Abstract
Background: Aβ pathology is associated with longitudinal changes of brain metabolism, atrophy, and cognition, in cognitively healthy elders. However, Aβ information is usually measured cross-sectionally and dichotomized to classify subjects as Aβ-positive or Aβ-negative, making it difficult to evaluate when brain and cognitive changes occur with respect to emerging Aβ pathology. In this study, we use longitudinal Aβ information to combine the level and rate of change of Aβ to estimate the time to Aβ-positivity for each subject and test this temporal proximity to significant Aβ pathology for associations with brain structure, metabolism, and cognition.Methods: In 89 cognitively healthy elders with up to 10 years of follow-up, we estimated the points at which rates of fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to the time to Aβ-positivity. Points of initial acceleration in rates of decline were estimated using mixed-effects models with penalized regression splines.Results: Acceleration of rates of FDG PET were observed to occur 20+ years before the conventional threshold for Aβ-positivity. Subtle signs of cognitive dysfunction were observed 10+ years before Aβ-positivity.Conclusions: Aβ may have subtle associations with other hallmarks of Alzheimer's disease before Aβ biomarkers reach conventional thresholds for Aβ-positivity. Therefore, we propose that emerging Aβ pathology occurs many years before cognitively healthy elders reach the current threshold for Aβ positivity (preclinical AD). To allow prevention in the earliest disease stages, AD clinical trials may be designed to also include subjects with Aβ biomarkers in the sub-threshold range.
Highlights
According to the amyloid cascade hypothesis (Hardy and Selkoe, 2002), the accumulation of β-amyloid (Aβ) pathology in the brain is a key initiating event in the pathogenesis of Alzheimer’s disease (AD)
Downstream, the accumulation of Aβ is thought to lead to accumulation and spread of tau pathology (Braak and Braak, 1991; Schöll et al, 2016), brain hypometabolism, brain atrophy, and cognitive and functional decline (Bourgeat et al, 2010; Chételat et al, 2010; Landau et al, 2012; Insel et al, 2016a)
Such biomarker-guided studies have contributed to the understanding that AD has a long prodromal [patients with mild cognitive impairment (MCI) who are Aβ+] and preclinical stage, where the build-up of brain pathologies is paralleled by a gradual development of cognitive and functional impairment (Zetterberg and Mattsson, 2014)
Summary
According to the amyloid cascade hypothesis (Hardy and Selkoe, 2002), the accumulation of β-amyloid (Aβ) pathology in the brain is a key initiating event in the pathogenesis of Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) biomarkers and positron emission tomography (PET) with tracers sensitive to Aβ, have made it possible to study the development of AD-related brain changes in the brain of living humans (Klunk et al, 2004; Perrin et al, 2009) Such biomarker-guided studies have contributed to the understanding that AD has a long prodromal [patients with mild cognitive impairment (MCI) who are Aβ+] and preclinical (cognitively normal individuals who are Aβ+) stage, where the build-up of brain pathologies is paralleled by a gradual development of cognitive and functional impairment (Zetterberg and Mattsson, 2014). We use longitudinal Aβ information to combine the level and rate of change of Aβ to estimate the time to Aβ-positivity for each subject and test this temporal proximity to significant Aβ pathology for associations with brain structure, metabolism, and cognition
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