Abstract
Neuro-inflammatory processes that contribute to development of Alzheimer’s are evident early in the latent prodromal phase and worsen during the course of the disease. Despite substantial mechanistic and clinical evidence of inflammation, therapeutic approaches targeting inflammation have failed to alter the course of the disease. Disparate results from epidemiological and clinical trials targeting inflammation, highlight the complexity of the inflammatory process. Herein we review the dynamics of the inflammatory process across aging, midlife endocrine transitions, and the APOEε4 genotype and their contribution to progression of Alzheimer’s disease (AD). We discuss the chronic inflammatory processes that are activated during midlife chronological and endocrine aging, which ultimately limit the clearance capacity of microglia and lead to immune senescence. Aging, menopause, and APOEε4 combine the three hits of a compromised bioenergetic system of menopause with the chronic low grade innate inflammation of aging with the APOEε4 dyslipidemia and adaptive immune response. The inflammatory immune response is the unifying factor that bridges across each of the risk factors for AD. Immune system regulators that are specific to stage of disease and inflammatory phenotype would provide a therapeutic strategy to disconnect the bridge that drives disease. Outcomes of this analysis provide plausible mechanisms underlying failed clinical trials of anti-inflammatory agents in Alzheimer’s patients. Further, they highlight the need for stratifying AD clinical trial cohorts based on inflammatory phenotype. Combination therapies that include targeted use of anti-inflammatory agent’s specific to the immune phenotype are considered.
Highlights
Alzheimer’s disease (AD) is characterized by an extended prodromal phase of typically 10–20 years duration prior to clinical manifestation of cognitive decline (Amieva et al, 2008)
This review addresses the interaction between inflammation and risk factors key to the pathogenesis of AD
The inflammatory processes that occur during aging, midlife endocrine transitions, and in the APOEε4 carrier contribute to risk and progression of AD
Summary
Alzheimer’s disease (AD) is characterized by an extended prodromal phase of typically 10–20 years duration prior to clinical manifestation of cognitive decline (Amieva et al, 2008). In comparison to pre-menopausal women, post-menopausal women showed an upregulation in microglial markers CD14, CD18, and CD45, as well as TLR4 and MHC-II markers CD74 and C3 (Sárvári et al, 2012) These findings in the human female brain were consistent with the pattern of gene expression in the frontal cortex of ovariectomized middle-aged rats (13 months old) (Sárvári et al, 2012). In the context of recognizing DAMPs and plaque formation, it was recently demonstrated that CD36 (expressed on monocytes, macrophages, and microglia) recognizes soluble ligands such as oxidized LDL and soluble Aβ and converts them to crystals and fibrils, respectively This leads to the assembly and activation of the NLRP3 inflammasome and the consequent release of the proinflammatory cytokine IL-1β (Sheedy et al, 2013; Oury, 2014). The E4 allele increases the reactivity of glial and peripheral immune cells, aggravating the neurotoxic proinflammatory response (Vitek et al, 2009; Heneka et al, 2015)
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