Overview

Clinical Phenotype: Alzheimer's Disease, Blood Lipids/Lipoproteins
Position: (GRCh38/hg38):Chr19:44906639 G>A
Position: (GRCh37/hg19):Chr19:45409896 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs777551553
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Nonsense
Codon Change: TGG to TGA
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 2

Findings

This variant is predicted to eliminate APOE expression and may reduce Alzheimer’s disease risk when it is on the same chromosome as the major AD risk allele C130R (APOE4). In a search for loss-of-function variants of APOE, four cognitively healthy elderly heterozygotes were identified  (Chemparathy et al., 2024, Aug conference news 2023). 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.

Two of the W5Ter heterozygotes were men and had an APOE3/E4 genotype, with the W5Ter variant in phase with APOE4. One was cognitively healthy until his death at 90 years of age. Post-mortem analysis of his brain revealed no appreciable Aβ pathology, no cerebral amyloid angiopathy, and only moderate hyperphosphorylated tau pathology (Braak stage IV of VI). This pattern of no plaques with some tangles suggested primary age-related tauopathy (PART) (Nov 2014 news),  making him a neuropathological outlier among age matched APOE3/E4 individuals. The other carrier of W5Ter in phase with APOE4 was cognitively normal at age 79 and, at age 76, had normal cerebrospinal fluid levels of Aβ and tau in contrast to the approximately two thirds of APOE3/E4 carriers who have pathological Aβ levels by age 75, often accompanied by mild cognitive impairment or AD.

The two other W5Ter carriers identified in this study also suggested that a reduction of ApoE is well tolerated, although they were uninformative regarding the functional loss of APOE4 specifically. One carrier was a cognitively healthy 88-year-old woman homozygous for APOE3. The other was an APOE3/E4 heterozygous woman. She was cognitively healthy at age 70-79, but the phasing of W5Ter with respect to her APOE3 and APOE4 alleles was unknown.

Together with data from heterozygotic carriers of other APOE loss-of-function mutations—L8Ter, Q39Ter, and g.45408560_45410359del—these findings support APOE4 knockdown as a potentially safe and effective therapeutic option.

W5Ter appears to also have been found in in two Norwegian families, although it was mistakenly reported as a deletion of a threonine (T) at position 5 (Leren et al., 2016). Some carriers in these families had elevated cholesterol and triglycerides in blood, but the variant did not segregate with the condition. It was identified in two ostensibly unrelated individuals in a screen of the APOE gene of 844 unrelated hypercholesterolemic patients who did not carry mutations in genes commonly associated with familial hypercholesterolemia (LDLR, APOB, and PCSK9).

Segregation analyses of both families indicated the W5Ter variant was on the same chromosome as the APOE4 allele. Moreover, because the families were both from a small area in Southern Norway, the authors predicted W5Ter likely originated in a common ancestor. Five heterozygote carriers were identified in the family of one of the probands, but only the proband and one additional family member had hypercholesterolemia as well as elevated triglycerides. While both affected carriers had an APOE2/4 genotype, the unaffected carriers had an APOE4/4 genotype. In the other family, eight heterozygote carriers were identified, but only the proband had hypercholesterolemia and hypertriglyceridemia. Of note, in this case, both affected and unaffected carriers had an APOE3/4 genotype. Differences in serum ApoE levels, which were somewhat reduced in W5Ter carriers, did not correlate with the presence of hyperlipidemia.

In the APOE2/4 background, LDLR binding in W5Ter mutation carriers is expected to be very low because one APOE copy carries the mutation and the other carries the APOE2 variant known to drastically reduce LDLR binding. This deficit may explain the carriers’ lipid profile which is similar to that of patients with hyperlipoproteinemia type III (HLPP3), also known as familial dysbetalipoproteinemia, a condition very often associated with APOE2 homozygosity. Indeed, heterozygote carriers of other mutations also coding for truncated ApoE species, such as W38Ter, R154Afs, and E114Gfs, suffered from HLPP3, but only when carrying APOE2, not APOE3 or APOE4, on the other chromosome. However, as noted by the authors, this does not explain the similar, HLPP3-like phenotype of the individual carrying W5Ter on an APOE3/4 background. Other genetic and/or environmental factors may play a role in this case.

Also of note, patients with established ApoE deficiencies have been diagnosed with HLPP3, with similar alterations of their blood lipid and lipoprotein profiles (see e.g. (see A227_E230del, W228Ter, E98fs, and G49fs).

W5Ter was reported in two non-Finnish European heterozygotes in the gnomAD variant database (gnomAD v2.1.1 Apr 2022).

Biological Effect

This mutation is predicted to abrogate the full-length synthesis of ApoE as it introduces a stop codon in the 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). As noted above, the cognitive health of several aged, heterozygous carriers of this variant suggests a 50 percent loss 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 appears 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, suggesting a deleterious effect (CADD v.1.6, Oct 2021).

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References

News Citations

1. Scientists Propose a New Definition for Tau-Only Pathology 7 Nov 2014

Mutations Citations

1. APOE L8Ter
2. APOE Q39Ter
3. APOE g.45408560_45410359del
4. APOE C130R (ApoE4)
5. APOE [R176C];[C130R] (ApoE2/4)
6. APOE A227_E230del
7. APOE W228Ter
8. APOE E98fs
9. APOE G49fs

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. Leren TP, Strøm TB, Berge KE. Variable phenotypic expression of nonsense mutation p.Thr5* in the APOE gene. Mol Genet Metab Rep. 2016 Dec;9:67-70. Epub 2016 Oct 25 PubMed.
3. 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.
4. 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 conference news 2023

Further Reading

No Available Further Reading