) and the CD40 ligand were analyzed. The latter biomarkers reflect inflammation. Results: After the first follow-up of around 5 years, 57 patients had developed AD dementia. The levels of T-tau, P-tau and Aβ42 could with high accuracy identify patients with prodromal AD. After the second follow-up was finished, approximately 9 years from baseline, 72 patients had developed AD dementia. The positive and negative predictive values of the Aβ42/ P-tau ratio after this follow-up were around 90%. The Aβ42 levels were pathological already 10 years before progression to dementia. Moreover, Tau and Aβ42 were quite stable over time in patients with AD dementia. The levels of TNFR 1 and 2 both in CSF and plasma and sCD40 in plasma were elevated in the MCI patients with AD 5 years before progression to dementia. Conclusion: CSF biomarkers can identify subjects with prodromal AD. Inflammation is an early feature of AD. These results have an impact on the diagnostic work-up of patients with MCI, as well as the development of AD therapies.