Early and Late CNS Inflammation in Alzheimer’s Disease: Two Extremes of a Continuum?

• Published in: Trends in pharmacological sciences (Regular ed.) 2017-11, Vol.38 (11), p.956-966
• Main Author: Cuello, A. Claudio
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - pathology; Animals; Disease Models, Animal; Encephalitis - pathology; Humans
• ISSN: 0165-6147; 1873-3735
• DOI: 10.1016/j.tips.2017.07.005

In 1990 it was reported that individuals receiving NSAIDs (non-steroidal anti-inflammatory drugs) showed a markedly reduced prevalence of Alzheimer’s disease (AD) compared to the overall population. Large epidemiological studies corroborated this assertion and provoked numerous prospective AD clinical trials with a variety of NSAIDs, all of which demonstrated lack of efficacy. It is postulated that the explanation for the success of NSAIDS in preventing AD onset when given at preclinical stages, and for their failure when administered after AD clinical presentation, lies in the changing nature of central nervous system (CNS) inflammation in the decades-long continuum of AD pathology. Early disease-aggravating CNS inflammation might start decades before the presentation of severe cognitive impairments or dementia, and the nature of this process will co-evolve with the neuropathological progression from preclinical to clinical AD stages. This early CNS inflammation should be considered a promising therapeutic target as we continue searching for an unequivocal diagnosis of AD preclinical stages. Research into AD-related CNS inflammation has focused on the highly cellular inflammatory reaction which exhibits a plethora of pro- and anti-inflammatory molecules surrounding amyloid plaques. The decreased prevalence of AD in NSAID users has provoked a large number of failed clinical trials with anti-inflammatories in individuals with AD. Animal studies indicate that some anti-inflammatories are beneficial at the early stages of AD-like amyloid pathology. As such, the earliest stages of AD-associated inflammation should be ‘disease-aggravating’ and a valid therapeutic target. It is proposed that at the extremes of the AD pathology continuum there are two different inflammatory responses: at early (preclinical) stages, a prevailing proinflammatory process that is amenable to therapy, while at later clinical stages tissue resolution and innate/adaptive immune reactions predominate that are not amenable to anti-inflammatory therapy.