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Association between hippocampal microglia, AD and LATE-NC, and cognitive decline in older adults
Alifiya Kapasi1,2, Lei Yu1,3, Sue E Leurgans1,3
1Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
Introduction:
This study investigates the relationship between microglia inflammation in the hippocampus, brain pathologies, and cognitive decline.
Methods:
Participants underwent annual clinical evaluations and agreed to brain donation. Neuropathologic evaluations quantified microglial burden in the hippocampus, amyloid beta (Aβ), tau tangles, and limbic age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy neuropathologic changes (LATE-NC), and other common brain pathologies. Mixed-effect and linear regression models examined the association of microglia with a decline in global and domain-specific cognitive measures, and separately with brain pathologies. Path analyses estimated direct and indirect effects of microglia on global cognition.
Result:
Hippocampal microglia were associated with a faster decline in global cognition, specifically in episodic memory, semantic memory, and perceptual speed. Tau tangles and LATE-NC were independently associated with microglia. Other pathologies, including Aβ, were not related. Regional hippocampal burden of tau tangles and TDP-43 accounted for half of the association of microglia with cognitive decline.
Discussion:
Microglia inflammation in the hippocampus contributes to cognitive decline. Tau tangles and LATE-NC partially mediate this association.
Insights
Microglia inflammation in the hippocampus accelerates cognitive decline, particularly in memory and processing speed. This link is partly explained by tau tangles and limbic-related TDP-43 encephalopathy neuropathologic changes.
Area of Science:
- Neuroscience
- Neuropathology
- Cognitive Aging
Background:
- Microglia play a crucial role in brain inflammation and are implicated in neurodegenerative diseases.
- Understanding the specific contribution of microglia to cognitive decline is essential for developing targeted therapies.
Purpose of the Study:
- To investigate the association between hippocampal microglia inflammation, neuropathological changes, and cognitive decline.
- To determine the mediating roles of tau tangles and LATE-NC in the relationship between microglia and cognition.
Main Methods:
- Analysis of post-mortem brain donations from participants with annual clinical evaluations.
- Quantification of hippocampal microglial burden, amyloid beta (Aβ), tau tangles, and limbic-related TDP-43 encephalopathy neuropathologic changes (LATE-NC).
- Statistical modeling, including mixed-effects, linear regression, and path analyses, to assess associations and mediation.
Main Results:
- Increased hippocampal microglia burden correlated with a faster decline in global cognition, episodic memory, semantic memory, and perceptual speed.
- Tau tangles and LATE-NC were independently associated with microglia burden.
- Tau tangles and TDP-43 in the hippocampus explained approximately half of the association between microglia and cognitive decline.
Conclusions:
- Hippocampal microglia-driven inflammation contributes significantly to cognitive decline.
- Tau tangles and LATE-NC partially mediate the detrimental effects of microglia on cognition.
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