Recent case-control studies reported an association between H. pylori infection and Alzheimer's disease (AD). Our aim was to compare cognitive impairment, neuroinflammation, and cerebrovascular lesion load in a group of AD patients according to their H. pylori status. For the 53 AD patients included, we assessed: clinical data (vascular comorbidities and cognitive assessment), biological data (especially fibrinogen, homocysteine levels, apolipoprotein E4 genotype; cerebrospinal fluid [CSF] total tau protein [Tau], phospho-tau181 protein [pTau181]), and amyloid beta peptide levels, serum/CSF-cytokines (interleukin [IL]-1β, IL-6, IL-8, tumor necrosis factor [TNF]-α) and pepsinogen I/pepsinogen II (PgI/PgII) ratio, and cerebrovascular lesion load (magnetic resonance imaging [MRI] fluid-attenuated inversion recovery [FLAIR] with the Fazekas and Schmidt scale). H. pylori infection was diagnosed by enzyme-linked immunosorbent assay (ELISA) and immunoblot test. H. pylori infection was associated with a decreased Mini Mental State Examination (MMS) (p = 0.024), and higher CSF pTau181 (p = 0.014) and tau (p = 0.021) levels. A decreased PgI/II ratio (i.e., an increased gastric atrophy) was associated with the infection (p = 0.005). Homocysteine levels were positively correlated to Fazekas score (r = 0.34; p = 0.032) and to H. pylori immunoglobulin (Ig)G levels (r = 0.44; p = 0.001). Higher CSF cytokine levels (IL-8, p = 0.003; TNF-α, p = 0.019) were associated with the infection, but systemic inflammation results were controversial. Finally, in multivariate analysis, a lower MMSE score (odds ratio [OR], 0.83 [0.72–0.97]; p = 0.017), plasma IL-1β level (OR, 0.31 [0.11–0.87]; p = 0.025), an increased gastric atrophy, i.e., a lower PgI/PgII ratio (OR, 0.63 [0.43–0.93]; p = 0.020) were still associated with the infection. AD patients infected by H. pylori tended to be more cognitively impaired. Studies are needed to attest to the impact of H. pylori infection on AD course, especially on cerebrovascular lesions and neuroinflammation.
Alzheimer's disease (AD) is the main cause of dependency and disability in the elderly, and its incidence is currently increasing at a rate of 220,000 new cases per year in France (Helmer et al., 2006). No curative treatment for dementia is available, and most of the currently identified risk factors such as age, sex, and genetic factors like apolipoprotein E allele ε4 are not subject to intervention (Farrer et al., 1997). It has therefore become urgent to identify risk factors on which interventions would be possible. As an attempt to determine the etiology of late-onset AD and to search for new treatment, several groups have investigated the association between various infectious agents and AD. The first agent concerned was herpes simplex virus type 1 (HSV-1). HSV-1 may persist in a quiescent but persistent form known as latent infection, notably in the peripheral nervous system rather than in the central nervous system, and the mechanism for how HSV-1 may reactivate in the hippocampus remains unknown (Itzhaki et al., 1997). However the involvement of HSV is still debated. Wozniak and Itzhaki provided evidence that supports a causal role for HSV-1 in AD. The cascade of events leading to AD might involve reactivation of latent HSV-1 in the brain. Infection would cause both direct and indirect damage, inflammatory-mediated damage, and in apolipoprotein E allele ε4 carriers the damage would be greater, possibly through greater viral replication and spread, eventually leading to AD (Wozniak and Itzhaki, 2010).
Another major infectious pathogen incriminated was Chlamydia pneumoniae as up to 90% of AD brain biopsy specimens may be positive for C. pneumoniae as detected by polymerase chain reaction (PCR), especially in brain regions that exhibit AD pathology ( Balin et al., 1998). However, in an interventional study in 100 patients, Loeb et al. (2004) could not prove a definite C. pneumoniae involvement in AD pathophysiology.
Recent observations also showed that several types of spirochetes, including Borrelia burgdorferi and oral Treponema may be involved in the pathogenesis of AD, but results remain controversial ( Miklossy, 2008).
More recently, an association between AD and Helicobacter pylori infection was reported. H. pylori infection is a chronic infection usually acquired in childhood and which remains for life when no specific treatment is given. An increase in H. pylori prevalence with age is explained by changes in socioeconomic conditions. In fact, studies reported that when cohorts of 70-year-old subjects born in 1901 or 1902 and 1922 were compared, the latter cohort showed a significantly lower H. pylori positive serology. In Western Europe there is still more than a third of the population older than 60 years who are infected. H. pylori is a heterogenous bacterial species. Genomic studies have shown that some strains may harbor a pathogenicity island namely cag (cag PAI), which encodes a type IV secretion system and 1 of its effectors, CagA, which triggers a strong inflammatory response ( Backert and Selbach, 2008).
Recent data suggested that H. pylori infection plays a role in extradigestive diseases ( Figura et al., 2010) and in AD but controversial results persist. Indeed, in addition to 2 case-control studies pointing out an association between H. pylori infection and AD ( Kountouras et al., 2006 and Malaguarnera et al., 2004), an interventional study has shown that H. pylori eradication positively influences AD manifestations, especially cognitive decline ( Kountouras et al., 2009). On the contrary, Shiota et al. (2011) showed negative results, but the authors based their diagnosis on antibody tests on urine samples which has been shown to be unreliable ( Leodolter et al., 2003).
Preliminary results of a cohort study conducted in our laboratory concluded that H. pylori infection was a significant risk factor for developing AD (submitted for publication). We hypothesized that H. pylori infection could act as a trigger in the clinical revelation of AD or in the accumulation of AD lesions via cerebral hypoperfusion due to atherosclerosis, or via an exacerbation of neuroinflammation.
In order to test this hypothesis, we have compared, in this study, the cognitive impairment, cerebrospinal fluid (CSF)-β amyloid1–42 (Aβ1–42), -total tau (Tau), and -phosphorylated tau (pTau181) proteins, cerebrovascular lesions assessed by brain magnetic resonance imaging (MRI), and markers of neuroinflammation in a group of AD patients according to their H. pylori status.
