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Condition report · Neurological

Alzheimer's Disease

Whole genome sequencing reads your APOE gene in full, so it finds your ε2, ε3 or ε4 status and rarer APOE variants a simple ε4 test can miss. It also checks PSEN1, PSEN2 and APP for the variants behind early-onset familial Alzheimer's.

A condition report looks for rare variants known to cause the conditions it covers.

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About this condition

A progressive, neurodegenerative disease characterized by loss of function and death of nerve cells in several areas of the brain leading to loss of cognitive function such as memory and language

Alzheimer's disease is the most common cause of dementia, accounting for 50-60% of all dementia cases and affecting over 50 million people worldwide. Two distinct genetic forms exist: early-onset familial AD (less than 65 years, ~5-10% of all cases) caused by highly penetrant autosomal dominant variants in PSEN1, PSEN2, or APP, with onset sometimes as early as the 30s; and late-onset AD (over 65 years, ~90% of cases), which has a complex genetic architecture. APOE ε4 is the most significant known genetic risk factor for late-onset disease, but the presence of APOE ε4 influences risk; it does not predict or cause Alzheimer's.

APOE ε4 is common: about one in five people carries at least one copy. One copy raises the risk of Alzheimer's two- to three-fold compared with ε3/ε3, and two copies raise it 8- to 12-fold. In 2024, a study of more than 10,000 people proposed treating two copies of ε4 as a distinct genetic form of Alzheimer's: from age 55, ε4 homozygotes had much higher levels of Alzheimer's biomarkers than ε3 homozygotes, and symptoms began earlier, at around 65 on average. Even so, many ε4 carriers never develop dementia, and many people without ε4 do. First-degree relatives of someone with Alzheimer's have a lifetime dementia risk of 20–25%, compared with about 10% in the general population.

Why do some ε4 carriers stay well? Part of the answer lies in other variants. A rare APOE variant, Christchurch (R136S), was found in a woman from a Colombian family whose PSEN1 variant usually causes dementia in the 40s; she carried two copies of Christchurch and had no memory problems until her 70s. In 2024, a rare variant in the fibronectin gene FN1 (rs140926439) was linked to about 70% lower odds of Alzheimer's in people with two copies of ε4, and to symptoms starting around three years later. In 2026, Columbia University researchers reported how this may work: ε4 drives fibronectin to build up around the brain's blood vessels and weaken the blood–brain barrier, and lowering fibronectin restored the barrier in cell and animal models. This is laboratory research, and no treatment has come from it yet.

Early-onset familial disease caused by PSEN1 or PSEN2 pathogenic variants follows autosomal dominant inheritance with ~100% penetrance; a diagnosis is definitive. For late-onset disease, APOE status alone provides incomplete information. APOE ε4 results require careful genetic counseling context because the risk is probabilistic, not deterministic. A genetic diagnosis enables enrollment in prevention trials, informed decision-making about lifestyle modifications, and reproductive counseling. Understanding your genetic status enables personalized prevention strategies before symptoms appear.

The condition we analyse

What a diagnosis changes

Enhanced screening, cognitive engagement, cardiovascular health optimization, anti-amyloid therapies (lecanemab), prevention trial eligibility

Genes analysed

Also known as

AD; Alzheimer dementia; Alzheimer disease, familial; Alzheimer's dementia; Alzheimers disease; presenile and senile dementia

Includes 21 related subtypes ↓
  • Alzheimer disease 10
  • Alzheimer disease 11
  • Alzheimer disease 12
  • Alzheimer disease 13
  • Alzheimer disease 14
  • Alzheimer disease 16
  • Alzheimer disease 17
  • Alzheimer disease 18
  • Alzheimer disease 19
  • Alzheimer disease 2
  • Alzheimer disease 3
  • Alzheimer disease 4
  • Alzheimer disease 5
  • Alzheimer disease 6
  • Alzheimer disease 7
  • Alzheimer disease 8
  • Alzheimer disease type 1
  • Alzheimer disease without neurofibrillary tangles
  • Alzheimer disease, familial early-onset, with coexisting amyloid and prion pathology
  • early-onset autosomal dominant Alzheimer disease
  • familial Alzheimer disease
MONDO:0004975Orphanet 238616MedGen 1853

Why whole genome sequencing

APOE testing alone misses early-onset variants and hundreds of risk loci. WGS captures the full genetic picture of dementia risk.

An ε4 test alone leaves out most of the picture

Many tests report only whether you carry ε4. Whole genome sequencing reads all of APOE, so it also finds rare variants such as Christchurch, and it reads PSEN1, PSEN2, APP and TREM2 in full. For families with early-onset Alzheimer's, an ε4 test misses the PSEN1, PSEN2 or APP variants that cause it. The many common variants found in genome-wide studies are combined separately, in our Alzheimer's risk score.

A genetic finding enables prevention and eligibility for emerging therapies

A disease-causing PSEN1, PSEN2 or APP variant confirms early-onset familial Alzheimer's. Relatives can then be tested for the same variant before symptoms, join prevention trials such as DIAN-TU, and get reproductive counselling. APOE status matters for treatment too: the lecanemab label asks for ε4 testing before treatment starts, because people with two copies of ε4 (about 15% of people with Alzheimer's) are most at risk of brain swelling and bleeding (ARIA) with these drugs. Knowing your status early also gives time to act on the risks you can change, such as blood pressure and exercise.

Limitations

  • APOE ε4 raises the risk of Alzheimer's but doesn't decide it. Many ε4 carriers never develop dementia, and many people without ε4 do.
  • This report reads APOE, APP, PSEN1, PSEN2 and TREM2. Protective variants in other genes, such as FN1, are not yet interpreted.
  • A finding in PSEN1, PSEN2 or APP, or two copies of APOE ε4, should be discussed with a genetic counsellor and confirmed by a clinical genetics service before it's used for care decisions.

References

  1. Fortea J, Pegueroles J, Alcolea D et al., 2024. APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease. Nature medicine
  2. Arboleda-Velasquez JF, Lopera F, O'Hare M et al., 2019. Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nature medicine
  3. Bhattarai P, Gunasekaran TI, Belloy ME et al., 2024. Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer's disease. Acta neuropathologica
  4. Bhattarai P, Yilmaz E, Cakir EÖ et al., 2026. Fibronectin mediates APOE4-driven blood-brain barrier dysfunction in Alzheimer's disease. Nature aging
  5. Eisai Inc., 2026. LEQEMBI (lecanemab-irmb) prescribing information. U.S. Food and Drug Administration

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