APOE4 testing

Don't get tested as a healthy adult without symptoms. If you are being considered for lecanemab or donanemab for mild cognitive impairment due to Alzheimer's or early Alzheimer's, that is when the test belongs. Whatever your genotype, the things that lower dementia risk are the same.

What it is

APOE is the gene for apolipoprotein E. Its ε4 version is the largest common genetic risk factor for late-onset Alzheimer's disease, and it modestly raises cardiovascular risk too. About 2% of people carry two ε4 copies (ε4/ε4).

Why it predicts poorly

On its own, the result discriminates poorly. About half of people clinically diagnosed with Alzheimer's carry no ε4 copy at all,^[1] although among those whose disease is confirmed by amyloid testing about two-thirds are carriers.^[2]

Two copies are a different story. In brain-donor and clinical cohorts, nearly all people with two copies had Alzheimer's brain changes, and by age 65 nearly all had abnormal amyloid in their spinal fluid and 75% had a positive amyloid scan. Earlier studies, summarised in the same paper, put their lifetime risk of Alzheimer's dementia at up to about 60% by age 85,^[3] so many never develop dementia even then.

Nothing to do with the result

No disease-modifying preventive treatment exists for carriers without symptoms, so the result delivers anxiety without an action. The measures that lower dementia risk (aerobic exercise, sleep, blood-pressure control, hearing, social contact) apply whether you carry ε4 or not; see Dementia prevention. In a large American trial of a structured lifestyle programme in 2,111 at-risk older adults, the added cognitive benefit was the same in carriers and non-carriers.^[4]

There is also a practical cost: in some countries a known genotype can affect long-term care and disability insurance.

The one place it belongs: before anti-amyloid drugs

The anti-amyloid antibodies lecanemab and donanemab, used for mild cognitive impairment due to Alzheimer's or early Alzheimer's, can cause amyloid-related imaging abnormalities (ARIA): brain swelling and small brain bleeds seen on scans. People with two ε4 copies get far more of them. On lecanemab, symptomatic brain swelling occurred in 9% of people with two copies, against 2% of those with one copy and 1% of non-carriers.^[5]

Regulators handle that risk differently:

• Europe and the UK. The EU licences for both drugs, and the UK licence for lecanemab, exclude people with two copies, so the genotype is checked first.^{[6] [7] [8]}
• The US. The labels say testing should be performed but allow treatment without it, and people with two copies remain eligible after counselling about their higher risk.^{[9] [10]}

That is pharmacogenetic testing, used to decide on a drug, not screening. The right time to draw it is at the start of an anti-amyloid treatment decision, not at 45 with no symptoms.

What to do

1. Skip predictive APOE testing if you are healthy and have no symptoms.
2. Put your effort into the shared risk factors: exercise, sleep, blood pressure, hearing and social contact.
3. If an anti-amyloid drug is on the table, expect an APOE test as part of the decision, and ask what your genotype means for the risk of brain swelling.

Further reading

• Ward A et al. Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4/4) among patients diagnosed with Alzheimer's disease: a systematic review and meta-analysis. Neuroepidemiology 2012.^[11]
• Mattsson N et al. Prevalence of the apolipoprotein E ε4 allele in amyloid β positive subjects across the spectrum of Alzheimer's disease. Alzheimers Dement 2018.^[12]
• Fortea J et al. APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease. Nat Med 2024.^[13]