Introduction On the last day of the year 2019 a novel Betacoronavirus (2019-nCov), now known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and causing the highly transmissible and lethal pneumonia COVID-19 was first reported in Wuhan, Hubei Province in Central China (Huang et al., 2020; Fu et al., 2022; Lu and Sun, 2022). Since then ongoing research and long-term studies of the sequelae of SARS-CoV-2 infection have indicated that post-infection, recovery from COVID-19 and/or COVID-19 aftermath is associated with long-term physiological and neurological deficits known generically as “long COVID” (Roy et al., 2021; Ahmad et al., 2022; Baazaoui and Iqbal, 2022). Multiple independent epidemiological and clinical studies further indicate that SARS-CoV-2 infection and “long COVID” strongly correlate with the onset of progressive neurological disturbances that include Alzheimer's disease (AD), prion disease (PrD) and other neurodegenerative disorders. These are apparent: (i) especially in aged and/or senile COVID-19 patients; (ii) in patients experiencing overlapping or inter-current illnesses that include heart disease, diabetes, hypertension, neuropsychiatric and other age-related neurological disorders; and (iii) in those COVID-19 patients who have experienced a particularly virulent and/or a near fatal episode of SARS-CoV-2 infection (Farheen et al., 2021; Flud et al., 2022; Fu et al., 2022). Conversely, increasing numbers of epidemiological studies suggest that elderly people with neurological deficits commonly observed in AD are highly vulnerable to SARS-CoV-2 infection, and especially the development of more severe forms of COVID-19 disease (Chiricosta et al., 2021; Hsu et al., 2021; Fu et al., 2022). The recent finding that the SARS-CoV-2 “S1” spike protein essential for viral infectivity contains prion-like domains associated with immune-evasion and the promotion of protein aggregation and aggregate “seeding” is particularly intriguing (Baazaoui and Iqbal, 2022; Bernardini et al., 2022; Tetz and Tetz, 2022). Based on these and other very recent findings this “Opinion” paper will: (i) address our current understanding of the emerging role of SARS-CoV-2 infection with “long COVID” with special reference to AD and PrD; (ii) will review the latest findings of the SARS-CoV-2 “S1” spike protein and its preferred interaction with the ubiquitous angiotensin converting enzyme-2 (ACE2) receptor (ACE2R); and (iii) will highlight the interplay of the molecular biology and neuropathology of SARS-CoV-2 with the unusual and immune-evasive character of prion neurobiology, AD and PrD. Open access, https://www.frontiersin.org/articles/10.3389/fnins.2022.1002770/full
