Abstract
BackgroundBrain inflammation has been increasingly associated with early amyloid accumulation in Alzheimer’s disease models; however, evidence of its occurrence in humans remains scarce. To elucidate whether amyloid deposition is associated with neuroinflammation and cognitive deficits, we studied brain inflammatory cytokine expression and cognitive decline in non-demented elderly individuals with and without cerebral amyloid-beta deposition.MethodsGlobal cognition, episodic, working, and semantic memory, perceptual speed, visuospatial ability, and longitudinal decline (5.7 ± 3.6 years) in each cognitive domain were compared between elderly individuals (66–79 years) with and without cerebral amyloid-beta deposition. The expression of 20 inflammatory cytokines was analyzed in frozen temporal, parietal, and frontal cortices and compared between older individuals with and without amyloid-beta deposition in each brain region. Correlation analyses were performed to analyze associations between amyloid-beta load, cytokine expression, and cognitive decline.ResultsIndividuals with cortical amyloid-beta deposition displayed deficits and a faster rate of cognitive decline in perceptual speed as compared with those individuals without amyloid-beta. This decline was positively associated with cortical amyloid-beta levels. Elderly individuals with amyloid-beta deposition had higher levels of IL-1β, IL-6, and eotaxin-3 in the temporal cortex accompanied by an increase in MCP-1 and IL-1β in the parietal cortex and a trend towards higher levels of IL-1β and MCP-1 in the frontal cortex as compared with age-matched amyloid-free individuals. Brain IL-1β levels displayed a positive association with cortical amyloid burden in each brain region. Finally, differential cytokine expression in each cortical region was associated with cognitive decline.ConclusionsElderly individuals with amyloid-beta neuropathology but no symptomatic manifestation of dementia, exhibit cognitive decline and increased brain cytokine expression. Such observations suggest that increased cytokine expression might be an early event in the Alzheimer’s continuum.
Highlights
Brain inflammation has been increasingly associated with early amyloid accumulation in Alzheimer’s disease models; evidence of its occurrence in humans remains scarce
Given that aging is the major risk factor for Alzheimer’s disease (AD) and that AD has a long, pre-symptomatic phase where neuropathology starts to ‘silently’ build-up; it is expected that a proportion of non-cognitively impaired individuals (NCI) individuals with AD neuropathology should be at the earliest, asymptomatic stages of AD
Our results indicate that non-demented individuals harboring amyloid pathology display impairments in perceptual speed accompanied by an increase in key cerebral pro-inflammatory markers across different brain regions, strengthening the evidence for an early dysregulation of inflammatory markers at presumable preclinical stages of AD
Summary
Brain inflammation has been increasingly associated with early amyloid accumulation in Alzheimer’s disease models; evidence of its occurrence in humans remains scarce. Epidemiological studies revealed that cognitively healthy individuals under long-term administration of anti-inflammatories have a reduced risk of developing symptomatic AD [1, 2]. Studies in transgenic models of amyloid pathology have demonstrated the presence of a disease-aggravating neuroinflammatory process concomitant with the intraneuronal accumulation of amyloid-beta (Aβ) oligomers [5,6,7,8,9]. While an incipient inflammatory process has been well characterized in AD animal models and has been associated with the abnormal deposition of Aβ, evidence from human studies remains scarce. Given that aging is the major risk factor for AD and that AD has a long, pre-symptomatic phase where neuropathology starts to ‘silently’ build-up; it is expected that a proportion of NCI individuals with AD neuropathology should be at the earliest, asymptomatic stages of AD
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