Basic Science and Pathogenesis

COVID-19 induces acute and long-term neurological symptoms. Alzheimer's disease (AD) is a risk factor for severe COVID-19, and COVID-19 survivors may experience cognitive decline. Because inflammation plays a significant role in both diseases, links between COVID-19 and AD have been hypothesized. However, it is unknown if COVID-19 patients with neurological disturbance present molecular alterations related to AD pathology. Identifying possible molecular links between COVID-19 and AD would improve patient follow-up and late-onset disease prevention. Here, we tested the possibility that COVID-19 neurological patients present early AD-related molecular neuropathological alterations.

In a retrospective analysis, we compared AD-related cerebrospinal fluid (CSF) biomarkers of amyloid-beta (Ab) proteinopathy (Ab42/40), tauopathy (phosphorylated Tau, pTau181), and total Tau from controls (n = 36), amnestic mild cognitive impairment (aMCI, n = 19), AD (n = 20), and COVID-19 patients presenting important neurological alterations at hospitalization (n = 35). CSF biomarkers were correlated with systemic and central nervous system inflammation markers. In a prospective cohort (n = 41), we evaluated plasma Ab42, Ab40, and Tau longitudinal changes up to one-year post-COVID using SIMOA. Plasma biomarkers were correlated with cognitive outcomes. The Brazilian Ministry of Health and IDOR approved the study protocol.

We found that, at hospitalization, severe COVID-19 patients with neurological symptoms presented elevated CSF Tau, like AD patients. However, we did not detect changes in CSF Ab42/Ab40, pTau-181/Ab42, or Tau/Ab42 ratios. CSF pro-inflammatory cytokine IL6 levels and AD-related biomarkers (Tau, pTau181, Tau/Ab42, pTau-181/Ab42) positivelycorrelated with systemic inflammatory index (SII). Up to one-year post-COVID, we found that plasma Tau/Ab42 selectively increased in patients with cognitive deficits. Plasma Tau longitudinal changes were most influenced by COVID-19 disease severity (negatively) and SII (positively) at hospitalization and the presence of post-COVID cognitive deficits (positively).

Collectively, our findings put inflammation as a primary correlate of acute and persistent AD-related molecular changes in COVID-19 patients, urging careful follow-up of COVID-19 survivors with lingering inflammation or cognitive symptoms for possible risk of future AD.