Overview

Clinical Phenotype: Alzheimer's Disease
dbSNP ID: NA
Coding/Non-Coding: Both
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: Deletion
Reference Isoform: APOE Isoform 1
Genomic Region: Promoter, Exon 1, Exon 2

Findings

This variant, predicted to abrogate synthesis of ApoE, was identified in heterozygous form 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.

The carrier was a woman who had symptom onset at age 75, was diagnosed with Alzheimer’s disease at age 79, and died at age 87. Genetic analysis revealed she had an APOE3/E4 genotype, with the deletion mutation located on the same chromosome as the APOE3 allele and, consistent with this, only APOE4 mRNA was detected. Her disease onset was later than that of APOE4 homozygotes of European ancestry (mean=69.73) and close to that of APOE3/E4 heterozygotes (mean=73.55), prompting the authors to note that partial knockdown of APOE4 in APOE4 homozygotes may delay AD onset.

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

Neuropathology

Neuropathology was consistent with AD (CERAD score = 2, Braak stage VI; Chemparathy et al., 2024).

Biological Effect
As predicted, this variant eliminates APOE expression since it deletes 1,798 base pairs, including most of the APOE promoter region, as well as exons 1 and 2, including the start codon and signal peptide. 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 Q39Ter—suggests partial loss of ApoE protein is benign and likely 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).

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References

Mutations Citations

1. APOE W5Ter
2. APOE L8Ter
3. APOE Q39Ter

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