With the emergence of SARS-CoV-2, the Covid-19 virus, we now have an additional microbial threat to look out for, among many others.
Initially thought of as purely a respiratory virus only, SARS-CoV-2 is now known to infect blood vessels and neurons as well. As a result, SARS-CoV-2 can cause various cardiovascular and neurological symptoms in both clinical Covid-19 and sub-clinical long-Covid syndrome.
Like other brain viruses, SARS-CoV-2 is capable of invading the brain via crossing the blood-brain barrier or olfactory route. SARS-CoV-2 genetic material and protein have been detected in the brain of infected patients.
Although SARS-CoV-2 has not been shown to cause amyloid aggregation directly— probably due to the lack of research in this area — amyloid deposits have been detected in brain tissues of Covid-19 patients at a higher rate than non-Covid patients (Figure 1).
* Figure 1 caption: Representative section of the entire neocortex of a deceased Covid-19 patient, stained for beta-amyloid. Numerous amyloid deposits or aggregates were found (brown spots). Some of the amyloids were found within cells (arrowheads).
Such amyloids probably served as a defense mechanism against SARS-CoV-2 infection in the brain. In fact, as it turns out, amyloids also have antimicrobial properties, where amyloid aggregation in the brain actually traps microbes, thus hindering the spread of brain infections.
SARS-CoV-2 is capable of virus persistence by switching off immune surveillance to continue replicating. In fact, SARS-CoV-2 genetic material has been detected in brain tissues of Covid-19 patients up to 230-day after symptom onset, i.e., over 7 months of virus persistence.
So, SARS-CoV-2 may also pose a chronic threat that increases the brain amyloid burden over time, eventually leading to AD.
And epidemiological evidence supports this conjecture.
In a 2022 large cohort study of over 6 million older adults in the U.S., the risk of AD increased by 69% in those who had Covid-19 within a year of diagnosis compared to those without Covid-19.
Similarly, in another 2022 cohort study of nearly 3 million people in Denmark, Covid-19 patients had a 3.5-fold increased risk of AD compared to non-Covid patients at a 12-month follow-up (figure 2). However, patients who had Covid-19, influenza, or bacterial pneumonia all faced similar risks of AD, suggesting that the infectious etiology of AD is not limited to a single culprit. But this isn’t a good thing as it also means that the highly contagious Covid is now another culprit we have to watch out for.
* Figure 2 caption: Covid-19 patients, regardless of inpatients or outpatients, had an over 3-fold increased risk of AD at 12-month follow-up compared to non-Covid controls. Note: Bars that cross the horizontal dotted line are non-significant.
Another impactful longitudinal study in 2022 investigated brain changes in 785 older adults in the U.K., of which 401 had Covid-19. They discovered that those who had Covid-19 had reduced grey matter thickness in the cortical and hippocampal brain areas — as well as elevated tissue damage in brain areas that are functionally linked to the olfactory cortex — compared to their baseline brain scans and to non-Covid controls (Figure 3).
Covid-19 survivors also showed a greater cognitive decline compared to their baseline scores (taken 38 months ago before Covid-19) (Figure 4).
Figure 3 caption: Longitudinal analyses showed significantly reduced grey matter thickness or increased tissue damage in Covid-19 vs. control cases in four main brain regions (left parahippocampal gyrus, left orbitofrontal cortex, temporal piriform cortex, and olfactory tubercle functional network).
Figure 4 caption: Longitudinal analyses showed significantly greater cognitive impairment in Covid-19 vs. control cases, especially among the older age groups.
And these brain imaging and cognitive function effects still persist despite excluding hospitalized Covid-19 patients, indicating that even mild Covid-19 could adversely affect the brain, specifically the hippocampal and cortical areas that are also the main regions damaged in AD.
“These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease through olfactory pathways,” the study authors wrote. “The overlapping olfactory- and memory-related functions of the regions shown to alter significantly over time in SARS-CoV-2 — including the parahippocampal gyrus/perirhinal cortex, entorhinal cortex and hippocampus in particular — raise the possibility that longer-term consequences of SARS-CoV-2 infection might in time contribute to Alzheimer’s disease or other forms of dementia.”
You might wonder how olfaction (smell) and AD (memory loss disease) are related. Actually, the olfactory cortex is one of the earliest brain regions to be affected in the pre-AD stage. This is why AD patients often develop smell dysfunction even before full-blown AD.
Ultimately, the key question of whether we might see a wave of AD from the pandemic. But so far, no study has investigated this question. While the prevalence of AD is predicted to rise due to the rising aging population, the Covid-19 pandemic has decreased life expectancy in numerous countries. As such, both effects might even out with each other.
At least in 2022, the incidence of AD doesn't seem to be increasing compared to previous years, probably due to better healthcare and sociocultural situations. But whether the present Covid-19 pandemic will lead to a wave of AD in the future is still unknown.