Table 1.

Proposed sequential steps in the pathogenesis of AD

Susceptibility factors in AD	Infection	Localization of infection	Bacterial response to infection	Cellular response to infection	Pathology at the time of cognitive change
Older Age – infection increased	Exposure in respiratory droplets to infection with Chlamydia pneumoniae followed by infection of nasal olfactory neuroepithelia	Tissues: Limbic system including: olfactory bulbs, entorhinal cortex, hippocampus	Organism produces lipopolysaccharide endotoxin and heat shock protein 60; the organism siphons from cells ATP and tryptophan	Prominent proinflammatory – cytokines IL‐1β, IL‐6, TNFα; generation of reactive oxygen species including superoxide, nitric oxide, hydroxyl radicals, hydrogen peroxide; chronic neuroinflammation with blood brain barrier changes	Amyloid plaques and NFTs in the limbic region including: olfactory bulbs, entorhinal cortex, hippocampus
ApoEɛ4 genotype—facilitates uptake of organism into cells		Cellular localization: intracellular with growth in: neurons, microglia, astroglia, vascular endothelia, perivascular macrophages		Upregulation of indoleamine 2,3‐dioxygenase—results in breakdown of tryptophan—increased kynurenine and quinolinic acid, decreased serotonin and reduced T cells activation resulting in greater tolerance for the infection	Defects in the sense of smell
Decreased mucosal immunity—low IgA allows organism to infect nasal respiratory tract more readily				Increased processing of amyloid–amyloid cascade; activation of lysosomal‐phagosomal system; increased autophagy; apoptosis initiated but incomplete; mitochondrial damage; kinase over‐activation; accumulation of iron	Neurotransmitter dysregulation, especially of ACH
					Synaptic dysfunction

Note: All of the aspects of localization of infection and cellular changes have been observed in the sporadic late‐onset AD brain (for review see Balin et al. [25]) and (for AD review see Herrup [26]).