Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PP2, PP3
DIAN-TU Eligibility: Yes
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73171022 T>C
Position: (GRCh37/hg19):Chr14:73637730 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTT to CTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This variant was reported in a Chinese family with four affected members, spanning four generations (Jia et al., 2020). The proband was diagnosed with AD, with symptoms emerging at 63 years, and the mean age at onset in the family was 64 years. Two affected members, including the proband, were found to carry the mutation. The proband's APOE genotype was E3/E3.

The same amino acid substitution F105L (T>G) was identified in a German carrier (Finckh et al., 2000). It was also reported (underlying nucleotide change unspecified) in four members of a family suffering from early onset AD, a father and three children (Maarouf et al., 2008; Yang et al., 2022). Two daughters began experiencing symptoms at ages 60 and 56, and died after 8 and 11 years, respectively. The former had an APOE2/3 genotype.

This variant was absent from the gnomAD variant database (gnomAD v4.1.0, Mar 2025).

Neuropathology
Severe AD neuropathology, characterized by diffuse Aβ plaques and angiopathy, was found in brain tissues from the two sisters with an unspecified nucleotide change (Maarouf et al., 2008; Yang et al., 2022). Quantification of Aβ levels in the cerebral cortex of one sister revealed an Aβ42/Aβ40 ratio close to 1 (Maarouf et al., 2008). Moreover, cryo-electron microscopy images of Aβ42 fibrils in brain tissue from the other sister revealed a core of paired S-shaped protofilaments (Yang et al., 2022; Jan 2022 news). These filaments were arranged in a pattern distinct from that seen in sporadic AD, but similar to the pattern observed in the brain of another individual with familial AD (carrying the APP V717F Indiana mutation). Type II filaments were also found in related disorders and in APP knock-in mice.

Biological Effect
The F105L substitution appears to reduce γ-processivity (Liu et al., 2021). Analysis of secreted Aβs in the conditioned media of human embryonic kidney cells lacking endogenous PSENs and expressing this mutant (nucleotide change unspecified) along with wildtype APP, revealed increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios. Interestingly, the authors also reported that Aβ42/40, Aβ38/42, and particularly Aβ37/42, ratios each correlated with reported ages of onset of clinical impairment across 16 PSEN1 mutations. This mutant also reduced total secreted Aβ levels.

Jia and colleagues reported that four of the five in silico algorithms they applied predicted a damaging effect, and the PHREDD CADD tool, which integrates diverse information, gave it a high deleteriousness score of 27 (Jia et al., 2020).

Pathogenicity

Alzheimer's Disease : Likely Pathogenic*

*Carriers of F105L variants 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 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

Mutations Citations

1. PSEN1 F105L (T>G)
2. APP V717F (Indiana)

News Citations

1. Cryo-EM Unveils Distinct Aβ42 Fibril Structures for Sporadic, Familial AD 14 Jan 2022

Paper Citations

1. Jia L, Fu Y, Shen L, Zhang H, Zhu M, Qiu Q, Wang Q, Yan X, Kong C, Hao J, Wei C, Tang Y, Qin W, Li Y, Wang F, Guo D, Zhou A, Zuo X, Yu Y, Li D, Zhao L, Jin H, Jia J. PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.
2. Finckh U, Müller-Thomsen T, Mann U, Eggers C, Marksteiner J, Meins W, Binetti G, Alberici A, Hock C, Nitsch RM, Gal A. High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet. 2000 Jan;66(1):110-7. PubMed.
3. Maarouf CL, Daugs ID, Spina S, Vidal R, Kokjohn TA, Patton RL, Kalback WM, Luehrs DC, Walker DG, Castaño EM, Beach TG, Ghetti B, Roher AE. Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations. Mol Neurodegener. 2008 Nov 20;3:20. PubMed.
4. Yang Y, Arseni D, Zhang W, Huang M, Lövestam S, Schweighauser M, Kotecha A, Murzin AG, Peak-Chew SY, Macdonald J, Lavenir I, Garringer HJ, Gelpi E, Newell KL, Kovacs GG, Vidal R, Ghetti B, Ryskeldi-Falcon B, Scheres SH, Goedert M. Cryo-EM structures of amyloid-β 42 filaments from human brains. Science. 2022 Jan 14;375(6577):167-172. Epub 2022 Jan 13 PubMed.
5. 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.

Further Reading

No Available Further Reading