Mutations

PSEN1 E280A (Paisa)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73664808 A>C
dbSNP ID: rs63750231
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GAA to GCA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

First documented about 20 years ago, the E280A mutation is by far the most common cause of familial early onset Alzheimer’s disease, affecting hundreds of people. The majority of E280A carriers belong to a large kindred from the Colombian state of Antioquia. In fact, the mutation is often called the Paisa mutation in reference to the people of this region. The Colombian kindred is remarkable not only for its unusual size, but also for a high level of participation in both longitudinal studies characterizing biomarker progression and pioneering prevention trials (see May 2012 news; crenezumabTariot et al., 2018).

Currently, there are about 5,000 living members of the Colombian kindred spread among 25 families who live in a historically isolated region in the Andes Mountains. The pedigree spans five to seven generations, originating with a couple from the Basque region of Spain who settled in Colombia in the early 1700s (Lalli et al., 2014). Nearly half the living members of the kindred live in Medellín, the second-largest city in Colombia, with the majority of the others scattered in outlying villages. Of the 5,000 living members, it is estimated that nearly 1,000 carry the mutation, with about 400 confirmed carriers.

In this kindred, mutation carriers typically develop memory deficits in the third decade of life, followed by progressive impairments in other cognitive domains, such as verbal fluency. Mild cognitive impairment sets in around age 45 and dementia by age 50. Although the vast majority of carriers develop dementia between age 45 and 50, a 30-year window has been documented, with rare cases experiencing onset as early as age 30 or as late as age 65. The mutation is, however, fully penetrant. The median duration from onset of dementia to death is approximately 10 years, ranging from nine to 12 years, with 59 being the median age at death (Acosta-Baena et al., 2011). There is no evidence of anticipation in subsequent generations. Homozygosity has been reported in this kindred. The age of onset for these individuals appears to be moderately accelerated relative to heterozygotes, although the sample is too small to reach statistical conclusions (Kosik et al., 2015).

APOE genotype has long been suspected of modifying age of onset in Paisa mutation carriers; however, results in small cohorts were conflicting (Lendon et al., 1997; Pastor et al., 2003). More recently, among 93 AD patients carrying the Paisa mutation, those with the APOE2 allele were found to develop AD at a later age than those without it. There was also a trend for those with an APOE4 allele to develop AD at an earlier age, although this effect was not significant (Vélez et al., 2015). Additional loci that modify age of onset have been reported (Vélez et al., 2013; Vélez et al., 2016a; Vélez et al., 2016b).

The majority of E280A carriers present with symptoms fairly typical of AD, including progressive memory loss and changes in personality and behavior; however, there is phenotypic variability. For example, some patients also present with epilepsy, verbal impairment, and cerebellar ataxia. Specifically, mutation carriers present with memory impairment (100 percent), behavioral changes (94 percent), language impairment (e.g., aphasia, 81 percent), headache (73 percent), gait difficulties (65 percent), seizures and myoclonus (45 percent), and cerebellar signs and Parkinsonism (each 19 percent) (reviewed in Sepulveda-Falla et al., 2012). Cognitive decline has been detected 12 years before clinical onset of disease. Analysis of total CERAD scores, as well as individual scores for memory, language, and praxis, identified word-list recall as a particularly early indicator of decline (Aguirre-Acevedo et al., 2016). Severe headaches also appear to be a frequent early symptom, typically occurring several years before dementia onset (Lopera et al., 1997).

Researchers are looking for early pathological changes in presymptomatic E280A carriers using several approaches, including neuroimaging, and blood and CSF analysis (see Mar 2011 news; Jul 2015 news). An early difference between carriers and non-carriers is hyperactivation within medial temporal lobe regions during the encoding of novel associations, suggesting that carriers push their memory-forming circuitry harder to achieve equivalent performance (Quiroz et al., 2010; Quiroz et al., 2015). Presymptomatic reduction of hippocampal volume has also been reported (Fleisher et al., 2015). In addition, functional alterations in the precuneus have been detected at presymptomatic stages of disease as revealed by FDG-PET imaging and quantitative electroencephalography (Fleisher et al., 2015; Ochoa et al., 2017).

Studies of Aβ and tau pathology using PET have also revealed early presymptomatic changes. For example, Aβ, as assessed by PiB-PET, was diffusely elevated in unimpaired carriers approximately 15 years prior to expected onset of mild cognitive impairment (Feb 2018 news; Quiroz et al., 2018). Age-related elevation of Aβ in the striatum, which had a larger Aβ burden than the neocortex, was associated with lower memory scores and entorhinal tau pathology, as assessed by FTP-PET (Hanseeuw et al., 2019).

Presymptomatic changes in CSF and plasma biomarkers have also been reported. A reduction in Aβ42 and increases in total tau and phosphorylated tau were observed in the CSF of unimpaired mutation carriers (Fleisher et al., 2015; Jan 2015 news). All three changes were age-associated. Plasma Aβ42 levels were also found elevated, but not correlated with age.

In the Colombian kindred, biomarker differences have been observed in teenagers and in children as young as nine years old. Specifically, young mutation carriers had elevated plasma levels of Aβ1-42 and higher Aβ42:Aβ40 ratios, as well as changes in resting-state connectivity, and regional gray matter volumes. It is not known if these differences are primarily neurodegenerative or neurodevelopmental (Quiroz et al., 2015; Jul 2015).

Related carriers have been identified in other Colombian regions (Arango et al., 2001) and in other countries (Kwok et al., 1997). In addition, the same E280A mutation was identified in a Japanese family (FAD-Ok) with two affected family members and a mean age of onset of 57 years (Tanahashi et al., 1996).

Neuropathology

Those affected by the E280A mutation show neuropathology consistent with a diagnosis of AD, including severe brain atrophy, Aβ pathology, and hyperphosphorylated tau-related pathology. Aβ42 may be particularly abundant in the cerebral cortex, hippocampus, cerebellum, midbrain, and basal ganglia. Prominent cerebral amyloid angiopathy has also been seen. Of note, cerebellar damage appears to be a common feature, including ubiquitin–positive plaques in the molecular layer surrounded by reactive astrocytes and dystrophic neurites (Lemere et al., 1996).

A subset of patients suffering from seizures developed greater neuronal loss and hippocampal sclerosis than patients without epileptic seizures (Velez-Pardo et al., 2004).

Biological Effect

In a variety of cell types, expression of mutant presenilin resulted in an increased level of secreted Aβ42, and an increased Aβ42/Aβ40 ratio (Murayama et al., 1999Kaneko et al., 2007Li et al., 2016). In vitro experiments with isolated proteins also revealed an increase in the Aβ42/Aβ40 ratio, but both Aβ40 and Aβ42 production were reduced (Sun et al., 2017).This mutation altered the specificity of the carboxypeptidase-like γ-cleavage, but spared the endoproteolytic ε-cleavage of APP and the presenilin-1 protein (Kaneko et al., 2007Li et al., 2016). Moreover, in vitro experiments testing the mutant’s γ-secretase activity at different temperatures showed the mutation increases enzyme-Aβn complex dissociation rates, enhancing the release of longer Aβ peptides (Szaruga et al., 2017; Jul 2017 news).

Effects on other cellular functions have also been reported for this mutation. For example, it reduced proteolytic processing of the Nav voltage-gated sodium channel in transfected rat neuroblastoma cells (Kim et al., 2014).

Research Models

Two isogenic iPSC lines, with either a homozygous or a heterozygous E280A mutation, have been generated using CRISPR-Cas9 technology to mutate PSEN1 in an iPSC line from a healthy individual (Frederiksen et al., 2019).

Last Updated: 14 Mar 2019

Comments

  1. Please see the following letter in Science related to this article: Alzheimer's disease and amyloid beta protein Koudinov AR et al Science online,> Published 25 June 2002 [ Full Text ]

    View all comments by Alexei Koudinov

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References

News Citations

  1. NIH Director Announces $100M Prevention Trial of Genentech Antibody
  2. Detecting Familial AD Ever Earlier: Subtle Memory Signs 15 Years Before
  3. Familial Alzheimer’s Gene Alters Children’s Brains
  4. In Familial Alzheimer’s, Tau Creeps into Cortex as Symptoms Show
  5. sAPP Binds GABA Receptor, and More News on APP

Paper Citations

  1. . The Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease Trial: A study of crenezumab versus placebo in preclinical PSEN1 E280A mutation carriers to evaluate efficacy and safety in the treatment of autosomal-dominant Alzheimer's dise. Alzheimers Dement (N Y). 2018;4:150-160. Epub 2018 Mar 8 PubMed.
  2. . Origin of the PSEN1 E280A mutation causing early-onset Alzheimer's disease. Alzheimers Dement. 2013 Nov 13; PubMed.
  3. . Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study. Lancet Neurol. 2011 Mar;10(3):213-20. PubMed.
  4. . Homozygosity of the autosomal dominant Alzheimer disease presenilin 1 E280A mutation. Neurology. 2015 Jan 13;84(2):206-8. Epub 2014 Dec 3 PubMed.
  5. . E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles. Hum Mutat. 1997;10(3):186-95. PubMed.
  6. . Apolipoprotein Eepsilon4 modifies Alzheimer's disease onset in an E280A PS1 kindred. Ann Neurol. 2003 Aug;54(2):163-9. PubMed.
  7. . APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease. Mol Psychiatry. 2015 Dec 1; PubMed.
  8. . Pooling/bootstrap-based GWAS (pbGWAS) identifies new loci modifying the age of onset in PSEN1 p.Glu280Ala Alzheimer's disease. Mol Psychiatry. 2012 Jun 19; PubMed.
  9. . Mutations modifying sporadic Alzheimer's disease age of onset. Am J Med Genet B Neuropsychiatr Genet. 2016 Dec;171(8):1116-1130. Epub 2016 Aug 30 PubMed.
  10. . A Mutation in DAOA Modifies the Age of Onset in PSEN1 E280A Alzheimer's Disease. Neural Plast. 2016;2016:9760314. Epub 2016 Jan 5 PubMed.
  11. . Phenotypic Profile of Early-Onset Familial Alzheimer's Disease Caused by Presenilin-1 E280A Mutation. J Alzheimers Dis. 2012 Jan 1;32(1):1-12. PubMed.
  12. . Cognitive Decline in a Colombian Kindred With Autosomal Dominant Alzheimer Disease: A Retrospective Cohort Study. JAMA Neurol. 2016 Apr;73(4):431-8. PubMed.
  13. . Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. JAMA. 1997 Mar 12;277(10):793-9. PubMed.
  14. . Hippocampal hyperactivation in presymptomatic familial Alzheimer's disease. Ann Neurol. 2010 Dec;68(6):865-75. PubMed.
  15. . Associations between biomarkers and age in the presenilin 1 E280A autosomal dominant Alzheimer disease kindred: a cross-sectional study. JAMA Neurol. 2015 Mar;72(3):316-24. PubMed.
  16. . Precuneus Failures in Subjects of the PSEN1 E280A Family at Risk of Developing Alzheimer's Disease Detected Using Quantitative Electroencephalography. J Alzheimers Dis. 2017;58(4):1229-1244. PubMed.
  17. . Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease. JAMA Neurol. 2018 May 1;75(5):548-556. PubMed.
  18. . Striatal amyloid is associated with tauopathy and memory decline in familial Alzheimer's disease. Alzheimers Res Ther. 2019 Feb 4;11(1):17. PubMed.
  19. . Brain Imaging and Blood Biomarker Abnormalities in Children With Autosomal Dominant Alzheimer Disease: A Cross-Sectional Study. JAMA Neurol. 2015 Aug;72(8):912-9. PubMed.
  20. . 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.
  21. . Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport. 1997 Apr 14;8(6):1537-42. PubMed.
  22. . Sequence analysis of presenilin-1 gene mutation in Japanese Alzheimer's disease patients. Neurosci Lett. 1996 Nov 1;218(2):139-41. PubMed.
  23. . The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology. Nat Med. 1996 Oct;2(10):1146-50. PubMed.
  24. . CA1 hippocampal neuronal loss in familial Alzheimer's disease presenilin-1 E280A mutation is related to epilepsy. Epilepsia. 2004 Jul;45(7):751-6. PubMed.
  25. . 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.
  26. . Enhanced accumulation of phosphorylated alpha-synuclein and elevated beta-amyloid 42/40 ratio caused by expression of the presenilin-1 deltaT440 mutant associated with familial Lewy body disease and variant Alzheimer's disease. J Neurosci. 2007 Nov 28;27(48):13092-7. PubMed.
  27. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
  28. . 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.
  29. . Alzheimer's-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions. Cell. 2017 Jul 27;170(3):443-456.e14. PubMed.
  30. . The E280A presenilin mutation reduces voltage-gated sodium channel levels in neuronal cells. Neurodegener Dis. 2014;13(2-3):64-8. Epub 2013 Nov 5 PubMed.
  31. . Generation of two isogenic iPSC lines with either a heterozygous or a homozygous E280A mutation in the PSEN1 gene. Stem Cell Res. 2019 Mar;35:101403. Epub 2019 Feb 7 PubMed.

Other Citations

  1. crenezumab

External Citations

  1. Jan 2015 news

Further Reading

Papers

  1. . Apolipoprotein Eepsilon4 modifies Alzheimer's disease onset in an E280A PS1 kindred. Ann Neurol. 2003 Aug;54(2):163-9. PubMed.
  2. . Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis. J Clin Invest. 2014 Apr 1;124(4):1552-67. Epub 2014 Feb 24 PubMed.
  3. . Spectral Analysis of EEG in Familial Alzheimer's Disease with E280A Presenilin-1 Mutation Gene. Int J Alzheimers Dis. 2014;2014:180741. Epub 2014 Jan 2 PubMed.
  4. . The Alzheimer's prevention initiative composite cognitive test score: sample size estimates for the evaluation of preclinical Alzheimer's disease treatments in presenilin 1 E280A mutation carriers. J Clin Psychiatry. 2014 Jun;75(6):652-60. PubMed.
  5. . Association between HFE 187 C>G (H63D) mutation and early-onset familial Alzheimer's disease PSEN-1 839A>C (E280A) mutation. Ann Hematol. 2008 Aug;87(8):671-3. PubMed.
  6. . E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles. Hum Mutat. 1997;10(3):186-95. PubMed.
  7. . Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology. 2014 Jul 15;83(3):253-60. Epub 2014 Jun 13 PubMed.
  8. . Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport. 1997 Apr 14;8(6):1537-42. PubMed.
  9. . Subjective memory complaints in preclinical autosomal dominant Alzheimer disease. Neurology. 2017 Oct 3;89(14):1464-1470. Epub 2017 Sep 6 PubMed.
  10. . Differential Pattern of Phospholipid Profile in the Temporal Cortex from E280A-Familiar and Sporadic Alzheimer's Disease Brains. J Alzheimers Dis. 2018;61(1):209-219. PubMed.
  11. . Behavioral and Electrophysiological Correlates of Memory Binding Deficits in Patients at Different Risk Levels for Alzheimer's Disease. J Alzheimers Dis. 2016 Jun 30;53(4):1325-40. PubMed.
  12. . Memory binding and white matter integrity in familial Alzheimer's disease. Brain. 2015 May;138(Pt 5):1355-69. Epub 2015 Mar 11 PubMed.
  13. . Dual memory task impairment in E280A presenilin-1 mutation carriers. J Alzheimers Dis. 2015;44(2):481-92. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database
  2. Clinical trial of Crenezumab in Preclinical E280A Mutation Carriers

Protein Diagram

Primary Papers

  1. . The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet. 1995 Oct;11(2):219-22. PubMed.
  2. . Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. JAMA. 1997 Mar 12;277(10):793-9. PubMed.
  3. . The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology. Nat Med. 1996 Oct;2(10):1146-50. PubMed.

Other mutations at this position

Alzpedia

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