Whether, when and how chronic inflammation increases the risk of developing late-onset Alzheimer's disease

Abstract

Neuropathological studies have revealed the presence of a broad variety of inflammation-related proteins (complement factors, acute-phase proteins, pro-inflammatory cytokines) in Alzheimer's disease (AD) brains. These constituents of innate immunity are involved in several crucial pathogenic events of the underlying pathological cascade in AD, and recent studies have shown that innate immunity is involved in the etiology of late-onset AD. Genome-wide association studies have demonstrated gene loci that are linked to the complement system. Neuropathological and experimental studies indicate that fibrillar amyloid-β (Aβ) can activate the innate immunity-related CD14 and Toll-like receptor signaling pathways of glial cells for pro-inflammatory cytokine production. The production capacity of this pathway is under genetic control and offspring with a parental history of late-onset AD have a higher production capacity for pro-inflammatory cytokines. The activation of microglia by fibrillar Aβ deposits in the early preclinical stages of AD can make the brain susceptible later on for a second immune challenge leading to enhanced production of pro-inflammatory cytokines. An example of a second immune challenge could be systemic inflammation in patients with preclinical AD. Prospective epidemiological studies show that elevated serum levels of acute phase reactants can be considered as a risk factor for AD. Clinical studies suggest that peripheral inflammation increases the risk of dementia, especially in patients with preexistent cognitive impairment, and accelerates further deterioration in demented patients. The view that peripheral inflammation can increase the risk of dementia in older people provides scope for prevention.

Figure 1

Pathological cascade in Alzheimer's disease brains. The occurrence of amyloid-β deposits, glial response and tau-neurofibrillary pathology in the mid-temporal cortex compared to the neuropathological staging of Alzheimer's disease (modified after [5]).

Figure 2

Relationship between inflammation and the etiology and clinical syndrome of Alzheimer's disease. Schematic diagram showing that interactions between innate immunity-related genetic risk factors and inflammation-inducing events (brain trauma, ischemia and infection) can contribute to the multifactorial etiology of the sporadic late-onset form of AD. The diagram illustrates also that delirium and AD share a neuroinflammatory response as a common pathogenic mechanism that could explain the vulnerability of AD patients to further cognitive worsening after an episode of delirium associated with a systemic inflammatory response. Aβ, amyloid-β peptide; AD, Alzheimer's disease; APOE4, apolipoprotein E4; APP, amyloid precursor protein; CLU, clusterin; CR1, complement receptor-1; PS1, presenilin-1; PS2, presenilin-2.