PSEN1 E280A (Paisa)

Other Names: Paisa


Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
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


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; Fuller et al., 2019; Aug 2019 conference news). 

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). 

Remarkably, a rare APOE variant, R154S, a.k.a. as the Christchurch mutation, was reported to confer what appears to be robust protection against the PSEN1 E280A mutation (Nov 2019 news, Arboleda-Velasquez et al., 2019). A Colombian carrier of E280A who was also homozygous for the Christchurch mutation, had only subtle short-term memory loss in her 70s. PET imaging revealed an unusually high burden of amyloid-β plaque in her brain, with tau pathology restricted to medial temporal and occipital regions, minimally affecting other areas typically involved in AD. Consistent with these observations, post-mortem analysis showed high levels of tau tangles in the occipital cortex, while the frontal cortex was relatively spared (Sep 2022 conference news, Sepulveda-Falla et al., 2022). ApoE expression was higher in spared regions, while inflammatory microglia were observed in regions with tangles. In addition, PET analysis showed glucose metabolism levels in areas associated with AD, such as the precuneus, were similar to those of age-matched, non-E280A carriers, as were plasma levels of neurofilament light chain, an indicator of neuronal damage. In a subsequent analysis of 117 members of the Colombian kindred, seven Christchurch heterozygous carriers were identified, including four who also carried the E280A mutation. In these four cases, however, onset of cognitive impairment occurred in midlife, suggesting that, if indeed the mutation is protective of AD, homozygosity is required.

Additional loci that modify age of onset have been reported, including several dominant major genes (Vélez et al., 2013; Vélez et al., 2016a; Vélez et al., 2016b), as well as recessive variants that delay onset, up to 11 years, or accelerate onset, up to eight years (Vélez et al., 2019).

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).  Interestingly, gender appear to contribute to some differences in cognition and neurodegeneration (Vila-Castelar et al., 2020; Fox-Fuller et al., 2021Vila-Castelar et al., 2022).

Several early signs of disease have been reported in carriers of this mutation. Cognitive decline, for example, 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). Even cognitively unimpaired E280A carriers score slightly lower on the Mini-Mental State Exam and memory tests than non-carriers (Rios-Romenets et al., 2020). Of note, awareness of memory function appears to decrease in the predementia stages, reaching anosognosia close to the age of mild cognitive impairment onset (Vannini et al., 2020). Severe headaches also appear to be a common early symptom, typically occurring several years before dementia onset (Lopera et al., 1997). The risk of mental disorders in mutation carriers under the age of 30, however, was found to be similar to that of non-carriers (Villalba et al., 2019).

Consistent with early signs of cognitive impairment, several early pathological changes have been detected as well (see Fuller et al., 2020 for review; Jul 2015 news). For example, 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). Of note, changes in retinal thickness, which can be detected in opthalmology clinics using optical coherence tomography, were reported in carriers several years before clinical onset (Armstrong et al., 2020).

Studies of Aβ and tau pathology using PET have also revealed early presymptomatic changes. For example, Aβ, as assessed by PiB-PET, was elevated in unimpaired carriers approximately 15 years prior to expected onset of mild cognitive impairment (Feb 2018 news; Quiroz et al., 2018). A longitudinal study tracking both amyloid and tau pathology confirmed this early Aβ accumulation, and mapped out subsequent pathological changes, including tau accumulation in the entorhinal cortex nine years prior to expected symptom onset, neocortical tau build-up and hippocampal atrophy six years prior to onset, and cognitive decline four years prior to onset (Sanchez et al., 2021). Of note, rates of tau accumulation among carriers were most rapid in the parietal neocortex, and tau levels in the entorhinal cortex predicted subsequent neocortical tau accumulation and cognitive decline.

Studies have also shown correlations between cognitive performance and amyloid and tau pathologies. For example, 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 (Hanseeuw et al., 2019). Moreover, subjective cognitive decline, difficulties in recall tests, and impaired visual memory showed a close relationship with both cortical amyloid and tau pathology in the inferior temporal and entorhinal cortices (Gatchel et al., 2019; Guzmán-Vélez et al., 2020; Norton et al., 2020; Bocanegra et al., 2020). 

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. Of particular interest, plasma neurofilament light (NfL), was reported to distinguish mutation carriers from noncarriers as early as 22 years before expected disease onset (Aug 2019 conference news, Quiroz et al., 2020, May 2020 news, Masters, 2020), and higher plasma NfL levels were correlated with greater regional tau burden and worse cognition (Guzmán-Vélez et al., 2021). Moreover, plasma levels of P-tau217, a tau species phosphorylated at amino acid 217 whose plasma levels accurately discriminate between AD and other neurodegenerative disorders, distinguished mutation carriers 20 years prior to estimated onset of mild cognitive impairment (July 2020 news; Palmqvist et al., 2020). 

Biomarker differences have been detected in children as young as nine years old (see Fuller et al., 2019 for review; Jul 2015 news). 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 unknown 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).

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


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. A study of frontal cortical tissue from 10 E280A carriers revealed an increased load of Aβ42 peptide and decreased loads of Aβ38 and Aβ43 peptides compared with cortical tissues from 10 individuals with sporadic AD (Dinkel et al., 2020). 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, Soto-Mercado et al., 2020). Two of these studies suggested the mutation altered the specificity of the carboxypeptidase-like γ-cleavage, but spared the endoproteolytic ε-cleavage of APP and PSEN1 (Kaneko et al., 2007; Li et al., 2016). A subsequent cell-based study confirmed the increase in the Aβ42/Aβ40 ratio, but indicated Aβ42 production was decreased in cells expressing the mutant protein, as was production of total Aβ, Aβ38, and Aβ40 (Kakuda et al., 2021). Of note, this study revealed an increase in the toxic peptide Aβ43. A switch in the stepwise γ-cleavage pathway leading to production of this peptide may underlie or contribute to this effect. 

Consistent with the above observations, in vitro experiments with isolated proteins revealed an increase in the Aβ42/Aβ40 ratio, with reductions in both Aβ40 and Aβ42 production (Sun et al., 2017). 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). 

As revealed by a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment, E280 appears to play a key role in stabilizing the hybrid β-sheet that forms between PSEN1 and APP in preparation for γ-secretase cleavage (Zhou et al., 2019; Jan 2019 news). The carboxylate side chain of E280 makes a bifurcated H-bond to the hydroxyl groups of Y154 and Y159, both from transmembrane domain 2 of PSEN1. These interactions are buttressed by two additional H-bonds from R278 to E280 and Y159. Based on these data, subsequent computational simulations suggest E280A reduces the stability of the protein and favors an open conformational state in which the substrate is held more loosely, resulting in imprecise cleavage and earlier release of longer Aβ peptides (Dehury et al., 2020).

Effects on other cellular functions have also been reported for this mutation. For example, in rodent neuroblastoma cells, it reduced proteolytic processing of the Nav voltage-gated sodium channel (Kim et al., 2014), and dysregulated mitochondrial function, autophagy, and calcium homeostasis (Rojas-Charry et al., 2020). Moreover, in cholinergic-like neurons derived from carrier mesenchymal stromal stem cells, the mutant was reported to increase tau phosphorylation at residues Ser202 and Thr205 (May 2020 newsSoto-Mercado et al., 2020). In addition, apoptosis markers were elevated accompanied by a disruption of mitochondrial potential and DNA fragmentation. Also in these cells, calcium flux was abnormal and acetylcholinesterase activity reduced. 

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).

Research Models

Several cell models carrying this mutation have been created. 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). Also, an iPSC line derived from a patient with early onset AD has been created (Vallejo-Diez et al., 2019). Using mesenchymal stromal stem cells from umbilical cords, researchers have also generated cholinergic-like neurons carrying the mutation (May 2020 newsSoto-Mercado et al., 2020). 


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.


Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.


The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. E280A: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.


Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. E280A: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.


Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.


Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.


Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. E280A: At least one family with >=3 affected carriers and >=1 unaffected noncarriers.


Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.


Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 07 Sep 2022


  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 ]

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News Citations

  1. NIH Director Announces $100M Prevention Trial of Genentech Antibody
  2. Crenezumab Update: Baseline Data from Colombian Prevention Trial
  3. Can an ApoE Mutation Halt Alzheimer’s Disease?
  4. Familial Alzheimer’s Gene Alters Children’s Brains
  5. In Familial Alzheimer’s, Tau Creeps into Cortex as Symptoms Show
  6. API Biomarker Data Mirror DIAN’s, Support Progression Models
  7. Colombian Cohort Delivers Data on Blood NfL
  8. In Colombian Alzheimer’s Kindred, Blood NfL Climbs 22 Years Before Symptoms
  9. Plasma p-Tau217 Set to Transform Alzheimer’s Diagnostics
  10. sAPP Binds GABA Receptor, and More News on APP
  11. CryoEM γ-Secretase Structures Nail APP, Notch Binding
  12. Umbilical Cord With Presenilin Mutation Births New Cell Model of Familial AD

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. . Biological and Cognitive Markers of Presenilin1 E280A Autosomal Dominant Alzheimer's Disease: A Comprehensive Review of the Colombian Kindred. J Prev Alzheimers Dis. 2019;6(2):112-120. PubMed.
  3. . Origin of the PSEN1 E280A mutation causing early-onset Alzheimer's disease. Alzheimers Dement. 2014 Oct;10(5 Suppl):S277-S283.e10. Epub 2013 Nov 13 PubMed.
  4. . 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.
  5. . Homozygosity of the autosomal dominant Alzheimer disease presenilin 1 E280A mutation. Neurology. 2015 Jan 13;84(2):206-8. Epub 2014 Dec 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. . Apolipoprotein Eepsilon4 modifies Alzheimer's disease onset in an E280A PS1 kindred. Ann Neurol. 2003 Aug;54(2):163-9. PubMed.
  8. . APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease. Mol Psychiatry. 2015 Dec 1; PubMed.
  9. . Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019 Nov;25(11):1680-1683. Epub 2019 Nov 4 PubMed.
  10. . Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer's dementia. Acta Neuropathol. 2022 Sep;144(3):589-601. Epub 2022 Jul 15 PubMed.
  11. . 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.
  12. . 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.
  13. . 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.
  14. . Familial Alzheimer's Disease and Recessive Modifiers. Mol Neurobiol. 2020 Feb;57(2):1035-1043. Epub 2019 Oct 29 PubMed.
  15. . 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.
  16. . Examining Sex Differences in Markers of Cognition and Neurodegeneration in Autosomal Dominant Alzheimer's Disease: Preliminary Findings from the Colombian Alzheimer's Prevention Initiative Biomarker Study. J Alzheimers Dis. 2020;77(4):1743-1753. PubMed.
  17. . Sex Differences in Cognitive Abilities Among Children With the Autosomal Dominant Alzheimer Disease Presenilin 1 E280A Variant From a Colombian Cohort. JAMA Netw Open. 2021 Aug 2;4(8):e2121697. PubMed.
  18. . Sex differences in cognitive resilience in preclinical autosomal-dominant Alzheimer's disease carriers and non-carriers: Baseline findings from the API ADAD Colombia Trial. Alzheimers Dement. 2022 Feb 1; PubMed.
  19. . Cognitive Decline in a Colombian Kindred With Autosomal Dominant Alzheimer Disease: A Retrospective Cohort Study. JAMA Neurol. 2016 Apr;73(4):431-8. PubMed.
  20. . Baseline demographic, clinical, and cognitive characteristics of the Alzheimer's Prevention Initiative (API) Autosomal-Dominant Alzheimer's Disease Colombia Trial. Alzheimers Dement. 2020 Jul;16(7):1023-1030. Epub 2020 May 17 PubMed.
  21. . Trajectory of Unawareness of Memory Decline in Individuals With Autosomal Dominant Alzheimer Disease. JAMA Netw Open. 2020 Dec 1;3(12):e2027472. PubMed.
  22. . 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.
  23. . Mental Disorders in Young Adults from Families with the Presenilin-1 Gene Mutation E280A in the Preclinical Stage of Alzheimer's Disease. J Alzheimers Dis Rep. 2019 Aug 29;3(1):241-250. PubMed.
  24. . Hippocampal hyperactivation in presymptomatic familial Alzheimer's disease. Ann Neurol. 2010 Dec;68(6):865-75. PubMed.
  25. . 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.
  26. . 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.
  27. . Retinal Imaging Findings in Carriers With PSEN1-Associated Early-Onset Familial Alzheimer Disease Before Onset of Cognitive Symptoms. JAMA Ophthalmol. 2021 Jan 1;139(1):49-56. PubMed.
  28. . Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease. JAMA Neurol. 2018 May 1;75(5):548-556. PubMed.
  29. . Longitudinal amyloid and tau accumulation in autosomal dominant Alzheimer's disease: findings from the Colombia-Boston (COLBOS) biomarker study. Alzheimers Res Ther. 2021 Jan 15;13(1):27. PubMed.
  30. . Striatal amyloid is associated with tauopathy and memory decline in familial Alzheimer's disease. Alzheimers Res Ther. 2019 Feb 4;11(1):17. PubMed.
  31. . Association of subjective cognitive decline with markers of brain pathology in preclinical autosomal dominant Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2020 Mar;91(3):330-332. Epub 2019 Dec 24 PubMed.
  32. . Associative memory and in vivo brain pathology in asymptomatic presenilin-1 E280A carriers. Neurology. 2020 Sep 8;95(10):e1312-e1321. Epub 2020 Jul 1 PubMed.
  33. . Visual short-term memory relates to tau and amyloid burdens in preclinical autosomal dominant Alzheimer's disease. Alzheimers Res Ther. 2020 Aug 21;12(1):99. PubMed.
  34. . Association Between Visual Memory and In Vivo Amyloid and Tau Pathology in Preclinical Autosomal Dominant Alzheimer's Disease. J Int Neuropsychol Soc. 2021 Jan;27(1):47-55. Epub 2020 Aug 7 PubMed.
  35. . Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional and longitudinal cohort study. Lancet Neurol. 2020 Jun;19(6):513-521. Epub 2020 May 26 PubMed.
  36. . Major risk factors for Alzheimer's disease: age and genetics. Lancet Neurol. 2020 Jun;19(6):475-476. Epub 2020 May 26 PubMed.
  37. . Associations between plasma neurofilament light, in vivo brain pathology, and cognition in non-demented individuals with autosomal-dominant Alzheimer's disease. Alzheimers Dement. 2021 May;17(5):813-821. Epub 2021 Feb 1 PubMed.
  38. . 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.
  39. . 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.
  40. . 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.
  41. . Sequence analysis of presenilin-1 gene mutation in Japanese Alzheimer's disease patients. Neurosci Lett. 1996 Nov 1;218(2):139-41. PubMed.
  42. . Decreased Deposition of Beta-Amyloid 1-38 and Increased Deposition of Beta-Amyloid 1-42 in Brain Tissue of Presenilin-1 E280A Familial Alzheimer's Disease Patients. Front Aging Neurosci. 2020;12:220. Epub 2020 Jul 28 PubMed.
  43. . 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.
  44. . 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.
  45. . 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.
  46. . 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.
  47. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
  48. . Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer's disease reveal intraneuronal sAPPβ fragments accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ dysregulation: Therapeutic implications. PLoS One. 2020;15(5):e0221669. Epub 2020 May 21 PubMed.
  49. . Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. Transl Psychiatry. 2021 Nov 3;11(1):558. PubMed.
  50. . 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.
  51. . Alzheimer's-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions. Cell. 2017 Jul 27;170(3):443-456.e14. PubMed. Correction.
  52. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  53. . A computer-simulated mechanism of familial Alzheimer's disease: Mutations enhance thermal dynamics and favor looser substrate-binding to γ-secretase. J Struct Biol. 2020 Dec 1;212(3):107648. Epub 2020 Oct 21 PubMed.
  54. . 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.
  55. . Susceptibility to cellular stress in PS1 mutant N2a cells is associated with mitochondrial defects and altered calcium homeostasis. Sci Rep. 2020 Apr 15;10(1):6455. PubMed.
  56. . 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.
  57. . 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.
  58. . Generation of one iPSC line (IMEDEAi006-A) from an early-onset familial Alzheimer's Disease (fAD) patient carrying the E280A mutation in the PSEN1 gene. Stem Cell Res. 2019 May;37:101440. Epub 2019 Apr 15 PubMed.

Other Citations

  1. crenezumab

External Citations

  1. gnomAD v2.1.1

Further Reading


  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.
  14. . Multi-Target Effects of the Cannabinoid CP55940 on Familial Alzheimer's Disease PSEN1 E280A Cholinergic-Like Neurons: Role of CB1 Receptor. J Alzheimers Dis. 2020 Nov 23; PubMed.
  15. . 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.
  16. . Substance Use-Related Cognitive Decline in Families with Autosomal Dominant Alzheimer's Disease: A Cohort Study. J Alzheimers Dis. 2022;85(4):1423-1439. PubMed.

Learn More

  1. 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


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