Alzheimer’s disease risk associated with the APOE gene just got even more complicated. In a bioRxiv preprint uploaded September 23, researchers led by William Bush, Case Western Reserve University, Cleveland, reported that another gene, HP, can play around with the effect of APOE. HP encodes the antioxidant blood protein haptoglobin, which binds to ApoE. HP comes in two variants, and one, HP2, tempers AD risk in APOE4/E2 carriers but heightens risk in people who are E4/E4, the authors report. They think that accounting for haptoglobin variants would improve AD risk prediction based on APOE genotype.

  • Haptoglobin reduces oxidative stress and binds to ApoE.
  • The blood protein comes in two variants.
  • One of them modulates AD risk linked to APOE genotype.

In the blood, haptoglobin mops up hemoglobin released from dying red blood cells. This prevents the heme iron from oxidizing molecules haphazardly. Haptoglobin also binds ApoE to shield it from oxidation, preserving the apolipoprotein’s lipid transport function (Salvatore et al., 2009; Yang et al., 2013). 

Haptoglobin comes in two flavors, HP1 and HP2. The latter is larger, having an extra copy of both exon 3 and exon 4, and forms trimers and multimers instead of dimers as HP1 does. The multimers cling less tightly to ApoE, exposing the lipoprotein to oxidation and limiting lipid transport (Melamed-Frank et al., 2001). Indeed, people who carry HP2 have high blood cholesterol, and APOE4/HP2 carriers on average die younger than those who are E4/HP1 (Boettger et al., 2016; Zheng et al., 2017; Napolioni et al., 2011).

This year, interest in the protein intensified. Screens for AD markers linked high-serum HP2 with worse cognition and Alzheimer’s disease (Qin et al., 2022; Laffoon et al., 2022). Could HP2 raise AD risk, perhaps by interacting with APOE?

To find out, first author Haimeng Bai sequenced APOE and haptoglobin genotypes from 23,000 old people—half with AD, half controls—from 29 cohorts in the AD Genetics Consortium (ADGC). Half were female, and all were of European descent. To see how alleles affected disease risk and age of onset, Bai compared APOE and HP genotypes in people with AD to those in controls.

About half the volunteers were E3/E3 carriers, followed by one-third E3/E4, then less than 8 percent for each remaining allele combination. As for haptoglobin, about half carried HP1/2, one-third HP2/2, the rest HP1/1. HP genotype did not influence a person’s likelihood to have AD.

What about the interaction between both genes? This is where things got complicated. One HP2 allele decreased AD risk in APOE2/4 carriers, and two HP2 alleles were even better. Oddly, HP2 increased risk in APOE2/2, E2/E3, and E4/E4 carriers. AD risk in APOE3/3 or E3/E4s was unaffected by HP2 (see image below).

HP Versus APOE. Having two copies of HP2 (right, x-axis) decreased Alzheimer’s risk (y-axis) in APOE2/4 carriers (purple) but increased it in APOE4/4 (teal), E2/3 (green), and E2/2 (yellow) carriers. HP2 did not affect AD risk in APOE 3/4 (orange) or E3/3 (pink) carriers. [Courtesy of Bai et al., bioRXiv, 2022.]

To get a better sense of how haptoglobin might be driving or slowing AD risk, the scientists first considered just one of the APOE alleles. People who had an APOE2 had a 40 percent higher AD risk per HP2, but people with an E4 had a 17 percent lower risk per HP2. HP2 did not change AD risk in people with an APOE3 allele.

Next, the researchers considered two APOE alleles. Curiously, the opposite relationship emerged when the second was APOE4. APOE2 carriers had a 25 percent lower AD risk per HP2 (not higher) if they also had an APOE4. And people who were E4/E4 had an 18 percent higher risk per HP2, not lower as they did if they had only one E4. Again, haptoglobin had no effect on risk in APOE3/E4 carriers.

All in all, HP2 lowered AD risk in APOE2/4 carriers but increased risk in people with E4/E4.

What about age of AD onset? This also depends on APOE genotype, with each E4 allele hastening it by 2.5 years. In keeping with the effect on disease risk, each HP2 allele delayed onset in APOE2/E4 carriers but hastened it in APOE2/E2 and slightly less so in E2/E3 and E4/E4 carriers. AD onset in APOE3/E3 and E3/E4 carriers was unaffected.

How could HP2 have this opposite effect? Bai thinks haptoglobin might prefer binding to one allele over the other. If it bound more tightly than HP1 to ApoE4, and more weakly to ApoE2, then it could protect against the former, while allowing the latter to become oxidized.

Bai thinks that HP2 may prompt Aβ binding to one APOE allele more than others, which would affect amyloid accumulation. In postmortem brain from people who had had AD, haptoglobin concentration was high, and it mingled with Aβ and ApoE (Philbert et al., 2021; Spagnuolo et al., 2014).—Chelsea Weidman Burke


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Paper Citations

  1. . Haptoglobin binds apolipoprotein E and influences cholesterol esterification in the cerebrospinal fluid. J Neurochem. 2009 Jul;110(1):255-63. PubMed.
  2. . VPO1 mediates ApoE oxidation and impairs the clearance of plasma lipids. PLoS One. 2013;8(2):e57571. Epub 2013 Feb 25 PubMed.
  3. . Structure-function analysis of the antioxidant properties of haptoglobin. Blood. 2001 Dec 15;98(13):3693-8. PubMed.
  4. . Recurring exon deletions in the HP (haptoglobin) gene contribute to lower blood cholesterol levels. Nat Genet. 2016 Apr;48(4):359-66. Epub 2016 Feb 22 PubMed.
  5. . A common deletion in the haptoglobin gene associated with blood cholesterol levels among Chinese women. J Hum Genet. 2017 Oct;62(10):911-914. Epub 2017 Jun 29 PubMed.
  6. . APOE haplotypes are associated with human longevity in a Central Italy population: evidence for epistasis with HP 1/2 polymorphism. Clin Chim Acta. 2011 Sep 18;412(19-20):1821-4. PubMed.
  7. . Phosphorylated Tau 181 Serum Levels Predict Alzheimer's Disease in the Preclinical Stage. Front Aging Neurosci. 2022;14:900773. Epub 2022 Jun 13 PubMed.
  8. . Analysis of plasma proteins using 2D gels and novel fluorescent probes: in search of blood based biomarkers for Alzheimer's disease. Proteome Sci. 2022 Jan 26;20(1):2. PubMed.
  9. . Widespread severe cerebral elevations of haptoglobin and haemopexin in sporadic Alzheimer's disease: Evidence for a pervasive microvasculopathy. Biochem Biophys Res Commun. 2021 May 28;555:89-94. Epub 2021 Apr 1 PubMed.
  10. . Haptoglobin interacts with apolipoprotein E and beta-amyloid and influences their crosstalk. ACS Chem Neurosci. 2014 Sep 17;5(9):837-47. Epub 2014 Aug 1 PubMed.

Further Reading


  1. . Identification of Potential Targets Linked to the Cardiovascular/Alzheimer's Axis through Bioinformatics Approaches. Biomedicines. 2022 Feb 6;10(2) PubMed.

Primary Papers

  1. . A Haptoglobin (HP) Structural Variant Alters the Effect of APOE Alleles on Alzheimer’s Disease. BioRxiv, September 23, 2023 bioRxiv