Assessment of Plasma Total Tau Level as a Predictive Biomarker for Dementia and Related Endophenotypes

Abstract

Importance: Blood-based biomarkers have the potential to improve the identification of persons with the greatest dementia risk for inclusion in dementia prevention trials through low-cost and minimally invasive screening.

Objective: To investigate the use of plasma total tau as a blood biomarker for dementia and related endophenotypes.

Design, setting, and participants: This prospective cohort study used data from the US community-based Framingham Heart Study with replication in the Memento study, a multicenter cohort of persons with mild cognitive impairment or subjective cognitive complaints recruited from memory clinics across France. Total tau levels were measured from stored plasma samples in Framingham Heart Study participants during 2004 to 2011. Dementia follow-up occurred across a median of 6 years (interquartile range, 5-8 years) for persons 65 years and older who were dementia free at baseline. Plasma and/or cerebrospinal fluid samples were obtained from Memento study participants from April 19, 2011, to June 22, 2016. Dementia follow-up took place over a median of 4 years (interquartile range, 3-5 years). Data analysis was performed from January to November 2018.

Exposures: Plasma total tau level measured using single-molecule array technology.

Main outcomes and measures: Incidence of dementia of any cause (all dementia) and dementia due to clinical Alzheimer disease (AD dementia).

Results: Among the 1453 participants in the Framingham dementia study sample, the mean (SD) age was 75 (7) years; 792 (54.5%) were female. Among the 367 individuals in the replication cohort, the mean (SD) age was 69 (9) years; 217 (59.1%) were female. Of 134 cases of incident all dementia in the Framingham sample, 105 were AD dementia. After adjustment for age and sex, each SD unit increase in the log of plasma total tau level was associated with a 35% increase in AD dementia risk (hazard ratio [HR], 1.35; 95% CI, 1.10-1.67). The addition of plasma total tau to a model including age and sex improved the stratification of participants for risk of AD dementia (net reclassification improvement, 0.382; 95% CI, 0.030-0.716). Higher plasma total tau level was associated with poorer cognition across 7 cognitive tasks (P < .05) and smaller hippocampi (hippocampal volume: β [SE] = 0.002 [0.001]; P = .003) as well as neurofibrillary tangles (β [SE] = 0.95 [0.45]; P = .04) and microinfarcts (odds ratio, 3.04; 95% CI, 1.26-7.37) at autopsy. In the replication cohort, plasma total tau level weakly correlated with cerebrospinal fluid total tau level (Spearman correlation coefficient, 0.16; P = .07), but plasma total tau was at least as strongly associated with incident AD dementia as cerebrospinal fluid total tau (log plasma total tau: HR, 2.33; 95% CI, 1.00-5.48; log cerebrospinal fluid total tau: HR, 2.14; 95% CI, 1.33-3.44) after adjustment for age and sex.

Conclusions and relevance: The findings suggest that plasma total tau levels may improve the prediction of future dementia, are associated with dementia endophenotypes, and may be used as a biomarker for risk stratification in dementia prevention trials.

Figure 1.. Selection of Study Participants in the Framingham Heart Study

APOE indicates apolipoprotein; MRI, magnetic resonance imaging; NFT, neurofibrillary tangles. ^aOther significant neurological conditions such as multiple sclerosis and brain tumor.

Figure 2.. Adjusted Cumulative Incidence of Dementia

Data are for cumulative incidence of (A) all dementia and (B) Alzheimer disease dementia among participants with and without plasma total tau levels greater than the median (4.09 pg/mL) in the Framingham Heart Study. Adjustments were made for age and sex.