Duff EP, Zetterberg H, Heslegrave A, Dehghan A, Elliott P, Allen N, Runz H, Laban R, Veleva E, Whelan CD, Sun BB, Matthews PM. Plasma proteomic evidence for increased β-amyloid pathology after SARS-CoV-2 infection. Nat Med. 2025 Jan 30; Epub 2025 Jan 30 PubMed.
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Since the SARS-CoV-2 outbreak in late 2019, more than 700 million people worldwide have been infected, resulting in more than 7 million deaths. CoV-2 infections can have long-lasting health effects that can develop months after the initial infection. But could CoV-2 also initiate the onset or accelerate the progression of Alzheimer's disease?
The research team led by Matthews asked just …More
Although observational studies cannot prove causality, this study provides another strong indication that viral infections may increase the risk of developing dementia later in life. Neurotrophic viruses such as herpesviruses have long been suspected of contributing to neurodegenerative diseases, but systemic viral infections could also affect neuronal integrity by inducing chronic inflammatory responses in microglia and astrocytes or by disrupting the blood-brain barrier and subsequent immune cell invasion.
These findings of Duff et al. are important and emphasize the need to investigate in detail the role of pathogens as triggers or contributors to neurodegenerative diseases. Extensive association studies linking several viral infections to neurodegeneration (Levine et al., 2023), and the recent identification of Epstein-Barr virus as the likely trigger of multiple sclerosis (Bjornevik et al., 2022), argue that research in this area must be strongly increased.
References:
Levine KS, Leonard HL, Blauwendraat C, Iwaki H, Johnson N, Bandres-Ciga S, Ferrucci L, Faghri F, Singleton AB, Nalls MA. Virus exposure and neurodegenerative disease risk across national biobanks. Neuron. 2023 Apr 5;111(7):1086-1093.e2. Epub 2023 Jan 19 PubMed.
Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, Elledge SJ, Niebuhr DW, Scher AI, Munger KL, Ascherio A. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022 Jan 21;375(6578):296-301. Epub 2022 Jan 13 PubMed.
View all comments by Ina VorbergUniversity of British Columbia
This study provides valuable insight into the impact of COVID-19 on amyloid-associated biomarkers. The ability to compare cases versus controls in the context of COVID-19 is a strength here, as within a year or two of the pandemic, finding individuals who had never been exposed to COVID-19 has become extremely difficult.
Observing greater biomarker changes after COVID-19 in those over …More
It would be interesting to understand if these biomarker changes reflect an altered biomarker trajectory post-COVID, or whether biomarker changes represent an acute shift that will then normalize and display the same trajectory as controls over time. As the authors hypothesize, it is likely that systemic inflammation links COVID-19 to a potential neuropathological change, raising important questions for future investigations to determine whether long-COVID drives any of these results. Since long-COVID is hypothesized to be related to prolonged inflammation, it could be that these biomarker changes persist for longer in those with long-COVD than in those without.
Ultimately, with the majority of the population having now been exposed to COVID-19, it will be important to identify who may be at greater risk for these biomarker changes, whether it is the older population in general, or those with more severe or persistent symptoms.
View all comments by Jennifer CooperMassachusetts General Hospital, Harvard
The authors successfully connect some well-known elements of AD to COVID. Retrospective cohort studies have extensively examined both AD's influence on COVID and COVID's influence on AD. There is a strong connection. It has also been shown that the shift in amyloid production with COVID is present. The important takeaway from this new publication is connecting these elements together …More
In terms of the bigger picture, the evidence for microbial involvement in AD is growing rapidly. As a fallout of the modest (at best) success of anti-amyloid antibody treatments, the amyloid cascade hypothesis is being seriously re-examined. Not to dismiss the importance and role of amyloid in AD, but the amyloid>tau>neurodegeneration linear path to disease is not so simple. The pandemic, as horrible as it has been, has provided the research community with a wealth of information about how a virus could impact systems that were previously not associated with an infection.
Long COVID is still an ongoing research topic, and the neurological symptoms can sometimes mirror AD a little too well. This publication provides another viewpoint that a viral infection influencing the central nervous system increases your risk of developing AD, just as HSV1, CMV, and EBV do. Their plasma biomarker findings of decreased Aβ42/40 ratios and increased p-tau are the classic expected results for future AD, but are also hallmarks of an infection.
Where does this leave us? Viral brain infections increase our risk of AD and vaccines against these viruses decrease our risk back to baseline, but don’t abolish this risk. Why? The case for microbial involvement in AD etiology is strong and growing stronger, but while we can see the strong connection and occasionally even see microbes (like HSV1) in the brain with amyloid or tau, there is still a blank space between the infection and the development of AD. Do pathogens weaken our management of amyloid and tau? Do they trigger the immune system and neurodegeneration that starts the amyloid cascade? Do risk factors for AD make us more susceptible to worse infection, starting a spiral toward full neurodegeneration? We have yet to unveil the mechanism behind how infection can result in AD, hence why we don’t have a targeted, effective treatment.
Our position is twofold. First, everyone looks for a one-to-one ratio: you get the flu from influenza, immune deficiency from HIV, cold sores from HSV. We don’t have a disease X that causes AD, and I think this has restrained the research community’s support of microbial involvement. We think the mechanism is more basic, and that any pathogen that makes it to the brain (intact or not) that can stimulate an immune response could be a player in AD progression.
This comes from our second stance: that amyloid and tau are antimicrobial peptides. It should have always been questioned why the APP sequence is highly conserved in the animal kingdom and why everyone has some degree of Aβ42 present. It doesn’t make sense for us to carry a cleavage byproduct without a function. Changes in amyloid and tau are a direct response to infection in an effort to battle it. This paper here fits in perfectly with our hypothesis.
View all comments by William EimerMake a Comment
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