Association between CSF biomarkers and incipient Alzheimerʹs disease in patients with mild cognitive impairment: a follow-up study

Summary Background Disease-modifying treatment strategies for Alzheimerʹs disease have led to an urgent need for biomarkers to identify the disease at a very early stage. Here, we assess the association between CSF biomarkers and incipient Alzheimerʹs in patients with mild cognitive impairment (MCI). Methods From a series of 180 consecutive patients with MCI, we assessed 137 who underwent successful lumbar puncture at baseline. Patients at risk of developing dementia were followed clinically for 4–6 years. Additionally, 39 healthy individuals, cognitively stable over 3 years, served as controls. We analysed CSF concentrations of β amyloid1–42 (Aβ42), total tau (T-tau), and phosphorylated tau (P-tau181) using Luminex xMAP technology. Findings During follow-up, 57 (42%) patients with MCI developed Alzheimerʹs disease, 21 (15%) developed other forms of dementia, and 56 (41%) remained cognitively stable for 5•2 years (range 4•0–6•8). A combination of CSF T-tau and Aβ42 at baseline yielded a sensitivity of 95% and a specificity of 83% for detection of incipient AD in patients with MCI. The relative risk of progression to Alzheimerʹs disease was substantially increased in patients with MCI who had pathological concentrations of T-tau and Aβ42 at baseline (hazard ratio 17•7, p<0•0001). The association between pathological CSF and progression to Alzheimerʹs disease was much stronger than, and independent of, established risk factors including age, sex, education, APOE genotype, and plasma homocysteine. The combination of T-tau and Aβ42/P-tau181 ratio yielded closely similar results (sensitivity 95%, specificity 87%, hazard ratio 19•8). Interpretation Concentrations of T-tau, P-tau181, and Aβ42 in CSF are strongly associated with future development of Alzheimerʹs disease in patients with MCI.