Abstract
Resting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer’s disease (AD) dementia. This impairment may be leveraged to aid investigation of the pre-clinical phase of AD. We developed a model that predicts brain age from resting state (rs)-fMRI data, and assessed whether genetic determinants of AD, as well as beta-amyloid (Aβ) pathology, can accelerate brain aging. Using data from 1340 cognitively unimpaired participants between 18–94 years of age from multiple sites, we showed that topological properties of graphs constructed from rs-fMRI can predict chronological age across the lifespan. Application of our predictive model to the context of pre-clinical AD revealed that the pre-symptomatic phase of autosomal dominant AD includes acceleration of functional brain aging. This association was stronger in individuals having significant Aβ pathology.
Highlights
Resting state functional connectivity is impaired early in persons who subsequently develop Alzheimer’s disease (AD) dementia
Functional brain alterations revealed by magnetic resonance imaging (MRI) measures of resting state connectivity become detectable almost synchronously with Aβ and tau measured by positron emission tomography (PET) and are evident several years before atrophy can be detected by structural MRI25,26
One way to circumvent this problem is the study of autosomal dominant AD (ADAD), a group of rare genetically determined variants of AD caused by mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2) genes, all involved in Aβ production[22,28]
Summary
Resting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer’s disease (AD) dementia. Such inter-individual differences between predicted biological and chronological age have been studied in relation to lifestyle variables[16,17,18,19] and to genetic determinants[14,17,20] It is currently unknown, whether accelerated brain aging precedes evidence of cognitive decline, and whether it can be detected in the pre-clinical phase of AD. Functional brain alterations revealed by MRI measures of resting state connectivity (rs-fMRI) become detectable almost synchronously with Aβ and tau measured by positron emission tomography (PET) and are evident several years before atrophy can be detected by structural MRI25,26 Conjunction of such functional and biological changes appears to extend throughout the development of AD from its pre-clinical to its dementia stages[24]. We tested whether individuals in the pre-clinical phase of ADAD, or at risk of pre-clinical sAD, show evidence of accelerated brain aging prior to the symptoms predicted by their genetic risk or Aβ status
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