Abstract
Cholinergic pathways in the peripheral nervous system suppress inflammatory responses of blood-based macrophages to pathogens. Because microglia are the resident macrophages of the central nervous system, we hypothesized that cholinergic input originating from the basal forebrain might similarly suppress early inflammatory microglial responses to Aβ and pTau. To explore this hypothesis, we leveraged the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. Cognitively normal older male and female human adults were differentiated according to their ratio of cerebrospinal fluid (CSF) pTau/Aβ, yielding neurotypical and preclinical, cognitively health, subgroups. We then tracked these two groups longitudinally with structural MRI and biomarkers of inflammation, including soluble TREM2 levels in the CSF and complement C3 expression in the blood transcriptome. We observed larger magnitudes of basal forebrain degeneration in the preclinical compared to the neurotypical subgroup. In the preclinical adults, increasing magnitudes of basal forebrain degeneration were associated with abnormally elevated levels of CSF TREM2 and peripheral blood C3 expression. None of these relationships were attributable to degeneration in the whole brain gray matter volume. Increased basal forebrain degeneration and C3 expression was most pronounced in preclinical APOE ε4 carriers. Consistent with the known anti-inflammatory influence of the peripheral cholinergic pathways on macrophages, our findings indicate that a loss of central cholinergic input originating from the basal forebrain might remove a key check on microglial inflammation induced by amyloid and tau accumulation.
Significance statement: In the peripheral nervous system, cholinergic modulation holds the reactivity of macrophages to blood-based pathogens in check, promoting clearance while preventing runaway inflammation and immune-triggered cell death. Microlia are the brain's resident macrophages and play an important role in clearing accumulated amyloid and tau from neurons. Here, we demonstrate that a loss of cholinergic integrity in the central nervous system—indexed by longitudinal decreases of basal forebrain volume—interacts with multiple biomarkers of inflammation in cognitively normal older adults with abnormal amyloid and tau pathology. These interactions were not detected in cognitively normal older adults with ‘neurotypical' levels of amyloid and tau. An age-related loss of cholinergic neuromodulation may remove key checks on microglial reactivity to amyloid and tau.
Footnotes
The authors declare no competing financial interests.
This work was supported in part by grants from the NIA (R03 RAG060263A) (T.W.S. and R.N.S.), the Canada First Research Excellence Fund (T.W.S. and R.N.S.). H.S. acknowledges support by the Israel Science Foundation (Grant 1016/18).
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