@article {Leal0485-18, author = {Stephanie L. Leal and Samuel N. Lockhart and Anne Maass and Rachel K. Bell and William J. Jagust}, title = {Subthreshold amyloid predicts tau deposition in aging}, elocation-id = {0485-18}, year = {2018}, doi = {10.1523/JNEUROSCI.0485-18.2018}, publisher = {Society for Neuroscience}, abstract = {Current approaches to the early detection of Alzheimer{\textquoteright}s disease (AD) rely upon classifying individuals as {\textquotedblleft}positive{\textquotedblright} or {\textquotedblleft}negative{\textquotedblright} for biomarkers related to the core pathology of beta-amyloid (Aβ). However, the accumulation of Aβ begins slowly, years before biomarkers become abnormal. We used longitudinal [11C] Pittsburgh Compound B (PIB) PET and neuropsychological assessment to investigate the earliest changes in AD pathology and how it affects memory in cognitively normal older humans (N = 71, mean age 75 yrs, 35\% male). We used [18F] AV-1451 PET at the end of the observation period to measure subsequent tau deposition in a subset of our sample (N = 37). We found evidence for an inverted-U relationship between baseline Aβ and Aβ slope in asymptomatic older adults, suggesting a slowing of Aβ accumulation even in cognitively normal adults. In participants who were nominally amyloid negative, both the rate of amyloid accumulation and the baseline levels of Aβ predicted early tau deposition in cortical Braak regions associated with AD. Amyloid measures were only sensitive to memory decline as baseline levels of Aβ increased, suggesting pathological accumulation occurs before impacting memory. These findings support the necessity of early intervention with amyloid lowering therapies even in those who are amyloid negative.SIGNIFICANCE STATEMENTThe progressive nature of Alzheimer{\textquoteright}s disease (AD) necessitates the earliest possible detection of pathological or cognitive change if disease progression is to be slowed. We examined cognitively normal older adults who are starting to develop AD pathology, with the goal of early detection of AD pathology or cognitive changes. We found amyloid measures to be sensitive early on in predicting subsequent early tau deposition. Further, it appears rates of amyloid accumulation already begin to slow in preclinical AD, suggesting it is a relatively late stage of AD progression. Thus, it is crucial to examine older adults early, before amyloid levels have saturated, to intervene to slow disease progression.}, issn = {0270-6474}, URL = {https://www.jneurosci.org/content/early/2018/04/23/JNEUROSCI.0485-18.2018}, eprint = {https://www.jneurosci.org/content/early/2018/04/23/JNEUROSCI.0485-18.2018.full.pdf}, journal = {Journal of Neuroscience} }