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Unraveling the Viral Connections to Alzheimer’s Disease: A Deep Dive

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During my third year as an undergraduate, I was tasked with conducting a literature review in neurobiology. As I delved into various studies, I stumbled upon the intriguing correlation between herpes simplex virus type 1 (HSV-1) and Alzheimer’s disease (AD), the leading neurodegenerative disorder associated with memory impairment.

My fascination with this subject ultimately led to the publication of my research in a top-tier journal in 2021, a year after my graduation. Drawing from my insights, I'd like to share the narrative regarding the infectious origins of AD and the involvement of the COVID-19 virus, which has captured global attention.

Alzheimer’s Disease and Its Infectious Roots

In 1982, Melvyn J. Ball, MD, a neuropathologist, highlighted that areas of the brain affected by herpes simplex encephalitis mirror those seen in AD, particularly the limbic system and temporal lobe.

Dr. Ball proposed that the dormant HSV-1 could reactivate and migrate to the brain, inducing subtle neuronal damage that accumulates over time and eventually manifests as AD. This hypothesis has gained considerable support over the years.

By 2017, the International Association of Gerontology and Geriatrics (IAGG) Congress convened in San Francisco to explore the intricate relationships between microbes and AD, recognizing the significant role of HSV-1 with over 130 studies corroborating its influence.

Research has detected HSV-1 genetic material within amyloid aggregates in the brains of deceased AD patients, a characteristic that is significantly less common in brains without AD (Figure 1). Amyloid aggregates are a critical hallmark of AD pathology.

Laboratory studies on cultured neurons and rodents showed that infection with HSV-1 resulted in amyloid aggregates, neuroinflammation, and neuronal loss. Infected rodents also exhibited memory deficits, establishing a clear cause-effect relationship between HSV-1 and AD.

Although HSV-1 typically remains dormant in the trigeminal ganglion of over 60% of the global population, it can reactivate during periods of immunosuppression or stress. This reactivation can lead to both cold sores and brain complications, including clinical encephalitis or subclinical impairments such as neuroinflammation or amyloid formation.

Repeated reactivations of HSV-1 may contribute to the accumulation of amyloid in the brain, paving the way for AD.

Epidemiological evidence further bolsters this hypothesis. A 2018 study of over 33,000 individuals in Taiwan found that those with HSV-1 infections had a 2.5-fold higher risk of developing dementia, with antiherpetic medications reducing this risk by 90%.

A 2021 cohort study involving over 250,000 individuals in Sweden indicated that those with HSV-1 or other herpes infections who did not receive antiviral treatment had a 1.5-fold increased risk of dementia, which was eliminated in patients who did receive treatment.

If HSV-1 indeed accelerates AD progression, then anti-HSV-1 medications could potentially halt its advancement. This notion is currently being tested in a clinical trial evaluating valacyclovir in mild AD patients, with results anticipated in 2023. If successful, this trial could transform our approach to treating this previously deemed untreatable condition.

“Given the failure of 413 trials of other types of therapy for AD from 2002 to 2012, antiviral treatments for AD patients could break the deadlock of ineffective drug development,” remarked Ruth F. Itzhaki, Ph.D., a leading figure in this research area.

Interestingly, a 2019 clinical trial highlighted that lactoferrin, an antimicrobial peptide that can inhibit HSV-1, improved cognitive function and biomarkers in patients with mild to moderate AD.

The Role of Amyloids and Other Herpesviruses

Moreover, amyloids possess antimicrobial properties; they can entrap microbes in the brain, potentially serving as a defense mechanism against infections.

For instance, a 2018 study illustrated that mice infected with HSV-1 developed amyloid aggregates that inhibited the virus, preventing severe encephalitis and extending their lifespan at the cost of increased amyloid levels.

This challenges the long-held belief that amyloids are solely harmful, suggesting they may also function as protective agents against brain infections.

Amyloids are believed to have emerged around 400 million years ago in vertebrates, and their evolutionary conservation hints at a critical role in pathogen defense.

The narrative extends beyond HSV-1. Another herpesvirus, varicella-zoster virus (VZV), which causes chickenpox and remains dormant in the body, may also contribute to AD. Recent findings indicate that while VZV infection alone does not induce amyloid or tau aggregation, it can reactivate latent HSV-1, leading to more substantial amyloid accumulation and neuroinflammation.

Dana Cairns, Ph.D., the study’s lead author, stated, “It’s a one-two punch involving two common and typically harmless viruses that could create significant complications if one triggers the other.”

Notably, a nationwide study in the U.K. found a 28% reduction in dementia risk among individuals vaccinated against VZV, aligning with smaller studies suggesting better cognitive outcomes in vaccinated populations. However, there is currently no effective vaccine for HSV-1.

Other pathogens, including Epstein-Barr virus, hepatitis C, Chlamydophila pneumonia, various Spirochetes species, and Candida, have also been linked to AD, albeit with less extensive research compared to HSV-1.

The National Institute of Health recognized the “Infectious Etiology of Alzheimer’s Disease” as a high-priority area in 2019, increasing funding for research that was once considered controversial and lacking credibility.

While these findings are significant, the precise causal mechanisms remain uncertain. Scientists speculate that age itself, a significant risk factor for AD, may increase susceptibility to microbial infections like HSV-1. The aging process is often accompanied by weakened immune responses and a more permeable blood-brain barrier, both of which may facilitate brain infections.

Thus, it's plausible that AD results from a complex interplay of age, microbial infections, genetics, lifestyle, and environmental factors. This complexity suggests that there may not be a singular cause of AD, complicating its resolution. However, the implications of viral contributions to AD remain alarming.

COVID-19: A New Complication

The arrival of SARS-CoV-2, the virus responsible for COVID-19, introduces another potential microbial risk factor for AD.

Initially perceived solely as a respiratory virus, SARS-CoV-2 is now recognized to affect blood vessels and neurons. Its ability to invade the brain occurs through the blood-brain barrier or olfactory pathways, rather than through reactivation like HSV-1.

Genetic material and proteins from SARS-CoV-2 have been found in the brains of infected individuals. Although direct amyloid aggregation due to SARS-CoV-2 has yet to be established, higher rates of amyloid deposits have been observed in the brain tissues of COVID-19 patients compared to non-COVID-19 patients (Figure 2).

These amyloids likely act as a protective response against SARS-CoV-2 infection within the brain.

Unlike HSV-1, SARS-CoV-2 does not alternate between latent and active states; however, it can evade immune surveillance to persist in the body. Notably, SARS-CoV-2 genetic material has been detected in brain tissues of infected patients up to 230 days post-symptom onset, indicating prolonged viral presence.

This persistence is a key factor in the phenomenon of long-COVID, a debilitating syndrome featuring diverse symptoms, including cognitive decline such as memory loss. Consequently, SARS-CoV-2 may represent a chronic threat that exacerbates the amyloid burden, potentially leading to AD.

Epidemiological studies reinforce this possibility. A 2022 cohort study involving over 6 million older adults in the U.S. revealed a 69% increased risk of AD in those diagnosed with COVID-19 within the preceding year compared to those who were not infected.

Similarly, a Danish study with nearly 3 million participants found that COVID-19 patients had a 3.5-fold higher risk of AD at a 12-month follow-up compared to non-COVID controls (Figure 3). This suggests that infections, not just limited to a single pathogen, may contribute to AD risk.

Another longitudinal study in 2022 analyzed brain changes in 785 older adults, 401 of whom had contracted COVID-19. This study found that COVID-19 survivors experienced reduced grey matter thickness in key brain areas linked to memory and olfaction compared to their baseline scans and non-COVID controls (Figure 4).

COVID-19 survivors also exhibited more significant cognitive decline relative to their prior assessment (Figure 5).

These cognitive and imaging effects persisted even when excluding hospitalized patients, suggesting that even mild COVID-19 can adversely impact the brain, particularly in areas associated with AD.

“Changes in limbic brain areas could be early signs of a degenerative spread of the disease through olfactory pathways,” the authors noted. The olfactory cortex is often one of the first regions affected in the preclinical stages of AD, explaining why patients frequently experience smell dysfunction prior to the onset of full-blown AD.

Ultimately, a pressing question remains: will the pandemic result in a surge of AD cases? While the prevalence of AD is expected to rise with an aging population, the COVID-19 pandemic has also negatively impacted life expectancy across many regions. The interplay of these factors may neutralize each other.

As of 2022, the incidence of AD does not appear to have increased relative to previous years, likely due to improvements in healthcare and societal conditions. However, the long-term consequences of the COVID-19 pandemic on AD rates remain uncertain.

In conclusion, we are still unraveling the infectious origins of AD. The implications of our findings regarding HSV-1 and potentially COVID-19 are concerning. If we can decode these connections, it may lead to solutions for AD, which has long been viewed as an unsolvable challenge.

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