The APOE gene: how one genetic variant might shape Alzheimer’s risk

NeuroprotectionBrain HealthAlzheimer'sCognitive Health

24 Jan

The fear of losing your mental edge

If you’re focused on thriving into your 7th or 8th decade, few scenarios are more unsettling than the thought of gradually losing your memory. Dementia robs people of their independence and quality of life, but the impact extends far beyond that of us as individuals. It is heartbreaking for friends and family too. In the UK alone, more than half a million people live with Alzheimer’s disease, and treatments offer only modest slowing of decline.

New research has tried to quantify how much of this burden may be linked to a single genetic locus[1]. APOE (apolipoprotein E) is a gene that codes for apolipoprotein E, a protein that helps move cholesterol and other fats around the body and, in the brain, supports processes like repair of neurones and the handling of amyloid protein, a key protein linked to the development of Alzheimer’s. People inherit one APOE copy from each parent, and the common versions are called ε2, ε3, and ε4: ε4 is associated with higher Alzheimer risk and an earlier average age of onset, ε2 is relatively protective, and ε3 sits in between rather than being truly neutral.

In a modelling analysis that pooled data from over 450,000 adults aged ≥60 across four cohorts (UK Biobank, FinnGen, the A4 Study and the Alzheimer’s Disease Genetics Consortium), researchers estimated that 72-93% of clinically diagnosed Alzheimer’s cases would not have occurred without the common APOE ε3 and ε4 versions.

The same variants seemed responsible for about 45% of all dementia cases. These proportions are population‑level estimates; they do not mean that an individual with these variants will inevitably develop dementia.

What the paper showed

The primary study assessed the contribution of APOE variants to Alzheimer’s and dementia risk across four large samples:

UK Biobank and FinnGen contributed 171,105 and 289,150 participants aged 60 or older. Relative to people with the low‑risk ε2/ε2 genotype, carriers of ε3 or ε4 showed a stepwise increase in risk across genotypes (ε2/ε3, ε3/ε3, ε2/ε4, ε3/ε4, ε4/ε4). The risk contributions from all ε3 and ε4 genotypes accounted for 75.7% of Alzheimer’s cases and 44.4% of all causes of dementia in UK Biobank; FinnGen results were similar at 71.5% and 45.6%, respectively.
The third cohort, the A4 Study analysed 4,415 participants, with normal cognitive function, who underwent amyloid‑PET scans (a specialised brain scan) to assess brain amyloid. Only 4% of individuals with ε2/ε2 showed brain amyloid, compared with 27.4% of ε3/ε4 carriers. 85.1% of brain amyloid was attributable to ε3 and ε4.
The Alzheimer’s Disease Genetics Consortium (ADGC) re‑analysed 5,007 confirmed cases with Alzheimer’s. Compared with ε2/ε2 individuals, those carrying ε3 or ε4 had a significantly increased risk; overall 92.7% of Alzheimer’s cases were attributable to ε3 and ε4. Analysing these variants separately suggested that ε4 accounted for 56.9% of the burden and ε3 for 35.8%.

However, it is essential to emphasise that Alzheimer’s is not a monogenic disease; even in the highest‑risk ε4/ε4 group, lifetime risk remains below 70%.

Where this sits in the wider evidence

Across three decades of research, APOE has emerged as the most influential common genetic contributor to late onset Alzheimer’s risk, with a consistent dose response pattern where risk rises stepwise as ε4 copies increase, and tends to fall with ε2. However, ancestry and sex matters.

Classic meta analytic work showed large effects in European ancestry cohorts, with roughly threefold higher odds for ε3/ε4 and an order of magnitude higher odds for ε4/ε4 versus ε3/ε3, alongside a protective signal for ε2, but with weaker and more variable estimates in African and Hispanic populations and stronger effects reported in some East Asian cohorts. More recent large multi ethnic analyses broadly confirm that same stepwise pattern, while also showing that effect sizes differ meaningfully by ancestry group and can vary by age and sex, including signals that women in mid to late life may carry higher risk than men with the same genotype.

Brain imaging meta analyses support these population findings, with ε4 carriage linked to greater hippocampal and parahippocampal size (centres in the brain associated with memory) in Alzheimer’s and groups with mild cognitive impairment compared with non carriers, which helps explain why APOE remains clinically relevant even when it is not determinative.

Newer systems biology and cohort work is furthering our understanding, suggesting plausible female specific pathways involving blood vessel dysfunction and other mechanisms across Hispanic and Latino subgroups, reinforcing a simple point: APOE is a powerful risk modifier, not a prophecy, and that its impact is shaped by ancestry, sex, age, and whatever else is pulling the trigger in a person’s biology and environment [2], [3], [4], [5], [6].

What this changes in practice

The new modelling strengthens the case for APOE as a therapeutic target. Current anti‑amyloid drugs offer modest benefit and have been rejected for routine use in the UK. By contrast, interventions that neutralise the harmful impact of ε3 and ε4 could theoretically prevent most Alzheimer’s cases. However, several caveats temper this idea:

Genetics is not destiny. Even carriers of two ε4 variants have a lifetime Alzheimer’s risk below 70%. Genetic risk interacts with lifestyle, vascular health and environmental factors. Evidence suggests up to half of dementia incidence could be prevented or delayed by modifying factors such as social isolation, high cholesterol or smoking. This does not mean that gene editing alone will solve the problem. Importantly, some evidence suggests lifestyle interventions may have greater cognitive impact in those at highest genetic risk: a 2025 meta analysis of three randomised multidomain trials reported larger cognitive benefit in ApoE4 carriers than non-carriers [7].
Therapies must preserve APOE’s physiological roles. APOE transports cholesterol and other lipids around the body. Knocking the gene out could cause harm. Future strategies may involve editing specific variants or modulating downstream pathways rather than total suppression.
Individual action focuses on modifiable risk factors. While you can’t change your genotype, you can optimise your cardiovascular health, avoid smoking, support social and cognitive engagement, and manage metabolic risk factors. These interventions have broader evidence and impact on cognitive health and may modify the effect of APOE.

Frequently asked questions

Why does one gene matter so much? The APOE gene encodes a protein involved in lipid transport in the brain. Its common variants alter amyloid processing and other pathways. Large cohort modelling suggests that ε3 and ε4 together account for most Alzheimer’s cases, but this reflects population‑level attribution rather than a deterministic effect.

If APOE accounts for 72-93% of cases, is Alzheimer’s essentially genetic? No. The attributable fraction describes the proportion of cases that would not have occurred if the risk conferred by ε3 and ε4 were removed. It does not mean individuals with these variants will always develop disease. Many carriers remain dementia‑free, and other factors influence risk.

Does carrying an ε4 variant mean I will get dementia? In meta‑analyses, one ε4 variant roughly triples Alzheimer’s risk and two variants can increase risk up to 15‑fold. However, the baseline lifetime risk in ε2 homozygotes is around 1-5%, so even a 15‑fold increase leaves many ε4 homozygotes unaffected. Age, sex, ancestry and lifestyle modify this risk.

Is the ε3 variant harmless? No. Compared with ε2/ε2, the ε3/ε3 genotype increases Alzheimer’s risk and contributes substantially to disease burden. The perception of ε3 as “neutral” is being revised.

Should I get my APOE genotype tested? This is an individual decision. The predictive value is limited, and there is possible psychological harm, with no approved interventions that specifically target APOE. It must thus be an individual, nuanced conversation with a healthcare professional.

Are there drugs that target APOE? Not yet. Gene editing and antisense therapies are being explored, but modifying APOE without disrupting its physiological roles remains challenging. Traditional dementia drugs target amyloid or tau and offer modest benefits.

Does APOE risk differ across ethnicities? Yes. A 2023 study found that ε3/ε4 carriers had odds ratios ranging from 1.90 (Hispanic) to 4.54 (East Asian) compared with ε3/ε3. Japanese cohorts in earlier meta‑analyses showed even higher ORs. More research is needed in non‑European populations.

What else can I do to protect my brain? Focus on modifiable risk factors with stronger evidence: control blood pressure and cholesterol, metabolic health, avoid nutritional deficiencies in key nutrients, avoid smoking, stay physically active, engage socially, and ensure adequate sleep. While these measures will not eliminate genetic risk, they are linked to lower dementia incidence and better cognitive performance.