Reciprocal Predictive Relationships between Amyloid and Tau Biomarkers in Alzheimer's Disease Progression: An Empirical Model

There is an urgent need to understand the relationships between amyloid-beta (A beta) and tau in the progression of Alzheimer's disease to identify treatment targets. Here we examine reciprocal predictions of brain A beta burden quantified by positron emission tomography and CSF concentrations of A beta 42 and phosphorylated tau (p-tau). Each biomarker was examined over 48 months in two separate cross-lagged models; one in asymptomatic healthy elderly people (men and women), and one in patients with Alzheimer's disease (AD) dementia or mild cognitive impairment (MCI). The models examine predictions of each biomarker on the progression of the others, considering each previous and concurrent measure. In healthy elderly, lower CSF A beta 42 predicted A beta deposition and reciprocally, A beta burden predicted a decrease in CSF A beta 42. Lower CSF A beta 42 predicted an increase in CSF p-tau, and CSF p-tau predicted A beta deposition. In AD/MCI, lower CSF A beta 42 predicted A beta deposition and A beta burden reciprocally predicted CSF A beta 42 changes; however, in contrast to healthy elderly, CSF p-tau concentrations did not predict A beta biomarkers, or vice versa. In post hoc models examining cognitive status, CSF A beta 42 predicted Mini Mental State Examination (MMSE) scores in healthy elderly, whereas A beta burden and CSF p-tau predicted MMSE scores in AD/MCI. The findings describe reciprocal predictions between A beta and tau biomarkers in healthy elderly and they implicate mechanisms underlying low CSF A beta 42 in Alzheimer's disease pathogenesis and progression. In symptomatic Alzheimer's disease, CSF A beta 42 and A beta deposition predicted each other; however, A beta and CSF p-tau progressed independently and they independently predicted cognitive decline.