Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Myoclonus
Reference Assembly: GRCh37/hg19
Position: Chr14:73640363 T>C
dbSNP ID: rs63750004
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATT to ACT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This variant has been found in several families worldwide, and in at least two, segregation with Alzheimer's disease was demonstrated. Although most carriers present with typical AD symptoms, clinical phenotypes are heterogenous with some carriers also developing movement disorders, as well as paranoia, hallucinations, and aggressiveness.

PSEN1 I143T was first identified by linkage analysis in a large Belgian family affected by early onset Alzheimer’s disease (Cruts et al., 1995). The family, known as AD/A, included at least 31 affected individuals over six generations, many of whom had neuropathologically confirmed AD. The mean age at onset in this family was 35 years.

This variant was also found in three other individuals with early onset AD. Of these mutation carriers, two were sisters who also carried a second PSEN1 mutation in trans. They both inherited the I143T mutation from their father and the PSEN1 I439V mutation from their mother, who was asymptomatic at age 55. The sisters both developed symptoms before age 35 (Rogaeva et al., 2001). The mutation was also reported in a Colombian family of Western European ancestry with very early onset, autosomal dominant AD (Arango et al., 2001).

Several French carriers have also been reported. A family, known as ROU 001, included at least three individuals affected by early onset AD. Symptom onset occurred at age 34 or 35. Note, the mutation was erroneously reported as I143W (Raux et al., 2005). A subsequent report described two additional French carriers from different families, whose AD onset also occurred in their mid-30s (Lanoiselée et al., 2017). One of these carriers had paraperesis, in addition to typical AD symptoms (Lacour et al., 2019).

Two Japanese sisters with early onset AD also carried the mutation (Arai et al., 2008). One became unable to communicate at age 33, followed by gradual memory decline. Five years later, she also had apraxia, agnosia, alexia, acalculia, and developed limb rigidity, dystonia, and myoclonus. Her APOE genotype was E3/E4. Her sister presented with memory impairment and time disorientation at age 41. She was homozygous for the APOE3 allele.

In a Swedish family, with three mutation carriers, five family members across three generations were affected with early onset dementia (Keller et al., 2010). The mean age of onset was 36 and mean age of death 42. Initial symptoms were typical of AD, including memory impairment, visuospatial difficulties, disorientation, dyspraxia, and dysphasia. In addition, patients presented with gradually worsening myoclonic jerks, multiple falls, and, in some cases, epileptic seizures. In the later stages of disease, paranoid delusions, hallucinations, and aggressiveness developed and, in the first generation, Pick's disease was suspected based on observed personality changes. The tree affected mutation carriers were APOE3 homozygotes. A 24-year-old study of this family includes prospective assessments of cognitive function, tissue sampling, and brain imaging of presymptomatic, at-risk individuals (Thordardottir and Graff, 2018).

The mutation was also found in two Chinese individuals. The first was a woman with memory impairment starting at age 30 (Xu et al., 2018). She developed emotional instability, tremor of an arm, and visual hallucinations. Her father and grandmother experienced similar symptoms at similar ages. The second was a man suffering from progressive memory loss, disorientation, executive dysfunction, apathy, social disinhibition (Liang et al., 2023). Of note, seizures emerged only two months after symptom onset at age 32, followed by apraxia and rigidity, symptoms that are rarely seen in the early stages of disease. The proband's genotype was APOE3/E4. The carrier had a family history of disease, including his maternal grandmother, mother, a maternal uncle, and a sister. Ages at onset in this family ranged from 32 to 48. 

This mutation was absent from several public variant databases, including gnomAD, ESP6500, and ExAC (Liang et al., 2023).

Neuropathology

Autopsies were performed on at least 11 affected family members from the AD/A family. Neuropathology consistent with the diagnosis of AD was observed, including amyloid plaques and neurofibrillary tangles in the cortex. A few cerebellar plaques were also noted (Martin et al., 1991). Post-mortem examination of a carrier in the U.S. also showed neuropathology consistent with AD (Course et al., 2023).

Severe AD pathology was also reported in the three Swedish mutations carriers (Keller et al., 2010). The frontal lobes were particularly affected by the thinning of gyri and the reduced cortical thickness, with a large number of plaques observed, often lacking a distinct core. Tau pathology, including numerous ghost tangles, was widespread and severe in the hippocampal areas, entorhinal cortex, and amygdala. Superficial spongiform changes and gliosis were present. Some neurons in the granular cell layer of the dentate gyrus had phosphorylated tau. The cerebellum was clearly affected by amyloid in two cases. In these same cases, Aβ42 and Aβ43 were found in both plaque cores and total amyloid preparations, and were each more frequent than Aβ40.

One carrier was reported to have Lewy body pathology limited to the amygdala, as assessed by α-synuclein staining (Leverenz et al., 2020). 

Cerebrospinal fluid biomarkers including Aβ42, tau, and phospho-tau were consistent with AD in at least one case (Lanoiselée et al., 2017). This individual had diffuse cortical atrophy as assessed by MRI, and bilateral temporo-pariteal hypometabolism as assessed by PET/SPECT imaging (Lacour et al., 2019).

Biological Effect

Multiple in vitro assays have shown that the I143T substitution results in an elevated Aβ42/Aβ40 ratio (Murayama et al., 1999, Li et al., 2016, Sun et al., 2017, Kakuda et al., 2021). Studies that surveyed Aβ production in greater detail revealed reduced Aβ46→Aβ43 trimming (Devkota et al., 2024), and decreases in the Aβ (37 + 38 + 40) / (42 + 43) ratio and the Aβ37/Aβ42 ratio, both of which reflect γ-processivity, compared with cells expressing wildtype PSEN1 (Apr 2022 news; Petit et al., 2022; Liu et al., 2022). The two ratios were reported to outperform the Aβ42/Aβ40 ratio as indicators of AD pathogenicity, with the former correlating with AD age at onset. Moreover, a follow-up study reported in a preprint, combined the Aβ (37 + 38 + 40) / (42 + 43) ratio with the commonly used Aβ42/Aβ40 ratio (a measure of the relative production of aggregation-prone Aβ) to yield a composite measure which reflects γ-secretase function as a percentage of wildtype activity (Schulz et al., 2023). This composite score (22.58 for I143T) was strongly associated, not only with age at onset, but with biomarker and cognitive trajectories. 

In addition to disrupting the processive carboxypeptidase-like activity of γ-secretase, this variant may alter ε-cleavage activity. Although one study reported no effect (Li et al., 2016), two subsequent studies found ε-cleavage to be substantially reduced (Do et al., 2023; Devkota et al., 2024). Molecular dynamics simulations suggested I143T prevents APP residue L49 from orienting properly in the γ-secretase active site and disrupts the distance between PSEN1 catalytic aspartates (Do et al., 2023). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that, in wild-type PSEN1, this residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).

It is possible that I143T, as well as other familial AD mutations, stall the γ-secretase-substrate complex and the presence of this membrane-anchored complex per se is toxic (Devkota et al., 2024; Nov 2023 news).

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, Liang et al., 2023).

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.

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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
2. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019
3. Patricidal Protein? Aβ42 said to Inhibit Its Parent, γ-Secretase 17 Nov 2023

Paper Citations

1. Cruts M, Backhovens H, Wang SY, Van Gassen G, Theuns J, De Jonghe CD, Wehnert A, De Voecht J, De Winter G, Cras P. Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Hum Mol Genet. 1995 Dec;4(12):2363-71. PubMed.
2. Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P. Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
3. Arango D, Cruts M, Torres O, Backhovens H, Serrano ML, Villareal E, Montañes P, Matallana D, Cano C, Van Broeckhoven C, Jacquier M. Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia. Am J Med Genet. 2001 Oct 1;103(2):138-43. PubMed.
4. Raux G, Guyant-Maréchal L, Martin C, Bou J, Penet C, Brice A, Hannequin D, Frebourg T, Campion D. Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.
5. Lanoiselée HM, Nicolas G, Wallon D, Rovelet-Lecrux A, Lacour M, Rousseau S, Richard AC, Pasquier F, Rollin-Sillaire A, Martinaud O, Quillard-Muraine M, de la Sayette V, Boutoleau-Bretonniere C, Etcharry-Bouyx F, Chauviré V, Sarazin M, le Ber I, Epelbaum S, Jonveaux T, Rouaud O, Ceccaldi M, Félician O, Godefroy O, Formaglio M, Croisile B, Auriacombe S, Chamard L, Vincent JL, Sauvée M, Marelli-Tosi C, Gabelle A, Ozsancak C, Pariente J, Paquet C, Hannequin D, Campion D, collaborators of the CNR-MAJ project. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.
6. Lacour M, Quenez O, Rovelet-Lecrux A, Salomon B, Rousseau S, Richard AC, Quillard-Muraine M, Pasquier F, Rollin-Sillaire A, Martinaud O, Zarea A, de la Sayette V, Boutoleau-Bretonniere C, Etcharry-Bouyx F, Chauviré V, Sarazin M, le Ber I, Epelbaum S, Jonveaux T, Rouaud O, Ceccaldi M, Godefroy O, Formaglio M, Croisile B, Auriacombe S, Magnin E, Sauvée M, Marelli C, Gabelle A, Pariente J, Paquet C, Boland A, Deleuze JF, Campion D, Hannequin D, Nicolas G, Wallon D, collaborators of the CNR-MAJ. Causative Mutations and Genetic Risk Factors in Sporadic Early Onset Alzheimer's Disease Before 51 Years. J Alzheimers Dis. 2019;71(1):227-243. PubMed.
7. Arai N, Kishino A, Takahashi Y, Morita D, Nakamura K, Yokoyama T, Watanabe T, Ida M, Goto J, Tsuji S. Familial cases presenting very early onset autosomal dominant Alzheimer's disease with I143T in presenilin-1 gene: implication for genotype-phenotype correlation. Neurogenetics. 2008 Feb;9(1):65-7. Epub 2007 Oct 30 PubMed.
8. Keller L, Welander H, Chiang HH, Tjernberg LO, Nennesmo I, Wallin AK, Graff C. The PSEN1 I143T mutation in a Swedish family with Alzheimer's disease: clinical report and quantification of Aβ in different brain regions. Eur J Hum Genet. 2010 Nov;18(11):1202-8. PubMed.
9. Thordardottir S, Graff C. Findings from the Swedish Study on Familial Alzheimer's Disease Including the APP Swedish Double Mutation. J Alzheimers Dis. 2018;64(s1):S491-S496. PubMed.
10. Xu Y, Liu X, Shen J, Tian W, Fang R, Li B, Ma J, Cao L, Chen S, Li G, Tang H. The Whole Exome Sequencing Clarifies the Genotype- Phenotype Correlations in Patients with Early-Onset Dementia. Aging Dis. 2018 Aug;9(4):696-705. PubMed.
11. Liang Z, Wu Y, Li C, Liu Z. Clinical and genetic characteristics in a central-southern Chinese cohort of early-onset Alzheimer's disease. Front Neurol. 2023;14:1119326. Epub 2023 Mar 27 PubMed.
12. Martin JJ, Gheuens J, Bruyland M, Cras P, Vandenberghe A, Masters CL, Beyreuther K, Dom R, Ceuterick C, Lübke U. Early-onset Alzheimer's disease in 2 large Belgian families. Neurology. 1991 Jan;41(1):62-8. PubMed.
13. Course MM, Gudsnuk K, Keene CD, Bird TD, Jayadev S, Valdmanis PN. Aberrant splicing of PSEN2, but not PSEN1, in individuals with sporadic Alzheimer's disease. Brain. 2023 Feb 13;146(2):507-518. PubMed.
14. Leverenz JB, Fishel MA, Peskind ER, Montine TJ, Nochlin D, Steinbart E, Raskind MA, Schellenberg GD, Bird TD, Tsuang D. Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype. Arch Neurol. 2006 Mar;63(3):370-6. PubMed.
15. Murayama O, Tomita T, Nihonmatsu N, Murayama M, Sun X, Honda T, Iwatsubo T, Takashima A. Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999 Apr 9;265(1):61-3. PubMed.
16. Li N, Liu K, Qiu Y, Ren Z, Dai R, Deng Y, Qing H. Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
17. 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.
18. Kakuda N, Takami M, Okochi M, Kasuga K, Ihara Y, Ikeuchi T. Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. Transl Psychiatry. 2021 Nov 3;11(1):558. PubMed.
19. Devkota S, Zhou R, Nagarajan V, Maesako M, Do H, Noorani A, Overmeyer C, Bhattarai S, Douglas JT, Saraf A, Miao Y, Ackley BD, Shi Y, Wolfe MS. Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes. Cell Rep. 2024 Feb 27;43(2):113761. Epub 2024 Feb 13 PubMed.
20. Petit D, Fernández SG, Zoltowska KM, Enzlein T, Ryan NS, O'Connor A, Szaruga M, Hill E, Vandenberghe R, Fox NC, Chávez-Gutiérrez L. Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset. Mol Psychiatry. 2022 Jun;27(6):2821-2832. Epub 2022 Apr 1 PubMed.
21. 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.
22. Schultz S, Liu L, Schultz A, Fitzpatrick C, Levin R, Bellier J-P, Shirzadi Z, Mathurin N, Chen C, Benzinger T, Day G, Farlow M, Gordon B, Hassenstab J, Jack C, Jucker M, Karch C, Lee J, Levin J, Perrin R, Schofield P, Xiong C, Johnson K, McDade E, Bateman R, Sperling R, Selkoe D, Chhatwal J, theDominantlyInheritedAlzheimer'sNetworkInvestigators. Functional variations in gamma-secretase activity are critical determinants of the clinical, biomarker, and cognitive progression of autosomal dominant Alzheimer's disease. 2023 Jul 25 10.1101/2023.07.04.547688 (version 2) bioRxiv.
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25. 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.

Other Citations

1. PSEN1 I439V

Further Reading