Injury markers predict time to dementia in subjects with MCI and amyloid pathology

Abstract

Objectives: Alzheimer disease (AD) can now be diagnosed in subjects with mild cognitive impairment (MCI) using biomarkers. However, little is known about the rate of decline in those subjects. In this cohort study, we aimed to assess the conversion rate to dementia and identify prognostic markers in subjects with MCI and evidence of amyloid pathology.

Methods: We pooled subjects from the VU University Medical Center Alzheimer Center and the Development of Screening Guidelines and Criteria for Predementia Alzheimer's Disease (DESCRIPA) study. We included subjects with MCI, an abnormal level of β-amyloid(1-42) (Aβ(1-42)) in the CSF, and at least one diagnostic follow-up visit. We assessed the effect of APOE genotype, CSF total tau (t-tau) and tau phosphorylated at threonine 181 (p-tau) and hippocampal volume on time to AD-type dementia using Cox proportional hazards models and on decline on the Mini-Mental State Examination (MMSE) using linear mixed models.

Results: We included 110 subjects with MCI with abnormal CSF Aβ(1-42) and a mean MMSE score of 26.3 ± 2.8. During a mean follow-up of 2.2 ± 1.0 (range 0.4-5.0) years, 63 subjects (57%) progressed to AD-type dementia. Abnormal CSF t-tau (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.1-4.6, p = 0.03) and CSF p-tau (HR 3.5, 95% CI 1.3-9.2, p = 0.01) concentration and hippocampal atrophy (HR 2.5, 95% CI 1.1-5.6, p = 0.02) predicted time to dementia. For subjects with both abnormal t-tau concentration and hippocampal atrophy, HR was 7.3 (95% CI 1.0-55.9, p = 0.06). Furthermore, abnormal CSF t-tau and p-tau concentrations and hippocampal atrophy predicted decline in MMSE score.

Conclusions: In subjects with MCI and evidence of amyloid pathology, the injury markers CSF t-tau and p-tau and hippocampal atrophy can predict further cognitive decline.

Figure 1. Survival curves for time to dementia in subjects with mild cognitive impairment (MCI) and abnormal CSF β-amyloid₁₋₄₂, corrected for age, gender, and education

Red lines indicate the subjects with an abnormal value of each respective marker, defined as CSF total tau (t-tau) ≥375 pg/mL (A), CSF tau phosphorylated at threonine 181 (p-tau) ≥52 pg/mL (B), and hippocampal volume <5.39 cm³ (C). Blue lines indicate the subjects with normal values of each marker.

Figure 2. Decline in Mini-Mental State Examination (MMSE) score in subjects with mild cognitive impairment (MCI) and abnormal CSF Aβ_1–42 according to CSF total tau (t-tau) and hippocampal volume

Slopes of decline in MMSE score in subjects with MCI and abnormal CSF β-amyloid_1–42 (Aβ_1–42) are shown. Subjects were classified according to their CSF t-tau levels and hippocampal volume at baseline. Abnormal values were defined as CSF tau ≥375 pg/mL and hippocampal volume <5.39 cm³.