The virus–Alzheimer’s tug of war continues. New data across several studies weaken the proposed, and much-debated, association; its proponents are holding fast.
- Short-term anti-herpes drug use slightly lowered dementia risk.
- Infection without antiviral treatment slightly upped risk.
- But results not consistent across European countries.
A new epidemiology study reports a weak link between herpes and dementia. Researchers led by Richard Lathe and Jürgen Haas at the University of Edinburgh combed through four European population-wide healthcare databases and, in a medRxiv preprint uploaded December 4, 2020, describe equivocal data. In Denmark and Wales, short-term antiviral drug use came with slightly fewer future dementia cases. Alas, in Germany and Scotland, this association did not hold. The opposite was also true; infected people who were not prescribed an antiviral had a slightly higher risk of dementia—but only in the German cohort. “The results are not very encouraging,” Lathe wrote to Alzforum.
Some of these associations held no matter what type of dementia or virus was considered. “Because neither dementia subtype nor herpes subtype modified the association, the small but significant decrease in dementia incidence with antiherpetic administration may reflect confounding and misclassification,” the authors concluded.
Twenty-five years ago, Ruth Itzhaki linked herpes simplex virus type 1 (HSV-1) infection with an increased risk of AD (Itzhaki et al., 1997). She later spotted the virus hiding in amyloid plaques in brain tissue, and postulated that it may trigger the deposits (Wozniak et al., 2009). Since then, other connections have emerged. Scientists linked viral DNA in the brain to expression changes of genes involved in amyloid metabolism; others proposed that amyloid acts as an antimicrobial (Jun 2018 news; May 2020 news).
Still, compelling evidence that viruses, particularly herpesviruses, cause AD remains elusive, although some researchers believe that the teeny irritants could speed disease along (Jul 2019 conference news). The debate has taken on a new sense of urgency since reports that COVID-19 causes long-term neurological symptoms in a fraction of people who contract the disease (Pilotto et al., 2021). Scientists are just beginning to study this aspect of the infection (see Jan 2021 news).
Previous population studies have been conflicting, and this latest one is no different. Co-first authors Christian Schnier and Janet Janbeck, University of Copenhagen, combed through health data from the Welsh Secure Anonymised Information Linkage (SAIL) Databank, the German IMS Disease Analyzer, the Danish National Registry (DNR), and the Scottish Electronic Data Research and Innovation Service (eDRIS).
They calculated, at best, a faint connection between herpes infection and subsequent dementia. In the Danish and Welsh cohorts, people who were prescribed at least one dose of herpes antiviral medication had up to an 11 percent decrease in dementia risk, with the two other cohorts showing no altered risk. It did not matter which antiherpetic drug they took, although acyclovir and valacyclovir were most prescribed. Herpes subtype also had no bearing on dementia outcomes.
“The fact that they saw any protection at all from extremely short durations of antiherpetic medications is quite interesting,” Joel Dudley, Icahn School of Medicine at Mount Sinai, New York, wrote to Alzforum.
The opposite was true too, but only in the German cohort. Namely, people with a herpes infection who were not prescribed an antiherpetic drug had an 18 percent higher risk of dementia compared to people who had no medical history of a herpes infection. People untreated for shingles, which is caused by the varicella zoster herpes virus, were 20 percent more likely to develop dementia, whereas those with a history of HSV-1 were just as likely to be diagnosed with dementia as controls.
Controlling for socioeconomic status (SES), including level of education, quality of health insurance, or poverty level, did not change the dementia risk in any country. Ben Readhead, Arizona State University, Tempe, thought this was a strength of analyzing multiple diverse cohorts. “The persistent protective effect after accounting for these heterogeneous SES measures suggests the primary effect is not obviously confounded by SES,” he wrote.
Schnier and colleagues were more cautious in interpreting the signal. To their mind, inconsistencies across cohorts, and similar trends for both AD and vascular dementia risk despite their having different neuropathologies, indicate that confounding factors are to blame.
Readhead warned against overemphasizing associations with dementia subtypes because these were likely based on clinical diagnoses, which can be unreliable. Subtypes often co-occur in the same person and can be misclassified. “I found the authors’ interpretation a little at odds with the results, which I thought were quite encouraging for at least a modest protective effect of antiherpetic medications on dementia diagnosis,” he wrote.
“Much like in previous meta-analyses, their conclusions were mixed,” wrote Rudolph Tanzi and William Eimer, both at Massachusetts General Hospital, Charlestown. “Heterogeneous results are not terribly surprising given the complex nature of AD etiology and pathogenesis, which, so far, does not exclude an infectious component.”
A Tenuous Signal Emerges
Lathe’s new findings somewhat jibe with three prior studies of the Taiwanese national healthcare database. They found a 2.5 to three times higher risk of dementia associated with severe herpes simplex virus (HSV) infection or severe shingles involving the eye (Tsai et al., 2017; Chen et al., 2018; Tzeng et al., 2018; for commentary, see Itzhaki and Lathe, 2018). Acyclovir and valacyclovir dramatically diminished the odds of getting dementia. Treatment for fewer than 30 days reportedly reduced risk by 40 percent and longer treatment by a whopping 90 percent.
Was this too good to be true? “The Taiwanese results were extremely puzzling because antivirals are quite short-lived in the body, so explaining a long-term effect was difficult,” Itzhaki wrote to Alzforum.
One possible explanation why the associations may not have held in the European cohorts could be treatment duration. In Taiwan, people took antivirals for 90 days on average, whereas most Europeans took them for fewer than 30 days.
More recent studies in Asia and Europe reported weak associations between microbes and dementia. In South Korea, older adults diagnosed with shingles were 12 percent more likely to develop dementia than those who weren’t, and antivirals reduced risk of dementia by 24 percent (Bae et al., 2020). In three Finnish population cohorts and in the U.K. Biobank, hospitalization for any viral or bacterial infection increased dementia risk 1.6-fold. Intriguingly, herpes and Gram-negative bacterial infections popped up as the main culprits, increasing dementia risk two- and 1.6-fold, respectively. Severe infections were more closely tied to subsequent vascular dementia than to AD (Sipilä et al., 2020).
However, not all population studies of herpes and dementia have found a link. Last year, a meta-analysis found inconsistencies (Warren-Gash et al., 2019). Some studies weakly associated HSV, cytomegalovirus (CMV), and human herpesvirus 6 (HHV-6) with future dementia but other studies did not. Higher-quality evidence is needed, claimed the authors.
Biases and confounds are major sticking points for epidemiological studies. A recent genetic analysis study using Mendelian randomization, a methodology designed to eliminate such confounds, searched several genome-wide association study (GWAS) datasets for links between people’s genetic susceptibility to viral infection since birth and dementia or cognitive decline late in life. As a proxy for the former, the scientists searched for single-nucleotide polymorphisms associated with infection. The authors found 129 of these SNPs among the more than 700,000 participants, of whom 300,486 came from the CHARGE, COGENT, and UK Biobank GWAS of cognition, and 455,258 came from the PGC-ALZ, IGAP, and ADSP GWAS of late-onset AD. Importantly, the researchers found no association between a person’s genetically predicted odds of herpes infection and subsequent cognitive decline or AD (Kwok and Schooling, 2020).
Neither this nor any of the other studies took ApoE genotype into account, even though APOE4, the strongest genetic risk factor for late-onset AD, has been linked to more robust immune responses against invading herpes viruses (Jul 2019 conference news). “HSV-1 infection tends to cause worse damage in those with the APOE4 allele,” Itzhaki said.
AD Antiviral Trials
Itzhaki noted that the epidemiology studies did not investigate the effect of antivirals on people with dementia. “People were treated years before dementia developed; it is a different matter than treating them when they are symptomatic,” she said. Indeed, multiple clinical studies are now evaluating if long-term antiviral treatment can slow cognitive decline in people who already have it.
The Swedish trial wrapped up in March 2020. “We have completed CSF and plasma analyses and plan to submit a manuscript of the main results within the next few months,” Hugo Lövheim, Umeå University, Sweden, wrote to Alzforum. The American trial was held up by COVID-19 but is now back on track. “Recruitment will hopefully finish this year, then we will follow the last participant for 18 months,” Davangere Devanand, Columbia University, New York, wrote.
A Phase 2 trial in Poland tested the picornavirus antiviral pleconaril as an add-on to acetylcholinesterase inhibitors or memantine for 12 months (Nov 2018 conference news). That trial, sponsored by Apodemus AB in Solna, Sweden, ended prematurely in March 2020. Issues with data quality led to legal charges against the contract research organization managing the trial. “As of now, we have no plans to restart,” Nina Lindblom of Apodemus told Alzforum.
More funding might help settle the question of what role, if any, viruses play in AD. Last year the Infectious Diseases Society of America Foundation awarded $100,000 to each of 10 researchers studying how microbes are linked to AD (press release). Earlier this month, the National Institute on Aging opened an R01 grant funding opportunity for the Infectious Etiology of Alzheimer’s Disease. It comes on top of the more than $8 million in research grants for ongoing studies of herpesviruses and dementia listed on the NIH RePORTER. Finally, anyone “who provides persuasive evidence that an infectious agent is the root cause of Alzheimer's disease,” can claim the $1 million prize offered by Leslie Norins, ALZgerm.org, Naples, Florida.—Chelsea Weidman Burke
- Herpes Triggers Amyloid—Could This Virus Fuel Alzheimer’s?
- Herpes Simplex Virus Triggers Amyloidosis in 3D Neural Cultures
- Going Viral: Alzheimer’s Research at Herpes Conference
- How Does COVID-19 Affect the Brain?
- Fits and Starts: Trial Results from the CTAD Conference
- Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA. Herpes simplex virus type 1 in brain and risk of Alzheimer's disease. Lancet. 1997 Jan 25;349(9047):241-4. PubMed.
- Wozniak MA, Mee AP, Itzhaki RF. Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques. J Pathol. 2009 Jan;217(1):131-8. PubMed.
- Pilotto A, Cristillo V, Piccinelli SC, Zoppi N, Bonzi G, Sattin D, Schiavolin S, Raggi A, Canale A, Gipponi S, Libri I, Frigerio M, Bezzi M, Leonardi M, Padovani A. COVID-19 severity impacts on long-term neurological manifestation after hospitalisation. MedRxiv. Posted January 02, 2021. doi.org/10.1101/2020.12.27.20248903 medRxiv.
- Tsai MC, Cheng WL, Sheu JJ, Huang CC, Shia BC, Kao LT, Lin HC. Increased risk of dementia following herpes zoster ophthalmicus. PLoS One. 2017;12(11):e0188490. Epub 2017 Nov 22 PubMed.
- Chen VC, Wu SI, Huang KY, Yang YH, Kuo TY, Liang HY, Huang KL, Gossop M. Herpes Zoster and Dementia: A Nationwide Population-Based Cohort Study. J Clin Psychiatry. 2018 Jan/Feb;79(1) PubMed.
- Tzeng NS, Chung CH, Lin FH, Chiang CP, Yeh CB, Huang SY, Lu RB, Chang HA, Kao YC, Yeh HW, Chiang WS, Chou YC, Tsao CH, Wu YF, Chien WC. Anti-herpetic Medications and Reduced Risk of Dementia in Patients with Herpes Simplex Virus Infections-a Nationwide, Population-Based Cohort Study in Taiwan. Neurotherapeutics. 2018 Apr;15(2):417-429. PubMed.
- Itzhaki RF, Lathe R. Herpes Viruses and Senile Dementia: First Population Evidence for a Causal Link. J Alzheimers Dis. 2018;64(2):363-366. PubMed.
- Bae S, Yun SC, Kim MC, Yoon W, Lim JS, Lee SO, Choi SH, Kim YS, Woo JH, Kim SY, Kim SH. Association of herpes zoster with dementia and effect of antiviral therapy on dementia: a population-based cohort study. Eur Arch Psychiatry Clin Neurosci. 2020 Jul 1; PubMed.
- Sipilä PN, Heikkilä N, Lindbohm JV, Hakulinen C, Vahtera J, Elovainio M, Suominen S, Väänänen A, Koskinen A, Nyberg ST, Pentti J, Strandberg TE, Kivimäki M. Hospital-treated infectious diseases and the risk of dementia: multicohort study with replication in the UK Biobank. MedRxiv. Posted April 24, 2020. doi.org/10.1101/2020.04.20.20072355 medRxiv.
- Warren-Gash C, Forbes HJ, Williamson E, Breuer J, Hayward AC, Mavrodaris A, Ridha BH, Rossor MN, Thomas SL, Smeeth L. Human herpesvirus infections and dementia or mild cognitive impairment: a systematic review and meta-analysis. Sci Rep. 2019 Mar 18;9(1):4743. PubMed.
- Kwok MK, Schooling CM. Herpes simplex virus and Alzheimer's disease: a Mendelian randomization study. Neurobiol Aging. 2021 Mar;99:101.e11-101.e13. Epub 2020 Oct 9 PubMed.
- Devanand DP, Andrews H, Kreisl WC, Razlighi Q, Gershon A, Stern Y, Mintz A, Wisniewski T, Acosta E, Pollina J, Katsikoumbas M, Bell KL, Pelton GH, Deliyannides D, Prasad KM, Huey ED. Antiviral therapy: Valacyclovir Treatment of Alzheimer's Disease (VALAD) Trial: protocol for a randomised, double-blind,placebo-controlled, treatment trial. BMJ Open. 2020 Feb 6;10(2):e032112. PubMed.
- Schnier C, Janbek J, Williams L, Wilkinson T, Laursen TM, Waldemar G, Richter H, Kostev K, Lathe R, G Haas J. Antiherpetic medication and incident dementia: Observational cohort studies in four countries. Eur J Neurol. 2021 Jun;28(6):1840-1848. Epub 2021 Mar 19 PubMed.