This study investigates the role of plasma brain-derived tau (BD-tau) as a biomarker for identifying individuals at risk of cognitive decline and brain atrophy in Alzheimer’s disease (AD). The research involved 1076 participants across four independent cohorts, revealing that BD-tau levels in blood increase with the presence of amyloid-beta (Aβ) pathophysiology and neurodegeneration. Participants with high levels of both phosphorylated tau (p-tau) and BD-tau showed the fastest cognitive decline and atrophy rates, regardless of their baseline cognitive status. BD-tau showed minimal correlation with age, renal function, and other factors compared to other blood biomarkers, suggesting its specificity for AD-related neurodegeneration. The study highlights that BD-tau is a promising blood-based biomarker for identifying Aβ-positive individuals at risk of short-term cognitive decline and atrophy. It supports the use of BD-tau in clinical trials and the implementation of anti-Aβ therapies. The findings suggest that BD-tau reflects the combined effects of Aβ pathology and neurodegeneration, which are detrimental to cognitive function in AD. The study also shows that BD-tau can be used to stage the severity of Aβ pathophysiology and the risk of cognitive decline, providing a valuable tool for clinical decision-making. The research further demonstrates that BD-tau levels are associated with AD-related neurodegeneration and can be used to differentiate between individuals at higher or lower risk of cognitive decline. The study emphasizes the importance of BD-tau in the context of anti-Aβ therapies, as it allows for the prioritization of high-risk individuals for treatment. The results indicate that BD-tau is a robust biomarker that can be used in blood to assess the presence of AD-related neurodegeneration and its interaction with Aβ pathology. The study also highlights the potential of BD-tau in clinical settings for early detection and management of AD.This study investigates the role of plasma brain-derived tau (BD-tau) as a biomarker for identifying individuals at risk of cognitive decline and brain atrophy in Alzheimer’s disease (AD). The research involved 1076 participants across four independent cohorts, revealing that BD-tau levels in blood increase with the presence of amyloid-beta (Aβ) pathophysiology and neurodegeneration. Participants with high levels of both phosphorylated tau (p-tau) and BD-tau showed the fastest cognitive decline and atrophy rates, regardless of their baseline cognitive status. BD-tau showed minimal correlation with age, renal function, and other factors compared to other blood biomarkers, suggesting its specificity for AD-related neurodegeneration. The study highlights that BD-tau is a promising blood-based biomarker for identifying Aβ-positive individuals at risk of short-term cognitive decline and atrophy. It supports the use of BD-tau in clinical trials and the implementation of anti-Aβ therapies. The findings suggest that BD-tau reflects the combined effects of Aβ pathology and neurodegeneration, which are detrimental to cognitive function in AD. The study also shows that BD-tau can be used to stage the severity of Aβ pathophysiology and the risk of cognitive decline, providing a valuable tool for clinical decision-making. The research further demonstrates that BD-tau levels are associated with AD-related neurodegeneration and can be used to differentiate between individuals at higher or lower risk of cognitive decline. The study emphasizes the importance of BD-tau in the context of anti-Aβ therapies, as it allows for the prioritization of high-risk individuals for treatment. The results indicate that BD-tau is a robust biomarker that can be used in blood to assess the presence of AD-related neurodegeneration and its interaction with Aβ pathology. The study also highlights the potential of BD-tau in clinical settings for early detection and management of AD.