Association between plasma phospho-tau181 and cognitive change from age 73 to 82: Lothian Birth Cohort 1936

INTRODUCTION: Plasma phospho-tau 181 (p-tau181) is a promising blood biomarker for Alzheimer's disease. However, its predictive validity for age-related cognitive decline without dementia remains unclear. Several forms of p-tau have been shown to contribute to synapse degeneration, but it is unknown whether p-tau181 is present in synapses. Here, we tested whether plasma p-tau181predicts cognitive decline and whether it is present in synapses in human brain. METHODS: General cognitive ability and plasma p-tau181 concentration were measured in 195 participants at ages 72 and 82. Levels of p-tau181 in total homogenate and synaptic fractions were compared with western blot (n=10-12 per group), and synaptic localisation was examined using array tomography. RESULTS: Elevated baseline plasma p-tau181 and increasing p-tau181 over time predicted steeper general cognitive decline. We observe p-tau181 in neurites, presynapses, and post-synapses in the brain. DISCUSSION: Baseline and subsequent change in plasma p-tau181 may represent rare biomarkers of differences in cognitive ageing across the 8th decade of life and may play a role in synaptic function in the brain. ### Competing Interest Statement HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, AZTherapies, CogRx, Denali, Eisai, Nervgen, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. TS-J serves as a scientific advisor to Cognition Therapeutics and receives collaborative funding from an anonymous pharmaceutical company.