Neuropathological correlates and genetic architecture of microglial activation in elderly human brain.
Daniel FelskyTina RoostaeiKwangsik NhoShannon L RisacherElizabeth M BradshawVladislav A PetyukJulie A SchneiderAndrew J SaykinDavid A BennettPhilip Lawrence De JagerPublished in: Nature communications (2019)
Microglia, the resident immune cells of the brain, have important roles in brain health. However, little is known about the regulation and consequences of microglial activation in the aging human brain. Here we report that the proportion of morphologically activated microglia (PAM) in postmortem cortical tissue is strongly associated with β-amyloid, tau-related neuropathology, and the rate of cognitive decline. Effect sizes for PAM measures are substantial, comparable to that of APOE ε4, the strongest genetic risk factor for Alzheimer's disease, and mediation models support an upstream role for microglial activation in Alzheimer's disease via accumulation of tau. Further, we identify a common variant (rs2997325) influencing PAM that also affects in vivo microglial activation measured by [11C]-PBR28 PET in an independent cohort. Thus, our analyses begin to uncover pathways regulating resident neuroinflammation and identify overlaps of PAM's genetic architecture with those of Alzheimer's disease and several other traits.
Keyphrases
- cognitive decline
- inflammatory response
- lipopolysaccharide induced
- lps induced
- neuropathic pain
- mild cognitive impairment
- genome wide
- public health
- healthcare
- resting state
- quality improvement
- patient safety
- copy number
- computed tomography
- traumatic brain injury
- cerebral ischemia
- type diabetes
- dna methylation
- mental health
- cerebrospinal fluid
- functional connectivity
- gene expression
- adipose tissue
- skeletal muscle
- risk assessment
- high fat diet
- depressive symptoms
- health promotion