Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Dementia with Lewy Bodies : Not Classified, Primary Progressive Aphasia : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192647 A>C
Position: (GRCh37/hg19):Chr14:73659355 A>C
dbSNP ID: rs63750311
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAA to GAC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was first discovered in a family of Japanese origin with early onset AD affecting four individuals across three generations (Yasuda et al., 1997). The mutation was found in the proband and his affected mother, but not in the proband’s three healthy sisters, 64 patients with early onset AD, 100 unrelated patients with probable AD, nor 100 healthy volunteers (Yasuda et al., 1997; Yokota et al., 2002). All affected members developed dementia, with symptoms emerging in their early 40s, and a mean duration of disease of nine years. Symptoms in the proband included memory loss, disorientation, mild extrapyramidal signs, and seizures in the advanced stages of disease. In three cases, the first symptom was memory impairment, and in one, personality change. Two members experienced myoclonus, while the other two developed parkinsonism.

The mutation was subsequently found in several other unrelated individuals suffering from AD. For example, in the U.K., it was reported in a family with five individuals affected by AD spanning three generations with a mean age at onset of 42 years (Janssen et al., 2003). Three U.K. families were subsequently reported with an average age at onset of 40 years (whether these three families included the previously reported family is unknown) (Ryan et al., 2016). One of three carriers tested had myoclonus, and one of three had spastic paraparesis. The variant was also found in a Brazilian family of Asian ancestry with autosomal dominant inheritance of AD and a mean age at onset of 48 years (Llibre-Guerra et al., 2021).  

Of note, the mutation has also been found in individuals diagnosed with dementia with Lewy bodies (DLB) and primary progressive aphasia (PPA). In the original Japanese pedigree, one case developed symptoms consistent with DLB, including hallucinations, delusions, and parkinsonism in the middle stages of disease (Yokota et al., 2002). Moreover, a 44-year-old Czech woman who carried the mutation and had a family history of early onset dementia, presented with the logopenic variant of PPA, including a severe difficulty finding words, but preserved language comprehension (Picková et al., 2017). This patient developed episodic memory impairment, progressing to dementia with behavioral changes including irritability and compulsiveness.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology

In five cases, neuropathology was consistent with AD (Yasuda et al., 1997; Yokota et al., 2002; Picková et al., 2017; Willumsen et al., 2021). However, unique features were also reported. In one case, there were heavy amyloid deposits in the walls of small meningeal arteries, as well as around small vessels within the brain parenchyma (Yasuda et al., 1997). Immunostaining showed that Aβ42 was predominant over Aβ40 in neuritic plaques of the temporal cortex, whereas Aβ40 was predominant in cerebral amyloid angiopathy lesions in the hippocampus (Yasuda 2000). In the patient who developed DLB symptoms, there was, additionally, robust α-synuclein pathology, including Lewy bodies and accumulation of the non-Aβ component of AD amyloid (NAC) in plaques and astrocytes (Yokota et al., 2002). Neuropathology involving α-synuclein was also observed in the amygdala of a female carrier with AD (Willumsen et al., 2021), and Lewy body pathology was found in the patient who developed PPA, meeting the diagnostic criteria for diffuse neocortical Lewy body disease (Picková et al., 2017).

In the original proband, MRI demonstrated mild atrophy of the left medial temporal lobe and moderate atrophy of the bilateral parietal lobes, whereas PET revealed mild temporoparietal and moderate parietal hypoperfusion bilaterally (Yasuda et al., 1997). In the patient diagnosed with PPA, MRI showed early left perisylvian and bitemporal atrophy (Picková et al., 2017).

Biological Effect

A study that examined the full set of Aβ peptides generated by this variant in transfected cells revealed a decrease in Aβ37 production and an increase in Aβ42, resulting in a decreased Aβ37/Aβ42 ratio and an increased Aβ42/Aβ40 ratio, both indicating reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Of note, the Aβ37/Aβ42 ratio outperformed the Aβ42/Aβ40 ratio as a biomarker for distinguishing between control and AD samples.

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate also revealed an elevated Aβ42/Aβ40 ratio, but both Aβ40 and Aβ42 production were decreased (Sun et al., 2017). This assay appears to be limited in its cleavage efficiency, however, given that 68 of 138 mutant recombinant PSEN1 enzymes tested produced less than 10 percent of the Aβ40 and Aβ42 produced by the wildtype protein (Liu et al., 2021).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Pathogenic*

*Carriers of this variant had heterogenous phenotypes.

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

News Citations

1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40? 20 Apr 2022

Paper Citations

1. Yasuda M, Maeda K, Ikejiri Y, Kawamata T, Kuroda S, Tanaka C. A novel missense mutation in the presenilin-1 gene in a familial Alzheimer's disease pedigree with abundant amyloid angiopathy. Neurosci Lett. 1997 Aug 22;232(1):29-32. PubMed.
2. Yokota O, Terada S, Ishizu H, Ujike H, Ishihara T, Nakashima H, Yasuda M, Kitamura Y, Uéda K, Checler F, Kuroda S. NACP/alpha-synuclein, NAC, and beta-amyloid pathology of familial Alzheimer's disease with the E184D presenilin-1 mutation: a clinicopathological study of two autopsy cases. Acta Neuropathol. 2002 Dec;104(6):637-48. PubMed.
3. Janssen JC, Beck JA, Campbell TA, Dickinson A, Fox NC, Harvey RJ, Houlden H, Rossor MN, Collinge J. Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
4. Ryan NS, Nicholas JM, Weston PS, Liang Y, Lashley T, Guerreiro R, Adamson G, Kenny J, Beck J, Chavez-Gutierrez L, de Strooper B, Revesz T, Holton J, Mead S, Rossor MN, Fox NC. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. Lancet Neurol. 2016 Dec;15(13):1326-1335. Epub 2016 Oct 21 PubMed.
5. Llibre-Guerra JJ, Li Y, Allegri RF, Mendez PC, Surace EI, Llibre-Rodriguez JJ, Sosa AL, Aláez-Verson C, Longoria EM, Tellez A, Carrillo-Sánchez K, Flores-Lagunes LL, Sánchez V, Takada LT, Nitrini R, Ferreira-Frota NA, Benevides-Lima J, Lopera F, Ramírez L, Jiménez-Velázquez I, Schenk C, Acosta D, Behrens MI, Doering M, Ziegemeier E, Morris JC, McDade E, Bateman RJ. Dominantly inherited Alzheimer's disease in Latin America: Genetic heterogeneity and clinical phenotypes. Alzheimers Dement. 2021 Apr;17(4):653-664. Epub 2020 Nov 23 PubMed.
6. Picková T, Matěj R, Bezdicek O, Keller J, van der Zee J, Van Broeckhoven C, Cséfalvay Z, Rusina R. Genetic Alzheimer Disease and Sporadic Dementia With Lewy Bodies: A Comorbidity Presenting as Primary Progressive Aphasia. Cogn Behav Neurol. 2017 Mar;30(1):23-29. PubMed.
7. Willumsen N, Poole T, Nicholas JM, Fox NC, Ryan NS, Lashley T. Variability in the type and layer distribution of cortical Aβ pathology in familial Alzheimer's disease. Brain Pathol. 2022 May;32(3):e13009. Epub 2021 Jul 28 PubMed.
8. Yasuda M, Maeda S, Kawamata T, Tamaoka A, Yamamoto Y, Kuroda S, Maeda K, Tanaka C. Novel presenilin-1 mutation with widespread cortical amyloid deposition but limited cerebral amyloid angiopathy. J Neurol Neurosurg Psychiatry. 2000 Feb;68(2):220-3. PubMed.
9. Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
10. Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
11. Liu L, Lauro BM, Wolfe MS, Selkoe DJ. Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 PubMed.
12. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

External Citations

1. gnomAD v2.1.1

Further Reading

Learn More

1. Japanese Familial Alzheimer's Disease Database