Overview

Pathogenicity: Vascular Dementia : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, BP4
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy, Vascular Dementia
Position: (GRCh38/hg38):Chr21:25897575 T>G
Position: (GRCh37/hg19):Chr21:27269887 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTG to GTG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 16

Findings

This variant has been found in two Greek families suffering from vascular dementia and Alzheimer’s disease. It was first identified by whole exome sequencing in a man diagnosed with hereditary cerebral amyloid angiopathy (CAA) with a clinical phenotype that mimicked another cerebrovascular disease, CADASIL (Psychogios et al., 2021). The patient developed depression and behavioral alterations at age 50, followed by memory deficits. By age 65, his cognition was severely impaired and he had motor deficits, including gait instability and brisk reflexes. Brain imaging revealed both CADASIL-like and CAA pathologies (see below). His APOE genotype was APOE3/APOE3.

The proband had a family history of disease. His father developed dementia in his mid-fifties and died of a stroke at 64. The proband’s brother, who also carried the mutation, developed a movement disorder and dementia, with symptoms starting at age 60. The proband’s daughter, a third mutation carrier, began experiencing migraines and depression in her early 20s. Two of the proband’s sisters were unaffected, but they were not genotyped so cosegregation with disease was not formally established.

This variant was also reported in a Greek woman diagnosed with mixed vascular and Alzheimer’s dementia (Kalampokini et al., 2021). She began experiencing epileptic seizures at age 58, and at 62 she developed depression and multiple cognitive deficits— difficulties with calculation, inability to concentrate, disorientation, and memory decline. The proband reported that her father and older brother (age 75) suffered from dementia. Genotyping revealed that her brother also carried the L688V mutation, but DNA was not available from her father. A younger sister, asymptomatic at 64 years, did not carry the mutation. Her daughter is a carrier, but has not developed symptoms at age 44.

This variant was absent from the gnomAD variant database (v2.1.1, Feb 2022).

Neuropathology
In the original proband, CT and MRI brain scans revealed leukoencephalopathy typical of CADASIL, with hyperintense lesions in the temporopolar area, external capsule, thalamus, centrum semiovale, and superior frontal regions, as well as cerebral microbleeds (Psychogios et al., 2021). They also revealed features of CAA, including occipital calcifications. His brother had similar pathology.

In the case of the woman with mixed vascular and Alzheimer’s dementia, at age 58 when her seizures first emerged, MRI showed severe white matter damage and global brain atrophy, most pronounced in the temporal lobe and hippocampus (Kalampokini et al., 2021).  Moreover, SPECT imaging showed hypoperfusion in the posterior temporal and parietal lobes, and EEG revealed epileptic activity in the temporal lobes. Notably, CSF biomarkers were normal at this stage. At 62, however, her CSF biomarkers showed an AD-like profile, with a decreased Aβ42/Aβ40 ratio and increased total-tau.

Biological Effect
A yeast cell-based assay to monitor Aβ aggregation suggested this substitution accelerates nucleation compared with wildtype Aβ (Seuma et al., 2022, suppl 3).

Also of note, the mutation is located on the C-terminal side of the γ-secretase cleavage site and a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment suggested L688 may interact with the NCT subunit of γ-secretase (Zhou et al., 2019). Moreover, this amino acid is conserved across evolution and several in silico algorithms (Homologene, GEPR, Varsom) predicted the L688V variant has a deleterious effect (Kalampokini et al., 2021). In addition, the variant is in the vicinity of several other variants tied to dementia. However, its PHRED-scaled CADD score (3.1), which integrates multiple lines of evidence, failed to reach 20, a threshold often used to predict deleteriousness (CADD, v.1.6, Feb 2022).

Pathogenicity

Vascular Dementia : Pathogenic*

*The cerebrovascular conditions associated with this variant appear to be inherited in an autosomal dominant manner, so its pathogenicity was classified using the ACMG-AMP guidelines.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

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References

Paper Citations

1. Psychogios K, Xiromerisiou G, Kargiotis O, Safouris A, Fiolaki A, Bonakis A, Paraskevas GP, Giannopoulos S, Tsivgoulis G. Hereditary cerebral amyloid angiopathy mimicking CADASIL syndrome. Eur J Neurol. 2021 Nov;28(11):3866-3869. PubMed.
2. Kalampokini S, Georgouli D, Patrikiou E, Provatas A, Valotassiou V, Georgoulias P, Spanaki C, Hadjigeorgiou GM, Xiromerisiou G. Τhe Greek Variant in APP Gene: The Phenotypic Spectrum of APP Mutations. Int J Mol Sci. 2021 Nov 16;22(22) PubMed.
3. Seuma M, Lehner B, Bolognesi B. An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation. Nat Commun. 2022 Nov 18;13(1):7084. PubMed.
4. Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

No Available Further Reading