Severe COVID-19 in Alzheimer's disease: APOE4's fault again?

Abstract

Challenges have been recognized in healthcare of patients with Alzheimer's disease (AD) in the COVID-19 pandemic, given a high infection and mortality rate of COVID-19 in these patients. This situation urges the identification of underlying risks and preferably biomarkers for evidence-based, more effective healthcare. Towards this goal, current literature review and network analysis synthesize available information on the AD-related gene APOE into four lines of mechanistic evidence. At a cellular level, the risk isoform APOE4 confers high infectivity by the underlying coronavirus SARS-CoV-2; at a genetic level, APOE4 is associated with severe COVID-19; at a pathway level, networking connects APOE with COVID-19 risk factors such as ACE2, TMPRSS2, NRP1, and LZTFL1; at a behavioral level, APOE4-associated dementia may increase the exposure to coronavirus infection which causes COVID-19. Thus, APOE4 could exert multiple actions for high infection and mortality rates of the patients, or generally, with COVID-19.

Keywords: APOE4; Biomarker; COVID-19; Comorbidity; Coronavirus; Peripheral mechanisms.

Fig. 1

Possible mechanisms of APOE4-mediated AD and COVID-19 comorbidity. Left panel: A ten-member network shared by both AD (all members) and COVID-19 (*), generated by using MetaCore. In the case of APOE4, reduced/altered APOE has three potential actions in this network alone: (1) disinhibition of ACE2, (2) transcriptional reduction of the protective LZTFL1, and (3) more indirect disinhibition of NRP1 via LZTF1, in exacerbation of COVID-19. Asterisks are for genetic association with severe COVID-19: APOE: rs429358 (APOE2/3 vs 4) p = 0.0026, OR = 1.31; ACE2: chr23:15564667 p = 0.0056, OR = 1.12; CTNNB1: chr3:41204313 p = 0.016, OR = 0.74; LZTFL1: chr3:45834967 p = 1.15 × 10⁻¹⁰, OR = 0.56; NOTCH1: chr9:136510909 p = 0.0092, OR = 0.87; MMP1: rs11621460 p = 0.010, OR = 0.84; NRP1: chr10:33292184 p = 0.00072, OR = 1.47; RelA: rs1049728 p = 0.0063, OR = 0.64 (II); SIRT1: rs12783242 p = 0.0019, OR = 0.78; where chromosome positions are based on HG38 in the absence of rs numbers; OR, odds ratio; II, adjusted with gender and age; all association signals are provided by the GWAS meta-analysis by Ellinghaus et al. Not shown here is the additional APOE-LRP1-PARP1-TMPRSS2 pathway (see text): LRP1: rs4759044 p = 0.023, OR = 0.89; PARP1: chr1:226405149 p = 0.0065, OR = 0.51 (II). Right panel: APOE4-based vulnerability for patients with COVID-19 and AD at double risk: attenuated protective behavior for exposure risk and APOE4-associated infection risk

Fig. 2

Summary: coronavirus targets AD patients carrying APOE4