Predictive blood biomarkers and brain changes associated with age-related cognitive decline

Growing evidence supports the use of plasma levels of tau phosphorylated at threonine 181 (p-tau181), amyloid-β, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) as promising biomarkers for Alzheimer’s disease. While these blood biomarkers are promising for distinguishing people with Alzheimer’s disease from healthy controls, their predictive validity for age-related cognitive decline without dementia remains unclear. Further, while p-tau181 is a promising biomarker, the distribution of this phospho-epitope of tau in the brain is unknown. Here, we tested whether plasma levels of p-tau181, amyloid-β, NfL, and GFAP predict cognitive decline between ages 72 and 82 in 195 participants in the Lothian Birth Cohorts 1936 study of cognitive ageing. We further examined post-mortem brain samples from temporal cortex to determine the distribution of p-tau181 in the brain. Several forms of p-tau have been shown to contribute to synapse degeneration in Alzheimer’s disease, which correlates closely with cognitive decline in this form of dementia, but to date there have not been investigations of whether p-tau181 is found in synapses in Alzheimer’s disease or healthy ageing brain. It was also previously unclear whether p-tau181 accumulated in dystrophic neurites around plaques which could contribute to tau leakage to the periphery due to impaired membrane integrity in dystrophies. Brain homogenate and biochemically enriched synaptic fractions were examined with western blot to examine p-tau181 levels between groups (n = 10-12 per group), and synaptic and astrocytic localisation of p-tau181 were examined using array tomography (n = 6-15 per group), and localisation of p-tau181 in plaque-associated dystrophic neurites with associated gliosis were examined with standard immunofluorescence (n = 8-9 per group).

Elevated baseline plasma p-tau181, NfL, and GFAP predicted steeper general cognitive decline during ageing. Further, increasing p-tau181 over time predicted general cognitive decline in females only. Change in plasma p-tau181 remained a significant predictor of g factor decline when taking into account Alzheimer’s disease polygenic risk score, indicating the increase of blood p-tau181 in this cohort was not only due to incipient Alzheimer’s disease. P-tau181 was observed in synapses and astrocytes in both healthy ageing and Alzheimer’s disease brain. We observed that a significantly higher proportion of synapses contain p-tau181 in Alzheimer’s disease relative to aged controls. Aged controls with pre-morbid lifetime cognitive resilience had significantly more p-tau181 in GFAP-positive astrocytes than those with pre-morbid lifetime cognitive decline. Further, p-tau181 was found in dystrophic neurites around plaques and in some neurofibrillary tangles. The presence of p-tau181 in plaque-associated dystrophies may be a source of leakage of tau out of neurons that eventually enters the blood. Together, these data indicate that plasma p-tau181, NfL, and GFAP may be useful biomarkers of age-related cognitive decline, and that efficient clearance of p-tau181 by astrocytes may promote cognitive resilience.