Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3
DIAN-TU Eligibility: Yes
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198042 G>A
Position: (GRCh37/hg19):Chr14:73664750 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTT to ATT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was found in an individual diagnosed with familial AD (Miravalle et al., 2005). Symptoms emerged at age 48 and death occurred at 55. The patient was homozygous for the APOE3 allele and had no mutations in exons 16 and 17 of the APP gene. Although the disease was described as familial, no information was reported for family members. In a subsequent paper, the mean age at onset in a group of affected carriers from the U.S. was noted as 41.8 (std error 6.3; Liu et al., 2025). It is uncertain if some or all of these carriers were related to the proband in the original report. 

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

Neuropathology
Neuropathology was consistent with AD, including neuritic plaques, diffuse amyloid deposits, and cotton wool plaques. The latter were the most abundant amyloid species, with widespread distribution in the neocortex, caudate nucleus, putamen, thalamus, amygdala, hippocampus, parahippocampus, and midbrain. The predominant Aβ species in cotton wool plaques were amino-terminally truncated Aβ42 and Aβ43 peptides, with no detectable Aβ40. A similar Aβ composition was observed in the diffuse amyloid deposits of the cerebellum. In contrast, in the amyloid deposits associated with parenchymal and leptomeningeal vessels, Aβ40 was the predominant species.

Biological Effect
The biological effect of this variant is unknown, but 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). 

This variant has been classified as likely pathogenic (Xiao et al., 2021; Liu et al., 2025).

Pathogenicity

Alzheimer's Disease : Not Classified*

*Carriers of this variant are eligible for inclusion in clinical trials organized by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) to test disease-modifying treatments for Alzheimer’s disease (Liu et al., 2025). This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum because data for either a pathogenic or benign classification are lacking: it is unclear if affected carriers are from the same family, and co-segregation and functional data are unavailable. 

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

Comments

1. • Andre Delacourte
     Inserm
   • Posted: 16 Aug 2005
   • Paper: Amino-terminally truncated Abeta peptide species are the main component of cotton wool plaques.

   This interesting paper corroborates the new concept that N-terminal truncated Aβ42 species are the seeds of amyloidosis, and a nice target for the vaccination approach.

   References:

   Sergeant N, Bombois S, Ghestem A, Drobecq H, Kostanjevecki V, Missiaen C, Wattez A, David JP, Vanmechelen E, Sergheraert C, Delacourte A. Truncated beta-amyloid peptide species in pre-clinical Alzheimer's disease as new targets for the vaccination approach. J Neurochem. 2003 Jun;85(6):1581-91. PubMed. …More

   View all comments by Andre Delacourte

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References

Paper Citations

1. Miravalle L, Calero M, Takao M, Roher AE, Ghetti B, Vidal R. Amino-terminally truncated Abeta peptide species are the main component of cotton wool plaques. Biochemistry. 2005 Aug 16;44(32):10810-21. PubMed.
2. Liu H, Marsh TW, Shi X, Renton AE, Bowling KM, Ziegemeier E, Wang G, Cao Y, Aristel A, Li J, Dickson A, Perrin RJ, Goate AM, Fernández V, Day GS, Doering M, Daniels A, Gordon BA, Benzinger TL, Hassenstab J, Ibanez L, Supnet-Bell C, Xiong C, Allegri R, Berman SB, Fox NC, Ryan N, Huey ED, Vöglein J, Noble JM, Roh JH, Jucker M, Laske C, Ikeuchi T, Sanchez-Valle R, Schofield PR, Chrem Mendez P, Chhatwal JP, Farlow M, Lee JH, Levey AI, Levin J, Lopera F, Martins R, Niimi Y, Rosa-Neto P, Morris JC, Bateman RJ, Karch CM, Cruchaga C, McDade E, Llibre-Guerra JJ. The landscape of autosomal-dominant Alzheimer's disease: global distribution and age of onset. Brain. 2025 Feb 4; Epub 2025 Feb 4 PubMed.
3. 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

No Available Further Reading