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The degree of the involvement of amyloid-\u03b2 versus existing tau pathology in tau propagation and neurodegeneration has not been fully elucidated in human studies. Careful quantification of these effects can inform the development and timing of therapeutic interventions. We conducted causal mediation analyses to investigate the relative contributions of amyloid-\u03b2 and existing tau to tau propagation and neurodegeneration in two longitudinal studies of individuals without dementia: the Baltimore Longitudinal Study of Aging (N\u2009=\u2009103, age range 57\u201396) and the Alzheimer\u2019s Disease Neuroimaging Initiative (N\u2009=\u2009122, age range 56\u201392). As proxies of neurodegeneration, we investigated cerebral blood flow, glucose metabolism, and regional volume. We first confirmed that amyloid-\u03b2 moderates the association between tau in the entorhinal cortex and in the inferior temporal gyrus, a neocortical region exhibiting early tau pathology (amyloid group \u00d7 entorhinal tau interaction term \u03b2 \u2009=\u20090.488, standard error [SE]\u2009=\u20090.126, P\u2009&amp;lt;\u20090.001 in the Baltimore Longitudinal Study of Aging; \u03b2 \u2009=\u20090.619, SE\u2009=\u20090.145, P\u2009&amp;lt;\u20090.001 in the Alzheimer\u2019s Disease Neuroimaging Initiative). In causal mediation analyses accounting for this facilitating effect of amyloid, amyloid positivity had a statistically significant direct effect on inferior temporal tau as well as an indirect effect via entorhinal tau (average direct effect =0.47, P\u2009&amp;lt;\u20090.001 and average causal mediation effect =0.44, P\u2009=\u20090.0028 in Baltimore Longitudinal Study of Aging; average direct effect =0.43, P\u2009=\u20090.004 and average causal mediation effect =0.267, P\u2009=\u20090.0088 in Alzheimer\u2019s Disease Neuroimaging Initiative). Entorhinal tau mediated up to 48% of the total effect of amyloid on inferior temporal tau. Higher inferior temporal tau was associated with lower colocalized cerebral blood flow, glucose metabolism, and regional volume, whereas amyloid had only an indirect effect on these measures via tau, implying tau as the primary driver of neurodegeneration (amyloid\u2013cerebral blood flow average causal mediation effect =\u22120.28, P\u2009=\u20090.021 in Baltimore Longitudinal Study of Aging; amyloid\u2013volume average causal mediation effect =\u22120.24, P\u2009&amp;lt;\u20090.001 in Alzheimer\u2019s Disease Neuroimaging Initiative). Our findings suggest targeting amyloid or medial temporal lobe tau might slow down neocortical spread of tau and subsequent neurodegeneration, but a combination therapy may yield better outcomes.<\/jats:p>","DOI":"10.1093\/braincomms\/fcac193","type":"journal-article","created":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T08:19:19Z","timestamp":1658737159000},"source":"Crossref","is-referenced-by-count":41,"title":["Causal links among amyloid, tau, and neurodegeneration"],"prefix":"10.1093","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5042-7422","authenticated-orcid":false,"given":"Murat","family":"Bilgel","sequence":"first","affiliation":[{"name":"Brain Aging and Behavior Section, Laboratory of Behavioral Neuroscience, National Institute on Aging , Baltimore, MD 21224 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean F","family":"Wong","sequence":"additional","affiliation":[{"name":"Mallinckrodt Institute of Radiology, Washington University School of Medicine , St. Louis, MO 63110 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhay R","family":"Moghekar","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine , Baltimore, MD 21224 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6273-1613","authenticated-orcid":false,"given":"Luigi","family":"Ferrucci","sequence":"additional","affiliation":[{"name":"Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging , Baltimore, MD 21224 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M","family":"Resnick","sequence":"additional","affiliation":[{"name":"Brain Aging and Behavior Section, Laboratory of Behavioral Neuroscience, National Institute on Aging , Baltimore, MD 21224 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the Alzheimer\u2019s Disease 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