The few people who carry two copies of the ApoE2 allele are blessed with remarkable protection against Alzheimer’s disease, according to a study published February 3 in Nature Communications. While the E2 allele has long been known to hedge AD risk, the new study used data from more than 5,000 neuropathologically confirmed AD cases and controls to make the most informed assessment of the allele’s protective capacity yet.

Alzforum covered the finding when it was presented at AAIC, and later in a medRxiv manuscript (Aug 2019 conference newsNov 2019 news). 

The study garnered data from the Alzheimer’s Disease Genetics Consortium’s 4,018 neuropathologically confirmed AD dementia cases and 989 cognitively normal controls, and calculated risk comparisons between all possible genotypes. E2 homozygotes faced a third of the AD risk that E2/E3 heterozygotes did, and 87 percent lower risk than people with the most common genotype, E3/E3. Compared with the E4 homozygotes—those at highest risk for the disease—E2 homozygotes had 99.6 percent lower odds. Findings from a larger cohort of more than 24,000 clinical AD cases and controls, though without neuropathological confirmation, fell along the same lines but underestimated ApoE2’s protective prowess.

Among ApoE2 carriers who did develop AD, the allele associated with an older age at onset, and a lower tau tangle burden, even after controlling for neuritic Aβ plaques.

“We think [our study] will remind stakeholders, including drug developers, that APOE and its variants may have a greater impact on the differential risk of AD and ensuing dementia than previously appreciated, and that it will underscore the opportunity to develop APOE-modifying drugs to treat and prevent AD,” wrote Reiman.—Jessica Shugart


  1. In general the data confirm previous findings, and highlights that intervening in APOE-related mechanisms is still a useful therapeutic avenue for AD.

    The neuropathological confirmation in a subset of 5,000 participants is a strong asset. It is of interest that the APOE e4 allele is not associated with hippocampal sclerosis and vascular brain injury. This may partly explain why the OR of e4 for AD is higher in the pathologically confirmed subgroup, since hippocampal sclerosis and vascular injury may lead to a clinical diagnosis of dementia mimicking clinical AD. The APOE-e4 allele is associated with Lewy body pathology, suggesting that aggregation of amyloid and α-synuclein share a common mechanism.

    View all comments by Pieter Jelle Visser
  2. Reiman et al. is a very interesting study, showing that the risk of Alzheimer's disease for APOE-ε2 homozygotes is extremely low even when compared with APOE-ε2 heterozygotes. This result, even not surprising, has an impact on how we should think about the effect of APOE genotype on Alzheimer's disease.

    Until now, due to the low frequency of the ε2 allele, few studies had focused their attention on its impact on Alzheimer's disease; and those that have done it have usually studied only the ε2 heterozygote group or ε2 carriers merging heterozygotes and homozygotes. Hence, studies like this, in emphasizing the ε2 homozygosity effect, are most interesting.

    One of the strongest points of this paper is the large amount of neuropathological data gathered. This allowed study of the actual APOE effects on Alzheimer's risk without confounding effects of misclassified patients. As shown here, in the non-autopsy cohort, both ε2 and ε2 allele effects are smaller than in the neuropathological cohort. Even if it cannot be confirmed with this data set, this suggests that AD-misclassified cases and preclinical AD cases could account for this difference, reinforcing the significance of autopsy results.

    Another interesting point was the differential effect found on tau tangle severity after adjusting by amyloid plaque severity. This result points toward additional mechanisms through which the ε2 allele confers its protective effect beyond decreasing amyloid deposition. We are starting to figure out the different mechanisms through which ε2 is protective. In that regard, we have recently conducted a multicohort study including MRI of an unprecedented number of cognitively unimpaired individuals including APOE-ε2 homozygotes. We analysed the ε2 allele dose-effect on gray-matter volumes, and found bigger volumes in key AD-related areas with increasing number of ε2 alleles. This suggests that ε2 homozygotes may confer additional resilience through distinct brain structural patterns, even before there is pathological protein accumulation.

    In summary, this study is a starting point to a more detailed study of the ε2 allele, specifically ε2ε2, regarding the mechanisms behind its protective effects on Alzheimer's disease. As it has been shown on these analyses, even with a limited amount of ε2 homozygotes, the protective effect of this allele is higher than previously reported, and the implications and causes of this should be further studied.

    View all comments by Gemma Salvadó
  3. This valuable paper from Eric Reiman and colleagues provides a strong rationale for targeting APOE in AD therapeutic research. APOE alleles are the most important risk factors and protective factors in sporadic AD; understanding the mechanisms of these effects should provide clues to therapeutic interventions. The impact of the rare APOE3 Christchurch mutation on the age of onset of cognitive impairment in an individual with autosomal dominant AD and a heavy plaque load points to the role of APOE in connecting amyloid to downstream neurodegeneration; if this mechanism can be translated into a therapeutic that delays symptom onset in AD for a decade or two, or three, we will have made enormous progress toward controlling the pandemic.

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News Citations

  1. Rare Luck: Two Copies of ApoE2 Shield Against Alzheimer’s
  2. Can an ApoE Mutation Halt Alzheimer’s Disease?

Further Reading

Primary Papers

  1. . Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat Commun. 2020 Feb 3;11(1):667. PubMed.