Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr19:44906647 T>A
Position: (GRCh37/hg19):Chr19:45409904 T>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs923895447
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Nonsense
Codon Change: TTG to TAG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 2

Findings

This variant, predicted to eliminate functional APOE expression, 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, a woman with an APOE3/E4 genotype, remained cognitively healthy at 71 years of age. Whether the loss of function affected her E3 or E4 allele is unknown, but the reduction in ApoE levels did not result in apparent neurological deficits.

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 a very early stop codon in the APOE coding region. 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, Q39Ter, 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 (33), suggesting a deleterious effect (CADD v.1.6, Aug, 2023).

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References

Mutations Citations

1. APOE W5Ter
2. APOE Q39Ter
3. APOE g.45408560_45410359del

Mutation Data Table Citations

1. APOE Loss of Function Variants 7 Mar 2024

Paper Citations

1. Chemparathy A, Le Guen Y, Chen S, Lee EG, Leong L, Gorzynski JE, Jensen TD, Ferrasse A, Xu G, Xiang H, Belloy ME, Kasireddy N, Peña-Tauber A, Williams K, Stewart I, Talozzi L, Wingo TS, Lah JJ, Jayadev S, Hales CM, Peskind E, Child DD, Roeber S, Keene CD, Cong L, Ashley EA, Yu CE, Greicius MD. APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's disease pathology. Neuron. 2024 Apr 3;112(7):1110-1116.e5. Epub 2024 Jan 31 PubMed.
2. 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.
3. 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. Aug 2023 conference news

Further Reading

No Available Further Reading