A growing body of evidence points towards the importance of inflammation in brain tissue, and chronic inflammation in general, to the development of neurodegenerative conditions. Chronic inflammation is disruptive of tissue function wherever it occurs in the body. This sustained, unresolved inflammation is one of the more important ways in which the accumulation of senescent cells cause harm in later life. With the discovery of senolytic therapies to clear senescent cells, and a mapping of the inflammatory signals secreted by senescent cells, increasing attention has been given to the role of inflammation in many conditions.
Beyond the removal of senescent cells, other approaches to the reduction of inflammation remain problematic. They largely take the form of interference in signaling that is needed for both excessive, unresolved inflammation and necessary, short-term inflammation. These therapies thus degrade essential functions of the immune system as an unwanted side-effect. Better means of suppressing unresolved inflammation are much needed.
Converging evidence from both genetically at-risk cohorts and clinically normal older individuals suggests that the pathogenesis of Alzheimer's disease (AD) begins years before the clinical diagnosis of dementia is established. Over time, the definition of AD has changed from a traditionally symptom-based disease entity to a clinico-biological construct encompassing a 15-20 year preclinical phase, a 3-6 year prodromal period and a terminal dementia stage.
In addition to deposition of extracellular amyloid-β plaques and intracellular neurofibrillary tangles, neuroinflammation has been identified as the third core characteristic crucial in the pathogenesis of AD. Accumulating evidence suggests that neuroinflammation, as well as activation of microglia and astrocytes, plays an important role in AD pathogenesis. Although whether or not inflammation itself is an initiator or consequence of the disease process, its importance in AD is undeniable.
Targeting of neuroinflammation is potentially an extremely effective strategy for AD prevention and therapy during the preclinical stage prior to the occurrence of significant neuronal loss. Several phase I/II clinical trials evaluating the targeting of TNF-α, TREM2, or CD33 have shown promising results. As reported data remain controversial, and most of the AD clinical trials - including those investigating anti-inflammatory compounds - failed, longitudinal studies enrolling large cohorts of participants with accurate clinical and biomarker-based characterizations are needed to identify potentially effective anti-inflammatory targets and drugs relevant to AD therapy.