Innate immunity and the etiology of late-onset Alzheimer's disease.

BACKGROUND: Neuropathological studies supported by experimental animal studies show that the constituents of the innate immunity are intimately involved in the early steps of the pathological cascade of Alzheimer's disease (AD). OBJECTIVES: To show the evidence that constituents of the innate immunity contribute to the etiology of late-onset AD. METHODS: Evaluation of the relationship between the constituents of the innate immunity and genetic risk factors for late-onset AD. RESULTS: Complement activation and activated microglia are early neuropathogical events in AD brains. Genome-wide association studies have demonstrated gene loci that are linked to the complement system. The production capacity for inflammatory cytokines is under genetic control and the offspring with a parental history of late-onset AD have a higher production capacity for inflammatory cytokines. CONCLUSION: Epidemiological and genetic data suggest that the innate immunity is involved in the etiology of late-onset AD.

Neuroinflammation - an early event in both the history and pathogenesis of Alzheimer's disease.

BACKGROUND: About hundred years ago, Oskar Fischer proposed that the senile plaques are the consequence of the deposition of a foreign substance that could induce an inflammatory response leading to an abnormal neuritic response of the surrounding neurons. OBJECTIVES: To show that the interest in inflammation in Alzheimer's disease (AD) is not only an early event in the history of AD but that inflammation is also an early event in the pathogenesis of AD. METHODS: Evaluation of the neuropathological, epidemiological and genetic evidence for a role of inflammation early in the pathogenesis of AD. RESULTS: Neuropathological studies show presence of activated microglia and inflammation-related mediators in the cerebral neocortex of autopsied patients with a low Braak stage for AD pathology. Prospective population-based cohort studies indicate that higher serum levels of acute phase proteins predict dementia. On a genetic level, it was found that the production capacity of proinflammatory cytokines after stimulation with lipopolysaccharide (a process that is under strong genetic control) is higher in offspring with a parental history of late-onset AD. CONCLUSION: Neuropathological studies show that a neuroinflammatory response in the cerebral neocortex parallels the early stages of AD pathology and precedes the late stage, tau-related pathology. Epidemiological and genetic studies indicate that systemic markers of the innate immunity are risk factors for late-onset AD.