The amyloid cascade hypothesis, focusing on pathological proteins aggregation, has so far failed to uncover the root cause of Alzheimer's disease (AD), or to provide an effective therapy. This traditional paradigm essentially explains a mechanism involved in the development of sporadic AD rather than its cause. The failure of an overwhelming majority of clinical studies (99.6%) demonstrates that a breakthrough in therapy would be difficult if not impossible without understanding the etiology of AD. It becomes more and more apparent that the AD pathology might originate from brain infection. In this review, we discuss a potential role of bacteria, viruses, fungi, and eukaryotic parasites as triggers of AD pathology. We show evidence from the current literature that amyloid beta, traditionally viewed as pathological, actually acts as an antimicrobial peptide, protecting the brain against pathogens. However, in case of a prolonged or excessive activation of a senescent immune system, amyloid beta accumulation and aggregation becomes damaging and supports runaway neurodegenerative processes in AD. This is paralleled by the recent study by Alam and colleagues (2022) who showed that alpha-synuclein, the protein accumulating in synucleinopathies, also plays a critical physiological role in immune reactions and inflammation, showing an unforeseen link between the 2 unrelated classes of neurodegenerative disorders. The multiplication of the amyloid precursor protein gene, recently described by Lee and collegues (2018), and possible reactivation of human endogenous retroviruses by pathogens fits well into the same picture. We discuss these new findings from the viewpoint of the infection hypothesis of AD and offer suggestions for future research. Author summary: More than a century after its discovery, Alzheimer's disease (AD) remains incurable and mysterious. The dominant hypothesis of amyloid cascade has succeeded in explaining the key pathological mechanism, but not its trigger. Amyloid beta has been traditionally considered a pathological peptide, and its physiological functions remain poorly known. These knowledge gaps have contributed to repeated failures of clinical studies. The emerging infectious hypothesis of AD considers central nervous system (CNS) infection the primary trigger of sporadic AD. A closely connected hypothesis claims that amyloid beta is an antimicrobial peptide. In this review, we discuss the available evidence for the involvement of infections in AD, coming from epidemiological studies, post mortem analyses of brain tissue, and experiments in vitro and in vivo. We argue there is no unique "Alzheimer's germ," instead, AD is a general reaction of the CNS to chronic infections, in the milieu of an aged immune system. The pathology may become self-sustained even without continuous presence of microbes in the brain. Importantly, the infectious hypothesis leads to testable predictions. Targeting amyloid beta should be ineffective, unless the triggering pathogen and inflammatory response are addressed as well. Meticulous control of selected infections might be the best near-term strategy for AD prevention. [ABSTRACT FROM AUTHOR]