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

TLDR: The association between pathological CSF and progression to Alzheimer's disease was much stronger than, and independent of, established risk factors including age, sex, education, APOE genotype, and plasma homocysteine.

Abstract: Summary Background Disease-modifying treatment strategies for Alzheimer's 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 Alzheimer's 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 amyloid 1–42 (Aβ42), total tau (T-tau), and phosphorylated tau (P-tau 181 ) using Luminex xMAP technology. Findings During follow-up, 57 (42%) patients with MCI developed Alzheimer's 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 Alzheimer's disease was substantially increased in patients with MCI who had pathological concentrations of T-tau and Aβ42 at baseline (hazard ratio 17·7, p APOE genotype, and plasma homocysteine. The combination of T-tau and Aβ42/P-tau 181 ratio yielded closely similar results (sensitivity 95%, specificity 87%, hazard ratio 19·8). Interpretation Concentrations of T-tau, P-tau 181 , and Aβ42 in CSF are strongly associated with future development of Alzheimer's disease in patients with MCI.

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Table 3. Cox proportional-hazards regression models examining the relation between baseline risk factors, including CSF biomarkers, and the risk of developing AD among patients with MCI.

Table 2. Baseline CSF levels of T-tau, P-tau181, Aβ42, and Aβ42/ P-tau181 ratio.

Table 1. Baseline demographic data and annual change of MMSE during follow-up of patients with MCI and healthy controls with CSF obtained at baseline.