Recent studies have reported an inverse relationship between ACE2 and transforming growth factor-β (TGF-β). In cancer models, decreased levels of ACE2 correlated with increased levels of TGF-β. In the context of SARS-CoV-2 infection, downregulation of ACE2 has been observed, leading to increased fibrosis formation, as well as upregulation of TGF-β and other inflammatory pathways. Moreover, patients with severe COVID-19 symptoms had higher blood serum TGF-β concentrations than those with mild symptoms, thus further implicating the role of TGF-β and warranting further investigation. Interestingly, reduced angiotensin/ACE2 activity has been associated with tau hyperphosphorylation and increased amyloid beta (Aβ) pathology in animal models of AD [15, 16].

Neuroinflammation is recognized as another characteristic pathophysiology of AD. Microglia and astrocytes are major sources of cytokines in individuals with AD. Dysfunction of the immune system may promote the release of proinflammatory cytokines and result in synaptic damage, neuronal death, and inhibition of neurogenesis, which are related to the pathogenesis of AD [17].

Although accumulating evidence indicates that SARS-CoV-2 can enter the CNS, the presence of the virus in the brain may not critically correlate with the neurological conditions, as postmortem studies have noted occurrence of pronounced neuropathological changes even in patients with COVID-19 in whom the virus was not detected in the CNS. Instead, extensive research on CSF and postmortem brain tissues has indicated that immune dysfunction and pronounced neuroinflammation within the CNS are the main driver of CNS damage and neurological symptoms in infected individuals. Neuroinflammation might result directly from coronavirus infection or from excessive peripheral inflammation. Both SARS-CoV-2 and proinflammatory mediators may promote BBB disruption, allowing the virus to cross the BBB, enter the CNS, and activate microglia and astrocytes, triggering a neuroinflammatory cascade that may contribute to the onset and progression of neurodegeneration[18].