Brain tocopherol levels are associated with lower activated microglia density in elderly human cortex

Abstract

Introduction Higher brain tocopherol levels have been associated with lower levels of Alzheimer's disease (AD) neuropathology; however, the underlying mechanisms are unclear. Methods We studied the relations of α‐ and γ‐tocopherol brain levels to microglia density in 113 deceased participants from the Memory and Aging Project. We used linear regression analyses to examine associations between tocopherol levels and microglia densities in a basic model adjusted for age, sex, education, apolipoprotein E ( APOE )ε4 genotype (any ε4 allele vs. none) , and post‐mortem time interval, and a second model additionally adjusted for total amyloid load and neurofibrillary tangle severity. Results Higher α‐ and γ‐tocopherol levels were associated with lower total and activated microglia density in cortical but not in subcortical brain regions. The association between cortical α‐tocopherol and total microglia density remained statistically significant after adjusting for AD neuropathology. Discussion These results suggest that the relation between tocopherols and AD might be partly explained by the alleviating effects of tocopherols on microglia activation.

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“…A metaanalysis of 31 articles indicated that individuals with AD, age-related cognitive impairment, or mild cognitive decline had lower circulatory concentrations of α-tocopherol compared to healthy controls [126]. Additionally, an analysis of 115 deceased and autopsied cases in the Rush Memory and Aging Project showed that higher levels of brain tocopherols such as α-tocopherol were related to lower activated microglia density in the cortical brain, which might protect against AD to lower levels of inflammation, amyloid, and neurofibrillary tangle severity [127].…”

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“…Given that high Aβ level sustained over a long period of time may increase Aβ catabolism, unaltered Aβ synthesis as observed by Arrozi et al could be explained by the treatment period of over six months [ 101 ]. A study investigating TP levels in the human cortex observed an association between higher α- and γ-TP levels and lower total and activated microglia density in cortical regions, suggesting a microglia-mediated beneficial effect on the slowly accumulating AD neuropathology [ 21 ]. In later stages of AD, continued microglial activation can exacerbate tau pathology and negatively affect neurons and synapses [ 103 , 104 ].…”

“…In contrast, patients with low cholesterol, minimal inflammatory burden and little oxidative stress may be adversely affected by supplementation. Regarding the effects of α- and γ-TP on activated microglial cell density [ 21 ], supplementation can lead to either desirable or detrimental effects, dependent on disease progression and method of administration.…”