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There is an urgent need to understand the relationships between amyloid-β (Aβ) and tau in the progression of Alzheimer's disease to identify treatment targets. Here we examine reciprocal predictions of brain Aβ burden quantified by positron emission tomography and CSF concentrations of Aβ42 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 Aβ42 predicted Aβ deposition and reciprocally, Aβ burden predicted a decrease in CSF Aβ42. Lower CSF Aβ42 predicted an increase in CSF p-tau, and CSF p-tau predicted Aβ deposition. In AD/MCI, lower CSF Aβ42 predicted Aβ deposition and Aβ burden reciprocally predicted CSF Aβ42 changes; however, in contrast to healthy elderly, CSF p-tau concentrations did not predict Aβ biomarkers, or vice versa. In post hoc models examining cognitive status, CSF Aβ42 predicted Mini Mental State Examination (MMSE) scores in healthy elderly, whereas Aβ burden and CSF p-tau predicted MMSE scores in AD/MCI. The findings describe reciprocal predictions between Aβ and tau biomarkers in healthy elderly and they implicate mechanisms underlying low CSF Aβ42 in Alzheimer's disease pathogenesis and progression. In symptomatic Alzheimer's disease, CSF Aβ42 and Aβ deposition predicted each other; however, Aβ and CSF p-tau progressed independently and they independently predicted cognitive decline. SIGNIFICANCE STATEMENT This study offers empirical evidence concerning the hypothesized "amyloid cascade", as it progressed over 4 years in healthy elderly people and in Alzheimer's disease patients. In healthy elderly, CSF amyloid changes predicted amyloid deposition, CSF phosphorylated tau concentrations, and a decline in cognitive status. Phosphorylated tau concentrations specifically predicted amyloid deposition. In Alzheimer's disease patients, although amyloid deposition and CSF amyloid changes continued to "cascade", there was no evidence to suggest that amyloid and tau biomarkers predicted each other, although both amyloid deposition and CSF tau progression predicted cognitive decline independently. Taking advantage of repeated amyloid PET and CSF measures, this dynamic view offers new insight into the progression of Alzheimer's disease biomarkers and their relationships with cognitive decline.

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