Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25897605 G>C
Position: (GRCh37/hg19):Chr21:27269917 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAC to CAC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 16

Findings

This mutation was first detected in a Taiwanese woman with early onset Alzheimer’s disease. She began to experience progressive memory impairment at the age of 51. Her symptoms also included slurred speech, restlessness, and persecutory delusions. She met NINCDS-ADRDA criteria for probable AD. Her mother and aunt had been affected by cognitive impairment; however, a specific diagnosis was not available. Segregation with disease could not be assessed due to lack of DNA from family members (Chen et al., 2012). Subsequent studies reported the variant in two large Taiwanese families with AD (Weng et al., 2018) and in at least two additional Taiwanese individuals with dementia (Lan et al., 2014, Hsu et al., 2021).

This variant was absent from the gnomAD database (V2.1.1, Oct 2021).

Neuropathology

Neuropathological data are unavailable, but several florbetapir-PET imaging studies have revealed heavy amyloid loads in carriers compared with those of individuals with sporadic AD. For example, a study of ten carriers showed high amyloid levels in cerebellar, and particularly occipital, cortical areas (Huang et al., 2019a). In addition, longitudinal PET imaging of seven carriers showed high levels of amyloid accumulation, particularly in carriers at early stages of disease suffering from mild cognitive impairment (MCI) (Weng et al., 2018). Also, in this study, the annual rate of change of the PET signal was greater in mutation carriers than in individuals with sporadic disease, with the rate being positive at the MCI stage, but negative at the AD stage. The authors speculated that brain atrophy or clearance might explain the negative rate of change.

PET imaging has also been used to assess tau deposition (Huang et al., 2019b). In five carriers with MCI, tau levels were increased compared with those of healthy controls, particularly in cerebellar cortex. In addition, tau was found in the temporal lobe. This localized accumulation was in contrast to the diffuse deposition of amyloid.

Also of note, in one carrier, MRI revealed leukoencephalopathy, cortical microhemorrhages, and focal superficial cortical hemosiderosis, consistent with cerebral amyloid angiopathy (Lan et al., 2014). In another, SPECT imaging showed hypoperfusion in the bilateral parietal cortices and the left temporal lobe (Chen et al., 2012). 

Biological Effect

This mutation alters an amino acid within the Aβ region of APP, specifically the aspartate at the seventh position, which is altered to a histidine (D7H). When expressed in HEK-293 cells, the D678H mutation favors the amyloidogenic pathway and increases production of Aβ40 and Aβ42. Aβ42 is preferentially increased, resulting in an elevated Aβ42/Aβ40 ratio in the conditioned media. In addition, when coincubated with Cu²⁺ and Zn²⁺, the mutant Aβ exhibits increased metal ion binding due to the metal-coordinating properties of histidine. The mutant Aβ is also more susceptible to the formation of ion-induced Aβ oligomers and exhibits greater toxicity in vitro compared with wild-type Aβ42 (Chen et al., 2012). Computer modeling suggests stable Zn²⁺-induced heterotrimers form between mutant and wildtype Aβ peptides, with zinc facilitating trimer-trimer interactions (Kechko et al., 2023). Moreover, a survey of the effects of a wide range of APP mutations in a yeast model system, found this variant accelerated Aβ aggregate nucleation, despite D7 being in a region that is usually unstructured in most mature Aβ fibrils (Seuma et al., 2022).

In neurons derived from induced pluripotent stem cells (IPSCs) from two carriers, Aβ accumulated intracellularly and tau was hyperphosphorylated (T181 and S396). Modest decreases in neurite outgrowth, synaptophysin expression, and GSK3β phosphorylation were also observed, while caspase 1 activity was increased (Chang et al., 2019). 

This variant's PHRED-scaled CADD score was above 20, suggesting a damaging effect (CADD v1.6, 2021).

Chen and colleagues classified the variant as “probably pathogenic” according to the algorithm proposed by Guerreriro et al., 2010 (Chen et al., 2012).

Pathogenicity

Alzheimer's Disease : Pathogenic

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

Research Models

Induced pluripotent stem cell (iPSC) lines from two heterozygous carriers have been created and used to generate neurons (Chang et al., 2019). As described in Biological Effects, several AD-related defects have been reported.

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References

Paper Citations

1. Chang KH, Lee-Chen GJ, Huang CC, Lin JL, Chen YJ, Wei PC, Lo YS, Yao CF, Kuo MW, Chen CM. Modeling Alzheimer's Disease by Induced Pluripotent Stem Cells Carrying APP D678H Mutation. Mol Neurobiol. 2019 Jun;56(6):3972-3983. Epub 2018 Sep 20 PubMed.
2. Chen WT, Hong CJ, Lin YT, Chang WH, Huang HT, Liao JY, Chang YJ, Hsieh YF, Cheng CY, Liu HC, Chen YR, Cheng IH. Amyloid-beta (Aβ) D7H mutation increases oligomeric Aβ42 and alters properties of Aβ-zinc/copper assemblies. PLoS One. 2012;7(4):e35807. PubMed.
3. Weng YC, Hsiao IT, Huang CY, Huang KL, Liu CH, Chang TY, Yen TC, Lin KJ, Huang CC. Progress of Brain Amyloid Deposition in Familial Alzheimer's Disease with Taiwan D678H APP Mutation. J Alzheimers Dis. 2018;66(2):775-787. PubMed.
4. Lan MY, Liu JS, Wu YS, Peng CH, Chang YY. A novel APP mutation (D678H) in a Taiwanese patient exhibiting dementia and cerebral microvasculopathy. J Clin Neurosci. 2014 Mar;21(3):513-5. Epub 2013 Aug 6 PubMed.
5. Hsu JL, Lin CH, Chen PL, Lin KJ, Chen TF. Genetic study of young-onset dementia using targeted gene panel sequencing in Taiwan. Am J Med Genet B Neuropsychiatr Genet. 2021 Mar;186(2):67-76. Epub 2021 Feb 13 PubMed.
6. Huang CY, Hsiao IT, Lin KJ, Huang KL, Fung HC, Liu CH, Chang TY, Weng YC, Hsu WC, Yen TC, Huang CC. Amyloid PET pattern with dementia and amyloid angiopathy in Taiwan familial AD with D678H APP mutation. J Neurol Sci. 2019 Mar 15;398:107-116. Epub 2019 Jan 3 PubMed.
7. Huang CC, Hsiao IT, Huang CY, Weng YC, Huang KL, Liu CH, Chang TY, Wu HC, Yen TC, Lin KJ. Tau PET With 18F-THK-5351 Taiwan Patients With Familial Alzheimer's Disease With the APP p.D678H Mutation. Front Neurol. 2019;10:503. Epub 2019 May 22 PubMed.
8. Kechko OI, Adzhubei AA, Tolstova AP, Indeykina MI, Popov IA, Zhokhov SS, Gnuchev NV, Mitkevich VA, Makarov AA, Kozin SA. Molecular Mechanism of Zinc-Dependent Oligomerization of Alzheimer's Amyloid-β with Taiwan (D7H) Mutation. Int J Mol Sci. 2023 Jul 8;24(14) PubMed.
9. 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.
10. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

Further Reading

No Available Further Reading