Compelling experimental evidence suggests that microglial activation is involved in the spread of tau tangles over the neocortex in Alzheimer's disease (AD). We tested the hypothesis that the spatial propagation of microglial activation and tau accumulation colocalize in a Braak-like pattern in the living human brain. We studied 130 individuals across the aging and AD clinical spectrum with positron emission tomography brain imaging for microglial activation ([11C]PBR28), amyloid-β (Aβ) ([18F]AZD4694) and tau ([18F]MK-6240) pathologies. We further assessed microglial triggering receptor expressed on myeloid cells 2 (TREM2) cerebrospinal fluid (CSF) concentrations and brain gene expression patterns. We found that [11C]PBR28 correlated with CSF soluble TREM2 and showed regional distribution resembling TREM2 gene expression. Network analysis revealed that microglial activation and tau correlated hierarchically with each other following Braak-like stages. Regression analysis revealed that the longitudinal tau propagation pathways depended on the baseline microglia network rather than the tau network circuits. The co-occurrence of Aβ, tau and microglia abnormalities was the strongest predictor of cognitive impairment in our study population. Our findings support a model where an interaction between Aβ and activated microglia sets the pace for tau spread across Braak stages.

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Nine young and 11 elderly men participated in this placebo-controlled, double-blind, crossover study (0.5 mg/kg cortisol or intravenous placebo). Participants learned a word list before cortisol administration, and delayed recall was then tested. A 2nd word list was learned and recalled after drug administration. In addition, the Paragraph Recall Test and tests measuring working memory (Digit Span), attention (timed cancellation), and response inhibition (Stroop Color and Word Test) were administered at 2 time points after drug administration. Cortisol reduced recall from the word list learned before treatment in both groups but did not influence recall of the list learned after treatment. In contrast, Digit Span performance was decreased by cortisol in young but not elderly participants. The possibility that differential age-associated brain changes might underlie the present results is discussed.

Abstract. Alzheimer's disease (AD) affects approximately 4.5 million people in the U.S. and this number will increase as the population ages and the life-span increases. Therefore, of paramount importance is identifying mechanisms and factors that affect the risk of developing AD. The etiology and pathogenic mechanisms for AD have not been defined, although inflammation within the brain is thought to play a role. Consistent with this hypothesis, studies suggest that peripheral infections contribute to the inflammatory state of the central nervous system. Periodontitis is a prevalent, persistent peripheral infection associated with gram negative, anaerobic bacteria that are capable of exhibiting localized and systemic infections in the host. This review offers a hypothetical link between periodontitis and AD and will present possible mechanistic links between periodontitis related inflammation and AD. It will review the pathogenesis of periodontitis and the mechanisms by which periodontal infections may affect the onset and progression of AD. Since periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD.

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