Does COVID-19 Push People Toward Alzheimer’s? New Data Say Yes.
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Some scientists have long suspected that neuronal viruses such as herpes can hasten or even cause dementia. What about infections that don’t attack neurons directly? The COVID-19 pandemic offered researchers a rare opportunity to answer that question, with hundreds of millions of people being infected over a few years. Now, scientists led by Paul Matthews and Eugene Duff at Imperial College London report that among people who had COVID-19, the plasma Aβ42/40 ratio fell on average more than it did among non-infected controls. The findings were published in the January 30 Nature Medicine.
- In people who had COVID-19, the Ab42/40 ratio fell.
- Cognitive performance declined after the infection.
- In older people, and those with comorbidities, Aβ42/40 fell even more, and p-tau181 ticked up.
- Findings add weight to theories linking systemic infections to neurodegenerative disease.
“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,” wrote Ina Vorberg of the German Center for Neurodegenerative Diseases (DZNE), who was not involved in the work. “The findings … are important and emphasize the need to investigate in detail the role of pathogens as triggers or contributors to neurodegenerative diseases,” she added (comment below).
Unlike other prior studies that detected changes in AD markers following COVID-19 infection (Jan 2021 news; May 2023 conference news), first author Duff and colleagues had baseline data on every participant from before the pandemic. The data came from 1,252 participants in the UK Biobank who were part of a substudy on COVID-19. They each donated blood at two timepoints, once within six years prior to the pandemic and again between February 2021 and February 2022. Half of the participants had had COVID-19 by the time of the second blood collection, with past infections confirmed by serology testing. The other half were matched controls. By comparing cases to controls, the scientists were able to distinguish biomarker changes associated with COVID-19 from changes attributable to other factors such as normal aging.
The strongest results emerged from plasma Aβ42/40. While the ratio fell by about 0.5 percent per year overall, COVID-19 appears to have pushed an additional 2 percent drop from baseline. That’s similar to the dip associated with four years of normal aging in the study, or about half that seen in people who carried one copy of APOE4. This was striking given the average age was only 60 at baseline, and the COVID-19 cases were overwhelmingly mild to moderate, with only 20 hospitalizations. People also did worse on cognitive tests after COVID-19, with losses equivalent to almost two years of additional aging.
Pandemic Experiment. Blood used for AD biomarker testing was collected twice from each participant, once before and once during the pandemic. Most participants were middle-aged. [Courtesy of Duff et al., 2025.]
The findings suggest that even a mild case of COVID-19 can skew at least one AD biomarker. Whether that puts infected people at increased risk for AD remains to be seen. “We don't have that answer, because none of these people to our knowledge has developed Alzheimer's,” said Matthews. “It's been a relatively short time since the pandemic, and the [study] population is relatively young.”
The Aβ42/40 ratios were more skewed in people whose COVID-19 cases were more severe or who were already older, as well as in those with AD disease risk factors such as high blood pressure, an APOE4 allele, or signs of AD on an MRI scan at baseline. In these more vulnerable participants, p-tau181, another marker of amyloid, also crept up. NfL and GFAP levels were no different between those who did or did not test positive for Sars-CoV-2.
“Observing greater biomarker changes after COVID-19 in those over age 70 suggests that infection over a certain age could exacerbate existing AD pathology, rather than inducing it,” wrote Jennifer Cooper at the University of British Columbia in Canada, who was not involved in the work. “Ultimately, with the majority of [the world’s] 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.”
Age Versus COVID. In this UK Biobank cohort, average AD biomarker levels change with age. COVID-19 skewed this relationship, particularly in people older than 75. For younger people, COVID-19 only affected the Aβ42/40 ratio. [Courtesy of Duff et al., 2025.]
Other studies have shown that COVID-19 can affect AD markers and amyloid formation (Sep 2021 conference news; Wang et al., 2022; Guanqin Ma et al., 2022; Priemer et al., 2022). “The important takeaway from this new publication is connecting these elements together while accounting for a myriad of comorbidities,” wrote William Eimer of Harvard Medical School, who was not involved in the work.
Will these AD biomarker changes persist over time? Matthews does not know. Data collection occurred about two months after infection on average, but the scientists are continuing to follow these people. The biomarkers themselves also should be interpreted with caution, he added, since data supporting their use as an early indicator of AD remain limited. “These are markers suggestive of pathology that may be accelerating the path towards AD,” he said Matthews. “It doesn't necessarily tell us they'll all develop Alzheimer's.”
While the study focused on COVID-19, it may have broader implications. Since the SARS-CoV-2 virus by and large does not invade the brain, Matthews thinks its effects on AD pathology are probably caused via the immune system’s response to the virus through processes such as chronic inflammation. Many kinds of infection could theoretically do the same thing. “There are plenty of reasons to control infection and to prevent infection,” said Matthews. “Now we have more evidence that control of systemic infection, vulnerability, and response to infection is a rational approach to reducing risk of future Alzheimer's disease.” On the other hand, some of those approaches might carry other risks. In some people, COVID vaccines can cause prolonged production of viral spike protein and long-lasting changes to the immune system, including exhaustion of T cell populations and reactivation of dormant Epstein Barr virus (Bhattacharjee et al., 2025).—Nala Rogers
Nala Rogers is a freelance science writer based in Silver Spring, Maryland.
References
News Citations
- How Does COVID-19 Affect the Brain?
- Long COVID and Dementia: The Link Is Still Elusive
- Aβ, Tau, and Other AD Markers Altered in COVID
Paper Citations
- Wang L, Davis PB, Volkow ND, Berger NA, Kaelber DC, Xu R. Association of COVID-19 with New-Onset Alzheimer's Disease. J Alzheimers Dis. 2022;89(2):411-414. PubMed.
- Ma G, Zhang DF, Zou QC, Xie X, Xu L, Feng XL, Li X, Han JB, Yu D, Deng ZH, Qu W, Long J, Li MH, Yao YG, Zeng J. SARS-CoV-2 Spike protein S2 subunit modulates γ-secretase and enhances amyloid-β production in COVID-19 neuropathy. Cell Discov. 2022 Sep 30;8(1):99. PubMed.
- Priemer DS, Rhodes CH, Karlovich E, Perl DP, Goldman JE. Aβ Deposits in the Neocortex of Adult and Infant Hypoxic Brains, Including in Cases of COVID-19. J Neuropathol Exp Neurol. 2022 Nov 16;81(12):988-995. PubMed.
- Bhattacharjee B, Lu P, Monteiro VS, Tabachnikova A, Wang K, Hooper WB, Bastos V, Greene K, Sawano M, Guirgis C, Tzeng TJ, Warner F, Baevova P, Kamath K, Reifert J, Hertz D, Dressen B, Tabacof L, Wood J, Cooke L, Doerstling M, Nolasco S, Ahmed A, Proal A, Putrino D, Guan L, Krumholz H, Iwasaki A. Immunological and Antigenic Signatures Associated with Chronic Illnesses after COVID-19 Vaccination. 2025 Feb 18 10.1101/2025.02.18.25322379 (version 1) medRxiv.
Further Reading
No Available Further Reading
Primary Papers
- Bhattacharjee B, Lu P, Monteiro VS, Tabachnikova A, Wang K, Hooper WB, Bastos V, Greene K, Sawano M, Guirgis C, Tzeng TJ, Warner F, Baevova P, Kamath K, Reifert J, Hertz D, Dressen B, Tabacof L, Wood J, Cooke L, Doerstling M, Nolasco S, Ahmed A, Proal A, Putrino D, Guan L, Krumholz H, Iwasaki A. Immunological and Antigenic Signatures Associated with Chronic Illnesses after COVID-19 Vaccination. 2025 Feb 18 10.1101/2025.02.18.25322379 (version 1) medRxiv.
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Comments
DZNE
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 that by analyzing blood samples, brain imaging data, and cognitive tests from 626 matched case-control pairs (~ 60 years old) before and after mild to moderate CoV-2 infection. The authors found levels of AD biomarkers, such as the ratio of Aβ42 to βb40 and ptau-181, changed following infection, shifts that are considered predictive of AD progression. Changes were estimated to be equivalent to a four-year increase in age and were more severe in older people, patients with severe CoV-2, or those with a history of high blood pressure.
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.
University 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 age 70 suggests that infection over a certain age could exacerbate existing pathology, rather than inducing it. Thus, we cannot discern from this study if infection at a younger age would necessarily promote the development of pathology or not.
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.
Massachusetts 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 while accounting for a myriad of comorbidities. Particularly, their analysis in Figure 5 of biomarkers versus different comorbidities is a very thorough analysis and reinforces the associations of Aβ and phosphorylated tau with infectious disease. While not revolutionary in its findings, this paper does provide strong support for pathogenic involvement in AD progression.
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.
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