Lewy body dementia: genes and variants

Genes linked to Lewy body dementia

• GBA1: Lysosomal acid glucosylceramidase

  It degrades glucosylceramide within lysosomes and is essential for normal sphingolipid turnover. Biallelic pathogenic variants cause Gaucher disease, while heterozygous pathogenic variants are among the strongest genetic risk factors for Parkinson disease.

  6 disease-causing and 7 uncertain variants in GBA1 are linked to Lewy body dementia.

• SNCA: Alpha-synuclein

  Alpha-synuclein is a neuronal protein that supports synaptic-vesicle trafficking, priming, and neurotransmitter release. Misfolded or aggregated alpha-synuclein is a defining feature of Parkinson disease and Lewy-body disorders.

  2 disease-causing and 2 uncertain variants in SNCA are linked to Lewy body dementia.

• 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 Lewy body dementia.

Weakly linked (only a few uncertain records): VCP.

Known disease-causing variants in Lewy body dementia

Which prediction tools work for Lewy body dementia

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 76 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 73 out of 100

Same protein, different disease

• Gaucher disease is also caused by GBA1 variants; they fall mostly in different places as the Lewy body dementia variants (132 disease-causing).
• Parkinson disease, late-onset is also caused by GBA1 variants; they fall mostly in different places as the Lewy body dementia variants (8 disease-causing).
• Gaucher disease perinatal lethal is also caused by GBA1 variants; they fall mostly in different places as the Lewy body dementia variants (5 disease-causing).
• Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome is also caused by GBA1 variants; they fall mostly in different places as the Lewy body dementia variants (3 disease-causing).

Diseases related to Lewy body dementia

• Parkinson disease, also linked to GBA1 and SNCA
• Familial hypercholesterolemia, also linked to APOE
• Gaucher disease, also linked to GBA1
• Alzheimer disease, also linked to APOE
• Type 2 diabetes mellitus, also linked to APOE
• Age related macular degeneration 9, also linked to APOE
• Hyperlipoproteinemia, also linked to APOE
• Autosomal dominant Parkinson disease 8, also linked to SNCA
• Familial type 3 hyperlipoproteinemia, also linked to APOE
• Diabetes mellitus, also linked to APOE
• Parkinson disease, late-onset, also linked to GBA1
• Myocardial infarction, also linked to APOE

Frequently asked questions

Which genes are linked to Lewy body dementia?

In CATVariant, Lewy body dementia is linked to 3 analyzed proteins: GBA1 (Lysosomal acid glucosylceramidase), SNCA (Alpha-synuclein) and APOE (Apolipoprotein E).

How many genetic variants are linked to Lewy body dementia?

18 variants: 8 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 9 are of uncertain significance or have conflicting reports.

Which uncertain variants in Lewy body dementia look disease-causing?

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

Which variant effect predictor works best for Lewy body dementia?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.73, based on 8 disease-causing and 11 harmless variants).

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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