Alzheimer disease (AD) is a progressive cognitive disorder leading to dementia¹ in which the brain gradually accumulates both amyloid-β (Aβ) and tau pathologies.² Autopsy studies identified the early stages of Aβ and tau pathologies in individuals who were clinically normal during life, representing a preclinical stage of AD.³ Based on autopsy studies,⁴ the prevailing research hypothesis posits that Aβ precedes and accelerates neocortical tau pathology, which together precipitate cognitive decline. Molecular positron emission tomography (PET) tracers for Aβ⁵ and tau⁶ have made it possible to detect these pathologies in living individuals, including in clinically normal adults. However, previous longitudinal PET studies tracked either Aβ^7,8 or tau^9,10 accumulation; to our knowledge, a temporal sequence of Aβ and tau accumulation has not yet been evaluated. To observe the sequence of these pathologic events, we investigated the trajectories and temporal courses of longitudinal Aβ-PET and longitudinal tau-PET data. Improved understanding of these trajectories is needed to efficiently test therapeutic strategies designed to halt the progression of pathology and delay cognitive decline. While cognitive decline has been demonstrated in longitudinal studies of older adults with elevated levels of Aβ pathology at baseline,^7,11-13 tau-PET may be more closely linked to neuronal injury and cognition.^14-16 We therefore conducted a prospective natural history study to determine whether serial Aβ and tau measures were associated with concurrent and subsequent, serial measures of cognitive performance.

Importance Mounting evidence suggests that sex differences exist in the pathologic trajectory of Alzheimer disease. Previous literature shows elevated levels of cerebrospinal fluid tau in women compared with men as a function of apolipoprotein E (APOE) ε4 status and β-amyloid (Aβ). What remains unclear is the association of sex with regional tau deposition in clinically normal individuals. Objective To examine sex differences in the cross-sectional association between Aβ and regional tau deposition as measured with positron emission tomography (PET). Design, Setting and Participants This is a study of 2 cross-sectional, convenience-sampled cohorts of clinically normal individuals who received tau and Aβ PET scans. Data were collected between January 2016 and February 2018 from 193 clinically normal individuals from the Harvard Aging Brain Study (age range, 55-92 years; 118 women [61%]) who underwent carbon 11–labeled Pittsburgh Compound B and flortaucipir F¹⁸PET and 103 clinically normal individuals from the Alzheimer’s Disease Neuroimaging Initiative (age range, 63-94 years; 55 women [51%]) who underwent florbetapir and flortaucipir F 18 PET. Main Outcomes and Measures A main association of sex with regional tau in the entorhinal cortices, inferior temporal lobe, and a meta-region of interest, which was a composite of regions in the temporal lobe. Associations between sex and global Aβ as well as sex and APOE ε4 on these regions after controlling for age were also examined. Results The mean (SD) age of all individuals was 74.2 (7.6) years (81 APOE ε4 carriers [31%]; 89 individuals [30%] with high Aβ). There was no clear association of sex with regional tau that was replicated across studies. However, in both cohorts, clinically normal women exhibited higher entorhinal cortical tau than men (meta-analytic estimate: β [male] = −0.11 [0.05]; 95% CI, −0.21 to −0.02;P = .02), which was associated with individuals with higher Aβ burden. A sex by APOE ε4 interaction was not associated with regional tau (meta-analytic estimate: β [male, APOE ε4+] = −0.15 [0.09]; 95% CI, −0.32 to 0.01;P = .07). Conclusions and Relevance Early tau deposition was elevated in women compared with men in individuals on the Alzheimer disease trajectory. These findings lend support to a growing body of literature that highlights a biological underpinning for sex differences in Alzheimer disease risk.

Alzheimer's disease (AD) is characterized by two hallmark molecular pathologies: amyloid aβ_1–42and Tau neurofibrillary tangles. To date, studies of functional connectivity MRI (fcMRI) in individuals with preclinical AD have relied on associations within vivomeasures of amyloid pathology. With the recent advent ofin vivoTau-PET tracers it is now possible to extend investigations on fcMRI in a sample of cognitively normal elderly humans to regional measures of Tau. We modeled fcMRI measures across four major cortical association networks [default-mode network (DMN), salience network (SAL), dorsal attention network, and frontoparietal control network] as a function of global cortical amyloid [Pittsburgh Compound B (PiB)-PET] and regional Tau (AV1451-PET) in entorhinal, inferior temporal (IT), and inferior parietal cortex. Results showed that the interaction term between PiB and IT AV1451 was significantly associated with connectivity in the DMN and salience. The interaction revealed that amyloid-positive (aβ⁺) individuals show increased connectivity in the DMN and salience when neocortical Tau levels are low, whereas aβ⁺individuals demonstrate decreased connectivity in these networks as a function of elevated Tau-PET signal. This pattern suggests a hyperconnectivity phase followed by a hypoconnectivity phase in the course of preclinical AD.SIGNIFICANCE STATEMENTThis article offers a first look at the relationship between Tau-PET imaging with F¹⁸-AV1451 and functional connectivity MRI (fcMRI) in the context of amyloid-PET imaging. The results suggest a nonlinear relationship between fcMRI and both Tau-PET and amyloid-PET imaging. The pattern supports recent conjecture that the AD fcMRI trajectory is characterized by periods of both hyperconnectivity and hypoconnectivity. Furthermore, this nonlinear pattern can account for the sometimes conflicting reports of associations between amyloid and fcMRI in individuals with preclinical Alzheimer's disease.