Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr19:44907831 C>T
Position: (GRCh37/hg19):Chr19:45411088 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Nonsense
Codon Change: CAG to TAG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 3

Findings

This variant, predicted to eliminate functional APOE expression, was identified in two heterozygotes in a search for loss-of-function variants of APOE (Chemparathy et al., 2024, Aug 2023 conference news). The search included whole-genome and whole-exome sequencing data from 20,856 AD cases and 26,605 older controls in the Alzheimer’s Disease Sequencing Project (ADSP), 448,049 whole-exomes from the UK Biobank, and 478 whole-exomes from the HEX dataset. Both carriers were APOE3 homozygotes. One, a woman who participated in the ADSP, remained cognitively healthy at age 82, while the other, a case from the UK Biobank, was diagnosed with AD in the 70-79 age range, although the authors noted limited specificity in some of the UK Biobank diagnoses. This latter carrier's age at onset was not reported; he was last evaluated between the ages of 80 and 89.

This variant was absent from the gnomAD variant database (v2.1.1, Aug 2023).

Biological Effect
This mutation is predicted to abrogate the full-length synthesis of ApoE introducing an early stop codon that would result in a truncated peptide devoid of ApoE’s key functional regions. How much a loss or reduction of ApoE function might affect or contribute to the pathology of AD has been an important question in the field (see e.g. Belloy et al., 2019). Data from this carrier together with heterozygotic carriers of other APOE loss-of-function mutations—W5Ter, L8Ter, and g.45408560_45410359del—suggests a 50 percent loss of ApoE protein is benign and perhaps protective when in phase with APOE4 (Chemparathy et al., 2024; Vance et al., 2024). Data from mouse models are mixed. In general, reducing or eliminating ApoE in mouse models of amyloid deposition has shown to reduce amyloid accumulation, but selectively reducing ApoE in astrocytes, microglia, neurons, or brain endothelial cells suggests cell type-specific effects that can be beneficial, neutral, or harmful (for more information, see APOE Loss of Function Variants).

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (30), suggesting a deleterious effect (CADD v.1.6, Aug, 2023).

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References

Mutations Citations

1. APOE W5Ter
2. APOE L8Ter
3. APOE g.45408560_45410359del

Mutation Data Table Citations

1. APOE Loss of Function Variants 7 Mar 2024

Paper Citations

1. Belloy ME, Napolioni V, Greicius MD. A Quarter Century of APOE and Alzheimer's Disease: Progress to Date and the Path Forward. Neuron. 2019 Mar 6;101(5):820-838. PubMed.
2. Vance JM, Farrer LA, Huang Y, Cruchaga C, Hyman BT, Pericak-Vance MA, Goate AM, Greicius MD, Griswold AJ, Haines JL, Tcw J, Schellenberg GD, Tsai LH, Herz J, Holtzman DM. Report of the APOE4 National Institute on Aging/Alzheimer Disease Sequencing Project Consortium Working Group: Reducing APOE4 in Carriers is a Therapeutic Goal for Alzheimer's Disease. Ann Neurol. 2024 Apr;95(4):625-634. Epub 2024 Jan 5 PubMed.

Other Citations

1. Chemparathy et al., 2024

Further Reading

No Available Further Reading