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. 2022 Jan 2;12(1):29. doi: 10.3390/jpm12010029

Table 1.

Summary of shared biological links between AD and COVID-19.

Pathway Evidences for Mechanisms in AD Evidences for Mechanisms in COVID-19 References
Aging
  • -

    Primary risk factor for developing AD
  • -

    Loss of BBB integrity facilitating SARS-CoV-2 neuroinvasion

 [23,24,25,29]
Aβ deposition
  • -

    Key mediator of AD pathology and one of the earliest brain AD-related molecular changes

  • -

    Increased intracellular Ca2+ concentration through formation of pores in cell membrane mediated by the Aβ oligomers
  • -

    Accelerated Aβ accumulation in the brain, as an antimicrobial peptide activating the innate immune response

  • -

    Promoting the aggregation of Aβ and tau by the binding to SARS-CoV-2 spike S1 protein

  • -

    Disruption of Ca2+ pumps and channels by SARS-CoV-2 infection

 [32,33,34,35,37]
ACE axis imbalance
  • -

    Reduced ACE2 activity and Ang-(1–7) levels in post-mortem AD brains inversely correlating with Aβ and hyperphosphorylated tau levels

  • -

    Decreased plasma levels of Ang-(1–7) in AD patients

  • -

    Ameliorated cognitive performance by enhancing/overexpressing ACE2

  • -

    Protective role of ACE2/Ang-(1–7)Mas axis against neurodegeneration
  • -

    Mediating SARS-CoV-2 entry to cells by ACE2 as receptor for spike protein, resulting in enzyme depletion and the consequent shift of the equilibrium towards ACE1/AngI

 [29,39,44,45,46,48,49]
ApoE ε4
  • -

    Increased risk of developing AD by enhancing Aβ deposition, promoting neuroinflammation, as well as disrupting synaptic plasticity and dendritic spine formation

  • -

    Decreased BBB integrity by activating MMP9 and inflammatory cascade
  • -

    Enhanced endocytic entry of SARS-CoV-2 to cells via ACE-2 receptors through blood cholesterol associated to ApoE receptor

  • -

    Increased risk of severe SARS-CoV-2 infection and mortality

 [60,61,63,66]
Neuroinflammation and microglia
activation
  • -

    Increased levels of IL-1β, IL-6 and TNF-α in AD brains and blood

  • -

    Improved spatial memory and cognitive performance by blocking endogenous IL-1 or knocking-out IL-6

  • -

    Aggravating neurodegeneration by microglial activation

  • -

    Impaired normal phagocytic capacity of microglia by activated NLRP3 inflammasome, resulting in reduced Aβ42 clearance in the brain

  • -

    Reduction ChAT activity in the cerebral cortex related with disease severity and resulting in presynaptic cholinergic impairment
  • -

    Increased levels of IL-1, IL-6, IL-8, IL-10, IP-10, and TNF-α in the CSF of COVID-19 patients

  • -

    Increased levels of IL-1 and IL-6 correlating with worse prognosis

  • -

    Microglia activation in post-mortem brains of severe COVID-19 cases

  • -

    Increased release of IL-1β, IL-6 and TNF-α partly due to SARS-CoV-2 ORF3a protein-mediated activation of NLRP3 inflammasome

  • -

    ACh involvement in COVID-19-driven inflammatory response

 [69,70,74,
75,77,78,79,82,83,84,86,90,93]
Oxidative stress
  • -

    Promoting the aberrant accumulation of Aβ in response to excessive ROS production
  • -

    Overproduction of ROS as initiators of the toxic innate immune response against SARS-CoV-2

  • -

    Aggravating disease severity if associated with cytokine storm, pulmonary dysfunction, and viral sepsis caused by SARS-CoV-2 infection

 [88,95,98,100]
Mitochondrial
dysfunction
  • -

    Increased cytoplasmic mtDNA levels promoting innate immunity and inflammation

  • -

    Cortical iron elevation contributing to the oxidative damage in AD brains
  • -

    Promoting abnormal mitochondrial activity in the host cells mediated by TMPRSS2

  • -

    SARS-CoV-2 protection against ROS and host proteases mediated by double-membrane budded by mitochondria

 [99,100,101,104,107]
Gut microbiota
  • -

    Altered gut microbiota composition associated with inflammatory markers

  • -

    Elevated levels of microbes involved in gut inflammation, oxidative damage, and mucin-degradation

  • -

    Involvement of some bacterial species in amyloidosis
  • -

    Altered gut microbiota composition, sometimes associated with inflammatory markers

  • -

    Dysfunction in gut barrier related with worsened outcomes

 [109,110,111,112,113,119,120,121,122]

ACE, angiotensin-converting enzyme; AD, Alzheimer’s disease; ApoE, apolipoprotein E; BBB, blood brain barrier; ChAT, choline acetyltransferase; COVID-19, Coronavirus disease 2019; CNS, central nervous system; CSF, cerebrospinal fluid; MMP9, matrix-metalloproteinase-9; mtDNA, mitochondrial DNA; NLRP3, NOD-like receptor protein 3; ORF3a, open reading frame 3a; ROS, reactive oxygen species; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; TMPRSS2, transmembrane serine protease 2.