Inflammation: Bridging age, menopause and APOEϵ4 genotype to Alzheimer's disease

Aarti Mishra, Roberta D. Brinton

Research output: Contribution to journalReview articlepeer-review

33 Scopus citations


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.

Original languageEnglish (US)
Article number312
JournalFrontiers in Aging Neuroscience
Issue numberOCT
StatePublished - Oct 9 2018


  • APOEϵ4
  • Aging
  • Alzheimer's disease
  • Inflammation
  • Menopause

ASJC Scopus subject areas

  • Aging
  • Cognitive Neuroscience


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