The concept that a viral infection may induce pathology in regions far from its active location is gaining traction. Could this phenomenon also be at play in Alzheimer’s disease?
Alzheimer’s disease is a devastating neurodegenerative disease affecting one in nine Americans 65 and older as of 2022. Effective treatments are notably absent.
A significant challenge is that the disease likely begins its destructive course decades before any cognitive symptoms emerge. Some argue that by the time cognitive symptoms surface, it is too late to reverse or significantly slow down the degeneration.
Consequently, current efforts prioritize promoting protective factors, such as regular exercise and a healthy diet, while addressing worsening factors like diabetes and hypertension.
Recently, viral infections have gained attention as potential modifiable risk factors. However, this remains a controversial and at times, contentious topic among researchers and healthcare professionals.
What do the numbers say?
Large-scale epidemiological studies have clearly shown viral infections as major risk factors for developing Alzheimer’s disease and related dementias.
These include transient seasonal infections such as influenza and SARS-CoV-2 as well as dormant viruses that reactivate throughout life such as herpes simplex virus type-1 (HSV-1; causative agent of cold sores) and varicella zoster virus (VZV; causative agent of chickenpox and shingles).
For instance, VZV reactivation in which the shingles rash occurs on the face (herpes zoster ophthalmicus) carries nearly a three-fold increased risk of being diagnosed with dementia within five years. However, prompt treatment with antivirals reduces this risk compared to infected patients not treated with antivirals.
Similarly, vaccination against VZV reduces the risk of dementia by about a third compared to unvaccinated individuals. A comparable reduced risk of dementia diagnoses is seen in individuals who receive the annual influenza vaccine. While an increased risk of dementia diagnoses has been noted in individuals with COVID-19 over 65 years of age, approximately 70% increased risk, it is a bit too early to know if the vaccine is similarly protective.
This compilation is by no means exhaustive, as numerous other high-quality investigations have explored various pathogens, consistently indicating that viral infections substantially elevate the risk of dementia, and that antiviral treatment or vaccines mitigate these risks.
It’s essential to acknowledge that these findings stem from epidemiological studies, which establish associations rather than causation. Therefore, while the evidence points in a certain direction, the need for further research, including clinical trial studies (which are underway), remains imperative to establish a concrete causal relationship between viral infections and Alzheimer’s diseases and related dementias.
The big problem
A disparity exists between the epidemiological evidence and the presence of viruses in the brains of individuals who succumbed to Alzheimer’s or related dementias. When post-mortem brain assessments are conducted in these cases, the suspected viruses are not consistently detectable in the brain regions significantly affected by the disease, such as the hippocampus.
To address this discrepancy, the ‘hit-and-run’ hypothesis has been proposed, suggesting that viruses may infiltrate these brain areas and trigger the destructive cascade, but are subsequently cleared. This hypothesis holds appeal because it could occur early and repeatedly in a person’s life, aligning with the suspected onset of Alzheimer’s pathophysiology.
However, not all researchers are convinced, with some contending that stable DNA viruses like HSV-1 and VZV should exhibit a disproportionately higher presence in the brains of Alzheimer’s patients compared to others - an observation that hasn’t consistently materialized.
Additionally, there’s the argument that an active viral infection in the hippocampus (the brain region most notably affected in Alzheimer’s disease) and other brain regions should manifest more pronounced symptoms akin to viral encephalitis, which, notably, is not commonly reported in Alzheimer’s cases.
Another proposed mechanism is gaining traction that does not require hippocampal infiltration of viruses and involves the site of our first line of defense, the olfactory system.
The olfactory system hypothesis
One of the most direct paths to our brain leads through the olfactory system, merely one synapse away. With an additional connection, we arrive in the entorhinal cortex and hippocampus, regions crucial for memory and notably affected in Alzheimer’s disease.
As we inhale, odor molecules dock onto our olfactory sensory neurons located deep within the nasal cavity, specifically in the olfactory epithelium. The axons of these neurons extend into our central nervous system (CNS), transmitting olfactory information to fresh neurons residing in the olfactory bulb (OB). Subsequently, these OB neurons project to and interact with neurons in the entorhinal cortex and hippocampus.
This refined circuitry is perpetually activated, reliant on robust olfactory input to sustain a healthy hippocampus. Intriguingly, loss of smell serves as an early indicator of Alzheimer’s disease for a substantial proportion - 85% to 90% - of patients, preceding any discernible cognitive decline. However, the precise mechanisms behind this phenomenon remain elusive. Could chronic or cumulative infections be the culprits?
Susceptible to degeneration
Much like muscles that atrophy from disuse, neural circuits are equally susceptible to degeneration when they lack regular stimulation. For instance, research in rodents demonstrates that obstructing olfactory input leads to significant hippocampal degeneration, accompanied by cognitive decline.
What’s more, there exists compelling evidence that the absence of olfactory sensory stimulation can contribute to the accumulation of toxic amyloid plaques in the hippocampus, a key pathological feature of Alzheimer’s disease.
Beyond detecting odors, our olfactory system encounters a constant barrage of environmental pathogens, necessitating a robust immune system and response to safeguard the OB and the CNS. While this defense mechanism is generally effective, it weakens with age and genetics, compromising the protective function of the olfactory epithelium.
Moreover, herpesviruses like HSV-1 and VZV have a unique advantage. These viruses remain dormant within neurons in our trigeminal ganglia (a cranial nerve that provides sensory and motor information to our face), and maintain direct synaptic connections to the OB.
Consequently, when these viruses reactivate, they can circumvent the olfactory epithelium’s protective shield entirely, infiltrating and disrupting the OB circuitry. While it’s theoretically plausible for the viruses to migrate from this region to the hippocampus, it might not be a prerequisite for disease induction.
A chronic inflammatory response within the OB could suffice to disrupt olfactory sensory input to the hippocampus, potentially triggering a degenerative cascade reminiscent of Alzheimer’s disease. Ongoing studies aim to investigate this hypothesis directly.
The concept that a viral infection may induce pathology in regions far from its active location is gaining traction. This phenomenon could also be at play in Alzheimer’s disease.
Consider the possibility that the virus doesn’t need to physically enter the hippocampus or deeper brain areas to trigger or worsen the disease. Could it be that we are focusing our viral search on the hippocampus simply because it’s where we see the most damage? Has it been in ‘the’ front of our noses the whole time?
Andrew N Bubak, MS, PhD, is an Assistant Research Professor of Neurology and Neurovirology, at University of Colorado School of Medicine – Anschutz Medical Campus.
His laboratory focuses on how viruses, mainly varicella zoster virus, contribute to multisystem diseases through clinically and diagnostically evasive mechanisms. He uses a variety of cutting-edge techniques such as single-cell and spatial transcriptomics, electrophysiology, and human organoid cultures to study the viral-olfactory system interactions in the context of neuroinvasion and neurodegenerative disease. His research is supported by the National Institutes of Health.