APOE & ALZHEIMER'S GENETIC RISK

APOE & Alzheimer's Genetic Risk — the APOE ε4 allele is the strongest common genetic risk factor for late-onset Alzheimer's disease, and your APOE genotype now influences treatment eligibility for the first FDA-approved disease-modifying therapies.

Whole genome sequencing determines your exact APOE genotype (ε2/ε3/ε4) and evaluates rare deterministic Alzheimer's genes — PSEN1, PSEN2, and APP — providing the complete genetic risk profile that shapes prevention, treatment, and clinical trial eligibility.

APOE
PSEN1
PSEN2
APP

About this condition

APOE & Alzheimer's Genetic Risk

The APOE gene (apolipoprotein E, chromosome 19q13.32) has three common alleles — ε2, ε3, and ε4 — producing six possible genotypes. APOE ε3/ε3 is the most common genotype (~60% of the population) and represents average Alzheimer's risk. APOE ε4 is the strongest known common genetic risk factor for late-onset Alzheimer's disease: one ε4 copy (ε3/ε4, ~25% of people) increases lifetime Alzheimer's risk approximately 3-4 fold; two ε4 copies (ε4/ε4, ~2-3% of people) increases risk approximately 8-12 fold and shifts typical onset 10-15 years earlier. Conversely, APOE ε2 is protective — ε2/ε3 carriers have approximately 40% reduced risk.

APOE ε4 affects Alzheimer's through multiple mechanisms: impaired amyloid-β clearance, increased neuroinflammation, compromised blood-brain barrier integrity, and reduced synaptic plasticity. Critically, APOE genotype now has direct therapeutic implications. Lecanemab (Leqembi) and donanemab, the first FDA-approved amyloid-clearing antibodies, are more effective in APOE4 carriers but also carry higher risk of ARIA (amyloid-related imaging abnormalities) — particularly in ε4/ε4 homozygotes, where ARIA risk is substantial enough to require careful benefit-risk discussion. APOE genotyping is now recommended before initiating anti-amyloid therapy.

Beyond APOE, rare deterministic Alzheimer's genes cause early-onset familial Alzheimer's disease (EOFAD): PSEN1 (presenilin 1, chromosome 14q24.2, most common — >300 pathogenic variants), PSEN2 (presenilin 2, chromosome 1q42.13), and APP (amyloid precursor protein, chromosome 21q21.3). These autosomal dominant variants cause Alzheimer's with near-complete penetrance, typically with onset between ages 30-60. EOFAD accounts for <1% of all Alzheimer's but is critical to identify because affected families have 50% risk per offspring and may benefit from presymptomatic prevention trials.

APOE genotyping is now recommended before starting lecanemab or donanemab — APOE4/4 homozygotes have substantially higher ARIA risk that must be weighed against the treatment benefit. This makes APOE one of the first pharmacogenomic markers in neurology.

Gene locus: APOE (19q13.32), PSEN1 (14q24.2), PSEN2 (1q42.13), APP (21q21.3)

APOE genotyping is increasingly clinically actionable — influencing anti-amyloid therapy decisions, clinical trial eligibility, and risk-stratified prevention strategies. WGS provides APOE plus all rare Alzheimer's genes in one test.

Anti-amyloid therapy decisions now require APOE genotype — lecanemab and donanemab risk-benefit differs by APOE status

The FDA labels for lecanemab and donanemab recommend APOE genotyping before treatment initiation. APOE4/4 homozygotes have approximately 35% risk of ARIA (vs. ~5-10% in non-carriers), including rare cases of serious cerebral edema. For ε4/ε4 homozygotes, the treatment decision requires careful informed consent discussion weighing cognitive benefit against ARIA risk. For ε4 heterozygotes, the benefit-risk is more favorable but still requires ARIA monitoring. WGS provides definitive APOE genotyping alongside comprehensive neurogenomic evaluation.

Rare familial Alzheimer's genes (PSEN1, PSEN2, APP) cause deterministic early-onset disease — identification enables prevention trial enrollment

PSEN1, PSEN2, and APP pathogenic variants cause autosomal dominant Alzheimer's with near-100% penetrance, typically with onset before age 60. The Dominantly Inherited Alzheimer Network (DIAN) and other prevention trials specifically enroll presymptomatic carriers of these deterministic variants — offering the possibility of preventing or delaying disease onset. Identification of a deterministic variant also has profound implications for family members, who have a 50% chance of carrying the same variant. WGS evaluates all three genes comprehensively.

APOE & Alzheimer's Genetic Risk — the APOE ε4 allele is the strongest common genetic risk factor for late-onset Alzheimer's disease, and your APOE genotype now influences treatment eligibility for the first FDA-approved disease-modifying therapies.

APOE & Alzheimer's Genetic Risk

APOE genotyping is increasingly clinically actionable — influencing anti-amyloid therapy decisions, clinical trial eligibility, and risk-stratified prevention strategies. WGS provides APOE plus all rare Alzheimer's genes in one test.

Anti-amyloid therapy decisions now require APOE genotype — lecanemab and donanemab risk-benefit differs by APOE status

Rare familial Alzheimer's genes (PSEN1, PSEN2, APP) cause deterministic early-onset disease — identification enables prevention trial enrollment

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