Plasma phospho‐tau181 in over 400 cognitively healthy 69‐ to 71‐year‐olds: Associations with cerebral amyloid, structural imaging and cognition in the Insight 46 study
Authors: Keshavan Ashvini , Karikari Thomas K , Lane Christopher A , Parker Thomas D , Lu Kirsty , Cash David M , Sudre Carole H , Nicholas Jennifer M , Heslegrave Amanda J , Wellington Henrietta , James Sarah‐Naomi , Murray‐Smith Heidi , Buchanan Sarah M , Keuss Sarah E , Thomas David L , Malone Ian B , Richards Marcus , Zetterberg Henrik , Blennow Kaj , Fox Nick C , Schott Jonathan M 
Published: December 2020

Background

We examined cross‐sectional associations between plasma phospho‐tau181 (p‐tau181) and amyloid PET, MRI and cognitive outcomes in Insight 46, a sub‐study of the British 1946 birth cohort.

Method

At age 69‐71, participants underwent blood sampling, neurocognitive assessment, and 3T‐MRI with simultaneous 18F‐florbetapir‐PET (yielding amyloid status binarized at grey matter:eroded white matter SUVR 0.6104). Plasma p‐tau181 was measured by a homebrew Simoa immunoassay. ROC analyses were performed for amyloid status incorporating p‐tau181 into a model combining age, sex and APOE ε4 carrier status (APOE ε4). Linear regression examined associations between p‐tau181 (predictor) and (A): cognitive measures (preclinical AD cognitive composite (PACC), digit‐symbol substitution (DSS), delayed logical memory (LMD), and 12‐item‐face‐name association memory (FNAME‐12)), adjusting for age, sex, APOE ε4, childhood cognition, socioeconomic position and education; and (B): imaging biomarkers of neurodegeneration (whole brain, ventricular and hippocampal volumes (WBV,VV,HV) and AD‐signature cortical thickness (CTh)) and vascular disease (white matter hyperintensity volume (WMHV)), adjusting for age, sex, APOE ε4, amyloid status and total intracranial volume as appropriate.

Result

After excluding those with prior neurological diagnoses, mild cognitive impairment or dementia, 444 individuals had complete plasma p‐tau181 data (Table 1); 410 had high‐quality amyloid PET data. An amyloid status ROC model using plasma p‐tau181 alone had an AUC of 0.720,95%CI[0.657,0.783]. This was not significantly different from the prediction of a base model incorporating age, sex and APOE ε4 (0.692[0.622,0.761]), but adding plasma p‐tau181 to the base model improved it significantly (0.787[0.737,0.837],2
p<0.001: figure 1). The numbers needed to pre‐screen for a pre‐symptomatic Alzheimer’s trial could be reduced by about 27% by using the latter compared to the base model (table 2). Higher p‐tau181 was associated with lower FNAME‐12 (z‐score‐change for 10% p‐tau181 rise: ‐0.020,95%CI[‐0.033,‐0.007],p=0.003) and lower PACC (‐0.013[‐0.022,‐0.005],p=0.002). Only the latter association was significantly attenuated by further adjustment for amyloid status. Higher p‐tau181 was associated with higher VV (ratio‐change for 10% p‐tau181 rise: 1.010, 95%CI[1.003,1.017],p=0.007) and lower CTh (0.999[0.998,1.000],p=0.007). DSS, LMD, HV, WBV and WMHV had no significant associations with p‐tau181.

Conclusion

In cognitively normal individuals, plasma p‐tau181 may contribute toward pre‐screening for amyloid PET positivity, and is associated with cognitive performance and imaging biomarkers of neurodegeneration.