A recent paper made some bold claims about the risk of Alzheimer’s Disease in carriers of the ApoE4 gene. But were those claims actually supported by the evidence cited in the paper? That’s the question we set out to answer in this episode of Better Brain Fitness.
If you’d prefer to listen to the podcast, just click below. Or, if you’d prefer to continue reading, then just keep scrolling for the edited transcript of our conversation.
Josh: So, today Tommy is going to be analyzing a paper that recently came out on the APOE gene and Alzheimer’s risk.
As we've talked about in prior episodes, there is evidence that the kind of APOE gene that each of us has can influence our risk of Alzheimer's, at least in certain environments. Specifically, having the APOE4 variant of the gene has been associated with the most significant increase in risk.
Recently, a study was published in the journal Nature Medicine that looked at the relationship between APOE4 homozygosity—meaning having both copies of the APOE4 variant—and the pathology associated with Alzheimer's. They did this with a large dataset, and the title was "APOE4 Homozygosity is a Distinct Genetic Form of Alzheimer's". The title itself is a bold statement, and not surprisingly, it generated a good bit of attention.
But I think, as is often the case, a closer inspection reveals that what it actually shows may not exactly be what was reported—even perhaps by the authors themselves. So, Tommy is going to give us a rundown of this paper and dig into some of the important details. Take it away, Tommy.
Study Overview: Methods and Findings
Tommy: Thanks. This was a very widely publicized paper, and lots of questions came in. I even had questions from other podcast hosts who wanted some information and were answering questions from their listeners about this, and I gave some information to help provide context about the paper.
So, I'll give a brief overview of what they did and some of their findings. I don't think we'll dig into it too much because a lot of the details are very technically complex. But in reality, I think we can get some pretty good takeaways just by coming at it from a first principles approach and knowing some of the background about this topic—this paper doesn’t exist in isolation.
Pathology Samples Are Not Representative of the Population
What they did is they started by looking at pathology samples and clinical data from the National Alzheimer's Coordinating Center, which collects a big set of data on individuals with dementia and some controls. But it is enriched for individuals who have dementia, particularly some rarer causes of dementia, including APOE4 homozygosity. Because they're trying to do research, they need to work hard to get as many samples as possible on some of the things they’re trying to study.
The first thing to say is that when you're looking in this kind of dataset, it’s not telling you about APOE4 homozygotes overall in the world. The data is enriched for individuals with dementia, so it’s not necessarily a fair comparison or reflective of the natural course of APOE4 homozygotes in the general population. They also used other cohorts, including some European and U.S. cohorts, but even these were enriched for people with either a family history or a very high risk of dementia.
Study Hypothesis Shows Bias Toward Autosomal Dominant Risk
The study's introduction is incredibly biased. They started with the assumption that APOE4 homozygosity is similar to an autosomal dominant genetic risk factor, meaning it would inevitably cause Alzheimer's disease—comparing it to Down syndrome and other familial Alzheimer's diseases. But this doesn’t align with what decades of research have shown about APOE4 and its associated risks.
Study Claims Contradict Previous Research
We know from previous studies that there is a dose response with the APOE4 genotype: having one copy increases your risk of Alzheimer's by maybe two to six times, while having two copies increases it by six to twenty times, with significant variability. However, the notion that homozygotes are their own distinct category has not been shown in other research, despite decades of data. Nowhere has APOE4 homozygosity been seen as an autosomal dominant form of dementia—an entirely new claim this paper makes.
Pathological Markers Are Poor Predictors of Dementia
The paper then discusses how APOE4 homozygotes at a given age or stage of dementia had a higher burden of neuropathological hallmarks—such as different types of tau and amyloid beta plaques. They found that APOE4 homozygotes had more of these hallmarks than APOE3 homozygotes. While I believe their data on this point, it’s still debatable whether this is actually important in terms of dementia risk.
When looking at the supplemental data, it’s interesting to note that these neuropathological hallmarks aren’t very good at distinguishing who does and doesn't have dementia. This study further shows that protein-based neuropathological markers are very poor predictors of dementia and cognitive function. The main takeaway here is that having higher neuropathological hallmarks doesn’t necessarily mean someone has worse cognition or will develop dementia.
Predictions of Onset Lack Support
The study included a prediction interval based on age and onset of symptoms of Alzheimer's disease, and they compared APOE4 homozygotes to other autosomal dominant forms, like Down syndrome. Interestingly, the youngest age for onset in APOE4 homozygotes was the same as for APOE3 homozygotes, which challenges the idea that APOE4 homozygosity is a distinct, high-risk genetic form of dementia. This suggests that the study's claims are not fully supported by their own data.
Lifestyle Risks and APOE4
We’ve talked previously about how APOE4 magnifies the risk caused by the environment rather than acting as an independent risk factor. In certain populations like the Bolivian Chimane or the Nigerian Yoruba, APOE4 is not associated with an increased risk of dementia, suggesting that genotype-environment interactions play a significant role.
Some studies have also shown that APOE4 magnifies the impact of lifestyle risks for dementia. A 2008 study, for example, found amplified risks of dementia with excess alcohol consumption, low physical activity, and low omega-3 intake. This means that if you have one or two copies of APOE4 but mitigate these lifestyle risk factors, you can potentially eliminate much of the increased risk.
Healthy Lifestyles Mitigate APOE4-Associated Risks
The recommendation remains the same regardless of genotype—focus on healthy lifestyle choices to reduce the risk of dementia. While having APOE4 increases risk at a population level, it does not necessarily determine an individual's future. The claims made in the title of the discussed paper are incorrect, as both the existing literature and some of their own data suggest otherwise.
Irresponsible Reporting Causes Unnecessary Fear
It’s important to recognize that this study was written in a sensationalized way, meant to generate a lot of press. However, it does a disservice to people who are APOE4 homozygotes, essentially telling them they have an inevitable risk of Alzheimer’s, which we know is not true. This can cause undue stress, which is itself a risk factor for dementia. I think it was irresponsible to frame the study this way without the evidence to back up these claims.
Send Us Your Questions!
Josh: Thanks for that analysis, Tommy. If you have questions about this topic or anything else related to brain health, head over to brainjo.academy/questions and let us know. We’d love to hear from you.
Summary of the Limitations of the Study
The dataset used was enriched for individuals with dementia, making it not representative of APOE4 homozygotes in the general population.
The study's introduction showed bias, assuming that APOE4 homozygosity acts like an autosomal dominant genetic risk factor without sufficient evidence.
The findings claimed that APOE4 homozygosity is a distinct form of Alzheimer's, which contradicts decades of research.
The neuropathological markers used were poor predictors of cognitive function and dementia, even in the study’s own data.
The prediction interval for onset of symptoms did not show a significant difference between APOE4 homozygotes and APOE3 homozygotes, challenging the study's main claim.
The study ignored the impact of environmental and lifestyle factors that can influence APOE4-associated risks, leading to an incomplete interpretation of the data.
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