Cerebrospinal fluid biomarkers and rate of cognitive decline in very mild dementia of the Alzheimer type

Background: Cerebrospinal fluid (CSF) levels of Aβ peptide 1-42 (Aβ42), tau, and phosphorylated tau (ptau) are potential biomarkers of Alzheimer disease. Objective: To determine whether Aβ42, tau, and ptau predict the rate of cognitive change in individuals with very mild dementia of the Alzheimer type (DAT). Design: Retrospective analysis of CSF biomarkers and clinical data. Setting: An academic Alzheimer disease research center. Participants: Research volunteers in a longitudinal study of aging and cognition. Participants (n=49) had a clinical diagnosis of very mild DAT with a Clinical Dementia Rating (CDR) of 0.5 at the time of lumbar puncture. All the participants had at least 1 follow-up assessment (mean [SD] follow-up, 3.5 [1.8] years). Main Outcome Measures: Baseline CSF levels of Aβ42, Aβ40, tau, and ptau at threonine 181 (ptau 181) and the rate of dementia progression as measured using the CDR sum of boxes (CDR-SB) score and psychometric performance. Results: The rate of dementia progression was significantly more rapid in individuals with lower baseline CSF Aβ42 levels, higher tau or ptau 181 levels, or high tau: Aβ42 ratios. For example, the annual change in the CDR-SB score was 1.1 for the lowest 2 tertiles of Aβ42 values and 0.3 for the highest tertile of Aβ42 values. Conclusions: In individuals with very mild DAT, lower CSF Aβ42 levels, high tau or ptau 181 levels, or high tau: Aβ42 ratios quantitatively predict more rapid progression of cognitive deficits and dementia. Biomarkers of CSF may be useful prognostically and to identify individuals who are more likely to progress for participation in therapeutic clinical trials.