Patients in early- and mid-life who contract with infections that require hospitalization appear to be at increased risk for neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD) at a relatively young age, new research suggests.
Investigators in Sweden analyzed data from several large national registries, and compared individuals diagnosed with AD, PD, and amyotrophic lateral sclerosis (ALS) to randomly selected age- and sex-matched controls from the general population.
They found that those who had a hospital-treated infection 5 or more years earlier were at a 16% increased risk for AD and a .04% increased risk for PD. Multiple infections before age 30 years conferred more than a 2.5-fold increased risk for AD and a 1.5-fold increased risk for PD before age 60 years.
Increased risks for AD and PD were associated with bacterial, viral, other infections and different sites of infection, including gastrointestinal, and genitourinary infections.
“Our study suggested that individuals with hospital-treated infections, especially in those occurring in early- and mid-life, had an increased risk of developing AD and PD, attributable to cases diagnosed before 60 years,” the investigators, led by Jiangwei Sun, PhD, a postdoctoral researcher in the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, write.
“Further studies are warranted to validate these findings, to elucidate underlying mechanisms, and to determine whether better control of hospital-treated infections could prevent or delay onset of neurodegenerative diseases, especially the ones with an onset relatively early in life,” they note.
The study was published online September 15 in PLOS Medicine.
Risk Factor, Comorbidity, or Secondary Event?
“A potential infectious etiology has been hypothesized for neurodegenerative diseases, as findings in animal studies have demonstrated that infectious processes might impact pathogenesis, phenotype, and progression of neurodegenerative disease,” Sun told Medscape Medical News.
However, he continued, “extrapolation of such findings to a human context is however not straightforward.”
Previous studies have focused the role of specific pathogens on a specific neurodegenerative disease rather than infection in general, but with inconclusive results.
Although several studies have assessed associations between infectious diseases and risk for dementia and AD, they did not fully address certain limitations such as the potential impact of reverse causation, on the association.
“Therefore, whether infection is indeed a risk factor rather a comorbidity or secondary event of neurodegenerative disease remains unknown,” the researchers note.
In addition, there has been less research on the potential link between infection and ALS.
To investigate the question, the researchers analyzed data from Swedish registries encompassing all individuals born after 1900 in Sweden whose parents were also born in Sweden, following them from 1970 until a diagnosis of neurodegenerative disease, emigration, death, or until the end of 2016.
The analysis then focused on individuals with AD, PD, and ALS, who were compared with five age- and sex-matched controls from the general population.
|
Condition |
n |
Median age at diagnosis |
Sex (male) |
|
AD |
291,941 |
76.2 years |
46.6% |
|
PD |
103,919 |
74.3 years |
55.1% |
|
ALS |
10,161 |
69.3 years |
56.8% |
Covariates included age, sex, area of residence, educational attainment, family history of neurodegenerative diseases, and comorbidities.
Unclear Mechanisms
Having a hospital-treated infection experienced 5 years or more earlier was associated with an increased risk for AD as well as PD (overall response [OR], 1.16; 95% CI, 1.15-1.18 and OR, 1.04 95% CI, 1.02-1.06, respectively; both P s < .001).
Increased risks for AD and PD were observed for bacterial, viral, and other infections, and across different sites of infection, including gastrointestinal, and genitourinary infections.
The greatest risk for AD and PD was associated with having multiple infections before age 40 yeas (OR, 2.62; 95% CI, 2.52-2.72 and OR , 1.41 95% CI, 1.29-1.53, respectively; both P s < .001).
The associations were attributable primarily to the diagnoses of AD and PD before age 60 years (OR, 1.93; 95% CI, 1.89-1.98- and OR, 1.29; 95% CI, 1.22-1.36], respectively; both P s < .001). By contrast, no association was found in individuals diagnosed when they were aged 60 years or older (OR, 1.00; 95% CI, .98-1.01; P = .508 and OR, 1.01; 95% CI, .99 – 1.03; P = 0.382, respectively).
Of note, “no association was observed for ALS (OR = 0.97 [.92 – 1.03] P = 0.384), regardless of age at diagnosis,” the authors report.
The findings were confirmed when the researchers excluded infections experienced within 10 years before diagnosis of neurodegenerative disease.
“Several mechanisms might explain the link between infection and neurodegenerative disease” — specifically AD and PD, Sun commented.
“As shown in animal research, infectious agents and their metabolites can promote aggregation of misfolded protein in neuron and its propagation from the periphery to the CNS—e.g., amyloid precursor protein and hyperphosphorylated tau protein in AD and alpha-synuclein in PD,” he added.
Moreover, infectious agents might also elicit inflammatory responses at infection site, resulting in production of pro-inflammatory cytokines and chemokines, which, like infectious agents, can cross the blood-brain barrier, enter the CNS, and elicit neuroinflammation through activating microglia and astrocyte,” he suggested.
He noted that the “underlying mechanisms for the link between infections and neurodegenerative disease may not be specific to certain pathogens or affected organs but possibly occur at the systemic level.”
Infectious events “may be a trigger or amplifier of a pre-existing disease process, leading to clinical onset of neurodegenerative disease at a relatively early age among individuals with disease predisposition.”
He cautioned that, “due to the observational nature of the study, these results do not formally prove a causal link.”
Important Player
Commenting for Medscape Medical News, Pyry N. Sipilä, MD, PhD, a researcher in the Department of Public Health, University of Helsinki, Finland, noted that the study “adds to the growing number of studies on the [potential role of infections in the development of AD]; but what is new is that the increased risk was only found among those who were diagnosed with Alzheimer’s disease before age 60.”
Sipilä, who was not involved with the current research, said that a “key limitation of the study is, as with all observational studies, that the possibility of bias cannot be excluded.”
Nevertheless, “although the causality of the observed associations remains unknown, the present study adds to the growing body of evidence, which suggests that the immune system could be an important player in the pathophysiology of AD.”
This study was supported by the Swedish Research Council , the Joint Program on Neurodegenerative Diseases , and the Chinese Scholarship Council . Sun reports no relevant financial relationships. The other authors’ disclosures are listed on the original paper. Sipilä receives funding from the Finnish Medical Foundation.
PLOS Med. Published online September 15, 2022. Full text
Batya Swift Yasgur MA, LSW is a freelance writer with a counseling practice in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).
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