Infections and neurodegeneration
Half of cases of early Alzheimer's disease were associated with infections
Sergey Zadvoryev, N+1
Statisticians from Sweden and the USA tracked what happens to the prevalence of neurodegenerative diseases in patients who suffered severe acute infections in their youth, and published the results of the study in an article in the journal PLoS Medicine (Sun et al., Hospital-treated infections in early- and mid-life and risk of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis: A nationwide nested case-control study in Sweden). A registry study involving 400 thousand patients showed that the risk of Alzheimer's and Parkinson's diseases was associated with infections that people suffered 5-20 years before the detection of these diseases. Infections are a factor so long—lasting that it is noticeable when analyzing statistics even within twenty years from the moment of acute illness. The association was most pronounced in patients with early onset of Alzheimer's disease (up to 60 years) — among such patients, the proportion of patients who suffered severe infections increased by 1.93 times. No such dependence was found in amyotrophic lateral sclerosis.
Inflammation in the central nervous system is a key stage in the development and progression of many neurodegenerative diseases. The epicenter of inflammation in this case may not be directly connected with the nervous system. With any systemic inflammatory reaction, inflammatory mediators circulate in the blood, which not only help to cope with the pathogen, but also activate the response from the immune cells of the nervous system, worsening microcirculation in the central nervous system in addition. As a result, cognitive deficits may develop, as happens with sepsis.
In recent years, the hypothesis of the neuroinflammatory genesis of neurodegenerative diseases has been increasingly confirmed. Scientists demonstrate the connection between individual infectious agents and known pathogens of neurodegenerative diseases. The interest in infections as a risk factor is due to the fact that there are no drugs yet that would prevent the progression of the most common diseases of this group, which indicates an incomplete understanding of the pathogenesis of these diseases.
In acute infectious diseases, pronounced inflammatory changes in the blood rarely persist for more than a few weeks. At the same time, the experience of the COVID-19 pandemic shows that cognitive impairments not only persist for a long time after the active phase of infection, but can also occur months later. This kind of assessment is applied to individual specific infections, but not to their totality, and there are no estimates of the duration of the impact of infections.
Statisticians from the Karolinska University of Stockholm and Columbia University from the USA decided to retrospectively assess the relationship between infectious diseases and the risk of developing neurodegenerative diseases, regardless of the pathogen. To do this, Dr. Sun Jiangwei and his colleagues turned to the Swedish national medical registers.
When planning the analysis, Dr. Sun and his colleagues proceeded from the fact that it is impossible to track all infections in people retrospectively, and one should pay attention only to cases that required hospitalization. To reduce the error associated with the retrospective nature of the study, the researchers focused on only three neurological diseases with highly sensitive diagnostic criteria that changed little during the study period (86 percent were included in the registries after 2001). These diseases are Alzheimer's disease (292 thousand patients), Parkinson's disease (almost 104 thousand people) and amyotrophic lateral sclerosis (about 10 thousand patients). For each of these groups, a demographic-comparable comparison group was formed from among patients without neurodegenerative diseases, five times larger than the main group.
The researchers recorded whether people were admitted to hospitals during their lifetime with diagnoses corresponding to infection codes of various localizations according to international classifications of diseases. The localization of infections, their number, the age of the patient at the time of occurrence and the time interval between infection and neurological diagnosis were taken into account. In addition, the comprehensive nature of the database made it possible to establish the presence of diagnoses of neurodegenerative diseases in relatives and (for some) data on education.
The risk of Alzheimer's disease (HR 1.16, 95% CI 1.15-1.18, p<0.001) and Parkinson's disease (HR 1.04, 95% CI 1.02-1.06, p<0.001) was increased in patients who had been hospitalized for infections for 5-20 years prior to these diagnoses. There was no similar association between infections and myotrophic lateral sclerosis (HR 0.97, 95% CI 0.93-1.03, p=0.384).
Prevalence of infections requiring hospital treatment in the Alzheimer's (AD) and Parkinson's (PD) disease groups Figure from the article Sun et al.
The most pronounced was the association of neurological diseases with early infections. Among patients whose Alzheimer's disease began before the age of 60, the proportion of those who had an infection at an early age was 1.93 times higher than in the control group. In patients with Parkinson's disease, this risk was increased by 1.29 times. Infections before the age of 40 increased the risks of two neurological diseases by 1.86 and 1.2 times, respectively.
The genesis of the infection (viral, bacterial or fungal) did not affect the nature of the relationship, and in patients with Alzheimer's disease, the localization of the infection did not affect either. After excluding from the analysis patients whose close relatives had neurodegenerative diseases, the picture remained the same.
The nonspecific nature of the connection between diseases allows the authors of the article to assume that the effect is mediated by neuroinflammation, a non-specific process in nature. It is most likely that different factors play a different role in the occurrence of neurodegenerative diseases with early and late onset, because these diseases differ from each other both clinically and genetically. But, as the authors of the article admit, it may also be due to the influence of some unaccounted-for factors that the retrospective nature of the study did not allow to identify — for example, in the peculiarities of the formation of early versions of the medical register. Future prospective studies will clarify the nature of this relationship.
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