Abstract
Alzheimer’s disease as the most common age-related dementia affects more than 40 million people in the world, representing a global public health priority. However, the pathogenesis of Alzheimer’s disease (AD) is complex, and it remains unclear. Over the past decades, all efforts made in the treatments of AD, with targeting the pathogenic amyloid β (Aβ), neurofibrillary tangles, and misfolded tau protein, were failed. Recently, many studies have hinted that infection, and chronic inflammation that caused by infection are crucial risk factors for AD development and progress. In the review, we analyzed the role of infections caused by bacteria, viruses, and other pathogens in the pathogenesis of AD and its animal models, and explored the therapeutic possibility with anti-infections for AD. However, based on the published data, it is still difficult to determine their causal relationship between infection and AD due to contradictory results. We think that the role of infection in the pathogenesis of AD should not be ignored, even though infection does not necessarily cause AD, it may act as an accelerator in AD at least. It is essential to conduct the longitudinal studies and randomized controlled trials in humans, which can determine the role of infection in AD and clarify the links between infection and the pathological features of AD. Finding targeting infection drugs and identifying the time window for applying antibacterial or antiviral intervention may be more promising for future clinical therapeutic strategies in AD.
Highlights
It has a great possibility that infectious pathogens invading the brain may play a triggering role in Alzheimer’s disease (AD) development, supporting the existence of a direct or indirect nexus between infections/chronic inflammation caused by infections and AD
Several groups have demonstrated that infections or chronic inflammation caused by infectious agents are strongly involved in the pathogenesis of AD, which reignited interest in the infectious theory that was largely disregarded by AD research (Ashraf et al, 2019; Beydoun et al, 2020; Haditsch et al, 2020; Schnaider et al, 2020), since the role of infection in the development and progress of AD has long been debated and is still uncertain (Allnutt et al, 2020; Ou et al, 2020)
Infections mainly caused by P. gingivalis, H. pylori, human immunodeficiency virus (HIV), and HSV-1, and chronic inflammation caused by infections as the most likely etiologies contribute to the pathogenesis of AD
Summary
Sundar et al, 2020; Woods et al, 2020), and Borrelia burgdorferi (Itzhaki et al, 2020), as well as fungi, such as Saccharomyces cerevisiae, Malassezia globosa, Candida albicans (C. albicans), and Cryptococcus neoformans (C. neoformans) (Alonso et al, 2014a, 2015; Pisa et al, 2015a; Carter, 2017; Santiago-Tirado et al, 2017), etc., pathogens, and the prion protein (PrP) (Snow et al, 1989; Come et al, 1993; Zhang B. et al, 2020), may be associated with development and progress of AD. A large number of research results in the past showed that elevated levels of inflammatory cytokines/chemokines and mediators were associated with infections and inflammation in patients with AD and its animal models.
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