Before you test for APOE ε4: what should you think through first?

APOE ε4 is the strongest common genetic risk factor for late-onset Alzheimer's disease, but it isn't a diagnosis or a prediction. Many people who carry it never develop Alzheimer's, and many people who do develop it don't carry it. Before you test, it's worth thinking through what the result can and can't tell you, how you might feel about it, who else it affects, and what you'd actually do differently once you know.

If you've heard longevity doctors talk openly about their own APOE status and wondered whether you should find out yours, this is the conversation to have with yourself first.

What is APOE, and what does the ε4 variant do?

APOE is the gene that makes apolipoprotein E, a protein that carries cholesterol and other fats around the body, including in the brain, where it supports lipid transport and repair after injury. It comes in three common versions: ε2, ε3 and ε4. You inherit one copy from each parent, so your genotype is one of six combinations. ε3 is the most common version.

The three versions behave differently. Compared with ε3, ε4 is linked to a higher risk of Alzheimer's disease, while ε2 is linked to a lower risk. The differences appear to come partly from how each version handles amyloid-β, the protein that builds up in Alzheimer's, and partly from effects on brain lipid transport, glucose metabolism, inflammation and mitochondrial function (Liu et al., 2013).

A quick note on terms: dementia is the umbrella name for symptoms such as memory loss and confusion that affect daily life, and Alzheimer's disease is its most common cause. This post focuses on Alzheimer's, because that's what APOE ε4 is most strongly linked to. Some of the best prevention research looks at dementia from all causes.

How much does APOE ε4 actually raise your risk?

This is where headlines and reality often part ways, because there are two very different ways of describing the same risk.

Relative risk compares carriers with non-carriers. In a large meta-analysis of nearly 6,000 people with Alzheimer's and over 8,600 controls, people of European ancestry with one copy of ε4 (ε3/ε4) had around 3 times the odds of Alzheimer's compared with ε3/ε3, and those with two copies (ε4/ε4) had around 15 times the odds (Farrer et al., 1997).

Absolute (lifetime) risk asks what proportion of people will actually develop it. Here the picture looks quite different. One study estimated that by age 85, the lifetime risk of Alzheimer's across the population was around 11% for men and 14% for women. For people with one copy of ε4, it was around 23% for men and 30% for women. For two copies, it was around 51% for men and 60% for women (Genin et al., 2011).

Put simply, most people with one copy of ε4 will not develop Alzheimer's by 85. Even with two copies, around half will not, depending on sex and the population studied.

Two copies does deserve a more careful conversation, though. A 2024 study of more than 13,000 people found that almost all ε4 homozygotes showed the biological changes of Alzheimer's (such as amyloid build-up) by their mid-60s, and that symptoms began on average around age 65, earlier than in ε3/ε3 carriers (Fortea et al., 2024). Having the biological changes is not the same as having dementia, and these were research cohorts, but the authors argue that two copies of ε4 should be treated as a distinct genetic form of the disease. If you're considering testing, it's worth knowing that this is one of the possible results.

Does your ancestry or sex change what an ε4 result means?

Yes. The same genotype doesn't carry the same risk for everyone. In the largest analysis of its kind so far, covering nearly 69,000 people, the odds of Alzheimer's for one copy of ε4 were highest in East Asian participants (around 4.5 times), followed by White (around 3.5 times), Black (around 2.2 times) and Hispanic participants (around 1.9 times). The protective effect of ε2 also varied between groups (Belloy et al., 2023).

Sex matters too. The same study found that women with one copy of ε4 had higher risk than men with the same genotype between the ages of 60 and 70. So any figure you read online should be treated as a population average, not your personal number.

If APOE isn't the whole story, what else shapes Alzheimer's risk?

A great deal. Alzheimer's develops in people with no copies of ε4, and many ε4 carriers live into old age without it, because APOE is one contributor among many.

The 2024 Lancet Commission identified 14 modifiable risk factors for dementia across a person's life. Because Alzheimer's is the most common cause of dementia, these are highly relevant, although the Commission's figures cover all types of dementia rather than Alzheimer's alone. Together, the Commission estimated that these factors account for nearly half (around 45%) of dementia cases worldwide (Livingston et al., 2024).

The 14 modifiable risk factors for dementia

*The proportion of dementia cases worldwide that could, in theory, be prevented if the risk factor were removed. Source: Livingston et al. (2024).

Hearing loss and high LDL cholesterol stand out as the two largest midlife factors, and several others (blood pressure, diabetes, smoking, inactivity and obesity) overlap with heart health.

Many of these are vascular. What's good for your heart and blood vessels is, broadly, good for your brain. Family history matters separately too: having a parent or sibling with Alzheimer's at least doubles the average lifetime risk, which on its own sits at around 10–12% (Goldman et al., 2011).

Can a healthy lifestyle offset APOE ε4 risk?

The evidence is encouraging, though not conclusive.

In a UK Biobank study of nearly 200,000 adults aged 60 and over, people at high genetic risk of dementia who had a favourable lifestyle (not smoking, regular physical activity, a healthy diet and moderate alcohol) were around a third less likely to develop dementia over eight years than those at high genetic risk with an unfavourable lifestyle (Lourida et al., 2019). Genetic risk here was measured with a polygenic score rather than APOE alone, and the study was observational, so it shows an association rather than proof.

Trial evidence points the same way. In the FINGER trial, a two-year programme combining diet, exercise, brain training and management of blood pressure and cholesterol improved cognition in older adults at risk of decline. ε4 carriers benefited too, and the effect was not significantly different from non-carriers (Solomon et al., 2018).

What the research doesn't yet offer is a proven way to prevent Alzheimer's in ε4 carriers specifically. The habits that seem to help are the same ones that help everyone. For many people, the question isn't "what would I do with this result?" so much as "would knowing it help me do the things I already know matter?"

How might you feel about your result?

This is the question most worth asking before you test.

The most robust evidence comes from the REVEAL study, a randomised trial in which 162 adults with a parent who had Alzheimer's either learned their APOE genotype or didn't. Over a year, there were no significant differences in anxiety or depression between the two groups, including among those who learned they carried ε4. Those who learned they were ε4-negative did have lower test-related distress than those who were ε4-positive. Importantly, people who were already highly distressed before testing were more likely to struggle afterwards (Green et al., 2009). These participants also received genetic counselling as part of the study, which isn't always the case when people test privately.

A few honest questions can help:

• Why do I want to know? Curiosity, planning, motivation to change habits and reassurance are all valid, but they lead to different decisions.
• How am I feeling right now? If you're going through a stressful period, or have recently lost someone to dementia, it may be worth waiting.
• How would I feel if the result was ε4/ε4? Picturing the hardest outcome in advance is a useful test of whether you're ready.

Knowing can change behaviour. In the same study, people who learned they were ε4-positive were nearly three times more likely to report making changes they believed might lower their Alzheimer's risk, even though they'd been told no proven prevention existed (Chao et al., 2008). That motivation can be a real positive, as long as it goes towards habits with good evidence behind them.

Who else does your result affect?

Your genes are shared. Your APOE result is also partial information about your parents, siblings and children. If you carry two copies of ε4, for example, each of your parents carries at least one, and each of your children will inherit at least one.

Some relatives may want to know, others may not. It's worth thinking about whether, how and when you'd share your result before you have it, and remembering that a family member's right not to know matters as much as your right to know.

What practical questions should you answer before testing?

Do you already have the data? If you've tested with a provider such as 23andMe or Ancestry, your raw data may already include the variants that determine APOE status. Uploading that file to a third-party service, or browsing it yourself, could reveal your result. Decide whether you want to see it before you do either.

Have data already? Purchase a DNA upload here.

Can you choose not to see it? With FitnessGenes, results linked to disease-associated genes are optional: you choose whether to receive them.

Could it affect insurance? In the UK, the Code on Genetic Testing and Insurance limits how insurers can use predictive genetic test results. It's worth reading the current code before you test.

Who will help you interpret it? APOE testing isn't routinely offered to healthy people on the NHS. Clinical guidelines describe it as having limited predictive value on its own, while noting it can be valuable and safe in the right context, with genetic counselling (Goldman et al., 2011). Talking to your GP or a genetic counsellor before or after testing is sensible, especially if you have a family history.

What would you actually do differently with the result?

For most people, the answer is "the same things, with more purpose". Whatever your genotype, the strongest evidence supports:

• Looking after your blood vessels: keep blood pressure and LDL cholesterol in a healthy range, and get them checked regularly.
• Moving every day: regular physical activity is one of the most consistent protective factors.
• Managing blood sugar and weight: diabetes and obesity in midlife are both on the Lancet Commission's list.
• Protecting your hearing and vision: treat hearing and vision loss rather than putting it off.
• Staying connected: social isolation is a risk factor in its own right.
• Limiting alcohol and not smoking.

If you already track blood markers, knowing your APOE status can give context to results such as LDL cholesterol and HbA1c, and a reason to keep a closer eye on trends over time.

Want to understand your genetics with the choice in your hands?

A FitnessGenes DNA analysis covers brain health, heart health, inflammation and more, with recommendations built around your results. Results linked to disease-associated genes, including APOE's link to Alzheimer's, are optional, so you decide what you see and when.

Get your FitnessGenes DNA test here.

FAQS

Does carrying APOE ε4 mean I will get Alzheimer's?

No. ε4 raises your risk, but most people with one copy won't develop Alzheimer's by age 85 (Genin et al., 2011). Lifestyle, vascular health, family history and other genes all play a part.

What's the difference between one and two copies of ε4?

One copy (ε3/ε4) is associated with around 3 times the odds of Alzheimer's compared with ε3/ε3, and two copies (ε4/ε4) with around 15 times the odds in people of European ancestry (Farrer et al., 1997). Two copies is also linked to earlier biological changes and earlier symptom onset (Fortea et al., 2024).

If I don't carry ε4, does that mean I won't get Alzheimer's?

No. Many people who develop Alzheimer's don't carry ε4. A negative result lowers your genetic risk from APOE, but the other risk factors still apply.

Can a DNA test diagnose Alzheimer's?

No. A DNA test can show whether you carry ε4, but it can't tell you whether you have or will develop Alzheimer's. Diagnosis involves clinical assessment and, in some cases, brain scans or spinal fluid tests.

Can I find out my APOE status from my 23andMe or Ancestry data?

Possibly. Raw data from these providers may include the variants used to determine APOE status. Decide whether you want to know before you upload or explore it.

Should I tell my family my result?

That's a personal choice. Your result carries information about your relatives, so it's worth thinking about how they might feel and whether they'd want to know, ideally before you test.

Can lifestyle changes reduce my risk if I carry ε4?

The evidence suggests they help. In the FINGER trial, ε4 carriers benefited from a combined diet, exercise, brain training and heart health programme just as much as non-carriers (Solomon et al., 2018).

Can I choose not to see my APOE result with FitnessGenes?

Yes. Results linked to disease-associated genes are optional, so you can choose whether to receive them.
 

References

Belloy ME, Andrews SJ, Le Guen Y, et al. (2023). APOE genotype and Alzheimer disease risk across age, sex, and population ancestry. JAMA Neurology, 80(12), 1284–1294. https://doi.org/10.1001/jamaneurol.2023.3599

Chao S, Roberts JS, Marteau TM, Silliman R, Cupples LA, Green RC. (2008). Health behavior changes after genetic risk assessment for Alzheimer disease: the REVEAL Study. Alzheimer Disease and Associated Disorders, 22(1), 94–97. https://doi.org/10.1097/WAD.0b013e31815a9dcc

Farrer LA, Cupples LA, Haines JL, et al. (1997). Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA, 278(16), 1349–1356. https://doi.org/10.1001/jama.1997.03550160069041

Fortea J, Pegueroles J, Alcolea D, et al. (2024). APOE4 homozygosity represents a distinct genetic form of Alzheimer's disease. Nature Medicine, 30(5), 1284–1291. https://doi.org/10.1038/s41591-024-02931-w

Genin E, Hannequin D, Wallon D, et al. (2011). APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Molecular Psychiatry, 16(9), 903–907. https://doi.org/10.1038/mp.2011.52

Goldman JS, Hahn SE, Catania JW, et al. (2011). Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genetics in Medicine, 13(6), 597–605. https://doi.org/10.1097/GIM.0b013e31821d69b8

Green RC, Roberts JS, Cupples LA, et al. (2009). Disclosure of APOE genotype for risk of Alzheimer's disease. New England Journal of Medicine, 361(3), 245–254. https://doi.org/10.1056/NEJMoa0809578

Liu CC, Kanekiyo T, Xu H, Bu G. (2013). Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nature Reviews Neurology, 9(2), 106–118. https://doi.org/10.1038/nrneurol.2012.263

Livingston G, Huntley J, Liu KY, et al. (2024). Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. The Lancet, 404(10452), 572–628. https://doi.org/10.1016/S0140-6736(24)01296-0

Lourida I, Hannon E, Littlejohns TJ, et al. (2019). Association of lifestyle and genetic risk with incidence of dementia. JAMA, 322(5), 430–437. https://doi.org/10.1001/jama.2019.9879

Solomon A, Turunen H, Ngandu T, et al. (2018). Effect of the apolipoprotein E genotype on cognitive change during a multidomain lifestyle intervention: a subgroup analysis of a randomized clinical trial. JAMA Neurology, 75(4), 462–470. https://doi.org/10.1001/jamaneurol.2017.4365

van Dyck CH, Swanson CJ, Aisen P, et al. (2023). Lecanemab in early Alzheimer's disease. New England Journal of Medicine, 388(1), 9–21. https://doi.org/10.1056/NEJMoa2212948