Early-onset autosomal dominant Alzheimer disease: genes and variants

Genes linked to Early-onset autosomal dominant Alzheimer disease

• PSEN1: Presenilin-1

  Its catalytic activity within gamma-secretase cleaves APP and many other membrane proteins, including Notch receptors. Pathogenic variants alter amyloid-beta production and are the most common known cause of autosomal dominant early-onset Alzheimer disease.

  2 disease-causing and 0 uncertain variants in PSEN1 are linked to Early-onset autosomal dominant Alzheimer disease.

• PSEN2: Presenilin-2

  Its gamma-secretase activity contributes to intramembrane cleavage of APP and other substrates in endolysosomal and cellular membranes. Pathogenic variants are a rare cause of autosomal dominant Alzheimer disease, generally with more variable penetrance and age of onset than PSEN1 variants.

  0 disease-causing and 0 uncertain variants in PSEN2 are linked to Early-onset autosomal dominant Alzheimer disease.

• APOE: Apolipoprotein E

  It redistributes cholesterol and other lipids between tissues by directing remnant lipoproteins to LDL-receptor-family members. The common epsilon4 isoform strongly increases late-onset Alzheimer disease risk and also influences plasma lipids and cardiovascular risk.

  0 disease-causing and 0 uncertain variants in APOE are linked to Early-onset autosomal dominant Alzheimer disease.

Known disease-causing variants in Early-onset autosomal dominant Alzheimer disease

Same protein, different disease

• Alzheimer disease is also caused by PSEN1 variants; they fall mostly in different places as the Early-onset autosomal dominant Alzheimer disease variants (88 disease-causing).
• Frontotemporal dementia is also caused by PSEN1 variants; they fall mostly in different places as the Early-onset autosomal dominant Alzheimer disease variants (63 disease-causing).
• Acne inversa, familial, 3 is also caused by PSEN1 variants; they fall mostly in different places as the Early-onset autosomal dominant Alzheimer disease variants (57 disease-causing).
• Pick disease is also caused by PSEN1 variants; they fall mostly in different places as the Early-onset autosomal dominant Alzheimer disease variants (26 disease-causing).

Diseases related to Early-onset autosomal dominant Alzheimer disease

• Alzheimer disease, also linked to APOE, PSEN1 and PSEN2
• Dilated cardiomyopathy, also linked to PSEN1 and PSEN2
• Dementia, also linked to APOE and PSEN1
• Familial hypercholesterolemia, also linked to APOE
• Telangiectasia, hereditary hemorrhagic, type 2, also linked to PSEN1
• Frontotemporal dementia, also linked to PSEN1
• Acne inversa, familial, 3, also linked to PSEN1
• Type 2 diabetes mellitus, also linked to APOE
• Age related macular degeneration 9, also linked to APOE
• Hyperlipoproteinemia, also linked to APOE
• Pick disease, also linked to PSEN1
• Familial type 3 hyperlipoproteinemia, also linked to APOE

Frequently asked questions

Which genes are linked to Early-onset autosomal dominant Alzheimer disease?

In CATVariant, Early-onset autosomal dominant Alzheimer disease is linked to 3 analyzed proteins: PSEN1 (Presenilin-1), PSEN2 (Presenilin-2) and APOE (Apolipoprotein E).

How many genetic variants are linked to Early-onset autosomal dominant Alzheimer disease?

94 variants: 2 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 0 are of uncertain significance or have conflicting reports.

Which uncertain variants in Early-onset autosomal dominant Alzheimer disease look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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