Dear Editor,

SARS-CoV-2 infection has spread uncontrollably worldwide. Among the most vulnerable groups in society are populations with multiple comorbidities, such as individuals with Down syndrome (DS). They often have anatomic differences in the upper respiratory tract, congenital heart disease, hypertension, obesity, and diabetes, which could put them at higher risk for SARS-CoV-2 infection and worse clinical outcomes. Moreover, chromosome 21 (Chr21), which is triplicated in individuals with DS, contains genes directly involved in SARS-CoV-2 cell entry (e.g., TMPRSS2, APP, SYNJ1, ITSN1), which may enhance SARS-CoV-2-specific susceptibility [1].

DS is nowadays considered to be a genetically determined form of Alzheimer's disease (AD). Consistent with this concept, characteristic lesions, including amyloid-β plaques and neurofibrillary tau tangles in and around brain cells, can be found in all DS individuals by age 40. Chr21 plays a key role in the relationship between DS and AD, carrying a gene that produces one of the key proteins involved in the brain changes caused by Alzheimer's—amyloid precursor protein (APP). Triplication of the APP gene on Chr21 is sufficient to cause early-onset dementia in DS. In addition, several other genes on Chr21 may also affect aging and contribute to an increased risk of AD (e.g., TREM2, CD33, APOE ε4) [2].

Interestingly, several years ago, the ‘‘infection hypothesis’’ of AD was proposed. This hypothesis states that the formation of plaques and tangles is the early response to microbial infection. In this case, the amyloid plaques could act as a defense mechanism by engulfing the microbes and rendering them harmless. However, if the amyloid plaque is not successfully cleared, inflammation intensifies and a toxic feedback loop develops. The newer version of the ‘‘infection hypothesis’’ states that the plaques in the brains of AD patients are actually biofilms that ensure the survival of various pathogens [3, 4].

In light of the widespread SARS-CoV-2 infection, which has neuroinvasive capabilities beyond the respiratory tract in more than one-third of cases [1] and the particular susceptibility of DS individuals to both SARS-CoV-2 infection and AD, several questions arise: Should we expect the number of DS individuals who have AD to increase in the coming years? Is there anything we can do to prevent this inflammatory response to infection at DS and subsequently the development of AD in these patients? Should we include prospective trials of antiviral or immune-enhancing therapies? What about vaccine development and use? Does SARS-CoV-2 exacerbate the already developed AD in DS?

The aim of this letter is to stimulate new research and theoretical perspectives to estimate the burden of SARS-CoV-2 infection in the formation of plaques and tangles in DS individuals. Future research is needed to better understand the role of the “neurobiome” in AD, which may lead to prevention and treatment of this progressive disease, especially in DS individuals.