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Longitudinal Cognitive and Biomarker Measurements Support a Unidirectional Pathway in Alzheimer’s Disease Pathophysiology

      Abstract

      Background

      Amyloid-β (Aβ) likely plays a primary role in Alzheimer’s disease pathogenesis, but longitudinal Aβ, tau, and neurodegeneration (A/T/N) measurements in the same individuals have rarely been examined to verify the temporal dynamics of these biomarkers.

      Methods

      In this study, we investigated the temporal ordering of Aβ, tau, and neurodegeneration using longitudinal biomarkers in nondemented elderly individuals. A total of 395 cognitively unimpaired individuals and 204 individuals with mild cognitive impairment (320 [53%] were female) were classified into 8 A±/T±/N± categories according to the abnormal (+)/normal (–) status of Aβ (18F-florbetapir or 18F-florbetaben) positron emission tomography (PET), 18F-flortaucipir PET, and adjusted hippocampal volume (aHCV). Follow-up Aβ PET, tau PET, and aHCV measurements at 0.6 to 4.1 years were available for 35% to 63% of the sample. Baseline Aβ, tau, and aHCV were compared between different A/T/N profiles. We investigated the associations of baseline and longitudinal Aβ, tau, and neurodegeneration in relation to one another continuously.

      Results

      Among T– participants, tau was higher for A+/T–/N– individuals compared with the A–/T–/N– group (p = .02). Among N– participants, neurodegeneration was worse among A+/T+/N– individuals compared with the A–/T–/N– group (p = .001). High baseline Aβ was associated (p < .001) with subsequent tau increase and high baseline tau was associated (p = .002) with subsequent aHCV decrease, whereas high tau and low aHCV at baseline were not associated with subsequent Aβ increase.

      Conclusions

      These findings define a sequence of pathological events in Alzheimer’s disease that support a current model of Alzheimer’s disease pathogenesis in which Aβ appears early, followed by deposition of abnormal tau aggregates and subsequent neurodegeneration.

      Keywords

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