Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637653 C>T
dbSNP ID: rs63749824
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GCC to GTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4


This autosomal dominant mutation is associated with a wide range of age at onset of Alzheimer’s disease. It was first identified in three Alzheimer’s disease patients from the Netherlands. The patients (1005, 1061, and 1087) were not known to be related, but genetic markers flanking PSEN1 suggested a relatively recent common ancestor. All three patients met NINCDS-ADRDA criteria for probable AD and had a family history of dementia. The ages at onset were 53, 55, and 58, consistent with early onset AD. The mutation was absent in the 118 control individuals screened (Cruts et al., 1998).

Two years later, the A79V mutation was reported in a German individual with AD, known as patient 1. Like the previously reported Dutch cases, her symptoms began at age 58. The disease course was initially mild, but ultimately culminated in severe dementia more than 10 years after symptom onset. A similar age at onset and a 10-year disease duration were reported for this patient's mother (Finckh et al., 2000).

A fifth family was identified with a later age at onset than observed previously, with greater variability within the family as well (mean age at onset of 69 years; range: 55 to 78 years) (Kauwe et al., 2007). The mutation segregated with disease in this family, which included three demented individuals who carried the mutation, five nondemented elderly siblings who were non-carriers, and five additional non-carriers whose parents were cognitively healthy. Of note, one affected individual was identified who did not carry the mutation and was thought to have sporadic AD (age at onset: 78 years).

Three additional AD patients carrying this mutation have been identified (Rogaeva et al., 2001; Miravalle et al., 2002), and more recently the A79V mutation was detected in a screen of 439 families with a history of late-onset AD (onset at age 65 or later) (Cruchaga et al., 2012). The mutation was found in four of these families, including in one individual from a previously reported family (Kauwe et al., 2007). The sequenced individual from this family had autopsy-confirmed AD and an age of onset of 76 years. A79V was found also in a sporadic AD case (out of 1,806 screened), but not in 1,346 unrelated controls. In addition, the mutation was identified in 10 of 22 members of a family of European ancestry who developed AD symptoms in their 70s and 80s (Day et al., 2016). Overall, their phenotypes were similar to those of patients with late-onset AD (LOAD), including onset age, duration of dementia, rate of progression, and associated symptoms and comorbidities. However, the early emergence of hallucinations and delusions was more frequent in this family than in sporadic LOAD. Age at onset was not influenced by APOE allele carrier status.

This mutation was described as most likely having reduced penetrance, however, with an allele count of four, and a frequency of 0.0014 percent in the gnomAD variant database (Koriath et al., 2018).

The A79V mutation also has been linked to other neurodegenerative phenotypes and pathologies. In a cohort including 490 Parkinson's disease (PD) patients, three individuals carried the mutation: an early onset case (44 years old at onset) and two late-onset cases (75 and 64 years old at onset). None of these carriers reported PD or AD family history. Neurological evaluation at 46, 86, and 82 years of age revealed no evidence of dementia after two, 11, and 18 years of disease onset, respectively (Ibanez et al., 2018). In addition, a 72-year-old carrier of the mutation, who suffered primarily from progressive memory loss, was diagnosed with probable dementia with Lewy bodies (Meeus et al., 2012), and another carrier from a Belgian study had mixed AD and vascular pathology (Perrone et al., 2020).


Autopsies from at least seven mutation carriers have revealed neuropathology consistent with AD (Cruchaga et al., 2012; Day et al., 2016; Del-Aguila et al., 2019). In the five cases reported by Day and colleagues, Aβ plaques and neurofibrillary tangles were prominent in cortical association areas including the medial temporal lobe, and less abundant in deep gray nuclei. Mild to moderate cerebral amyloid angiopathy was reported. Lewy bodies limited to the substantia nigra pars compacta were present in one case, and arteriolosclerosis with lacunar infarcts was present in two cases. At least in one case, diffuse plaques were the predominant type of Aβ deposit, and primitive plaques were abundant (Maarouf et al., 2008). In this same case, vascular amyloid was very mild and neurofibrillary tangles were sparse. 

Although CSF Aβ42 and Aβ42/Aβ40 concentrations were found to be very high in one nondemented mutation carrier (Kauwe et al., 2007), a subsequent study including two carriers with early onset AD, revealed decreased CSF levels of Aβ42 (Perrone et al,, 2020). Levels of Aβ40, sAPPα, and sAPPβ were also decreased. Interestingly, peptide levels, particularly those of Aβ43, varied between the two carriers, with lower levels seen in the carrier with an APOE3/4 genotype compared with the carrier with an APOE3/3 genotype. Tau and phospho-tau levels were available for one of the carriers and these were elevated compared with controls.

Biological Effect

Two in-depth studies of the Aβ peptides produced by cells transfected with this variant revealed a deleterious effect, decreasing both the Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios compared with cells expressing wildtype PSEN1 (Petit et al., 2022; Liu et al., 2022; Apr 2022 news). Both ratios were reported to outperform the Aβ42/Aβ40 ratio as indicators of AD pathogenicity, with the former correlating with AD age at onset.

Moreover, data from other experimental systems have revealed increases in the Aβ42/Aβ40 ratio, although different alterations have been found to underlie this change. In HEK-293 cells expressing APP with the Swedish mutation, A79V increased the Aβ42/Aβ40 ratio by decreasing Aβ40. There was no change in Aβ42 compared to cells expressing wild-type PSEN1 (Kumar-Singh et al., 2006). In contrast, in mouse embryonic fibroblasts lacking PSEN1 and PSEN2, expression of PSEN1 with the A79V mutation resulted in increased Aβ42 levels in conditioned media compared with concentrations produced by cells expressing wild-type PSEN1. Aβ40 levels and total Aβ (combined Aβ40 and Aβ42) levels were not significantly different from wild-type controls (Kauwe et al., 2007).

Yet another cell-based study, in CHO cells, reported decreases in the production of both peptides, with a reduction of greater magnitude in Aβ40 (Kakuda et al., 2021). This study also revealed a decrease in Aβ38 and an increase in Aβ43. Analyses of the short peptides generated from the stepwise processing of Aβ suggested Aβ43 may be generated from Aβ48 in several AD-associated mutants, rather than from the canonical Aβ49 precusor. Increased Aβ43 levels and increased production via this alternate pathway correlated with younger ages at disease onset. 

In an in vitro assay using purified proteins to test this mutant's ability to cleave the APP-C99 substrate, Aβ42 levels were dramatically reduced compared with those produced by wildtype PSEN1, and Aβ40 was undetectable (Sun et al., 2017). However, this assay appears to be limited in its cleavage efficiency given that 68 of 138 mutant recombinant PSEN1 enzymes tested produced less than 10 percent of the Aβ40 and Aβ42 produced by the wildtype protein (Liu et al., 2021).

Studies of how this variant affects gene expression in the brain have also been conducted. Single-nuclei RNA sequencing data were collected from the parietal cortices of a woman of European-American ancestry carrying this mutation and two non-carrier family members (May 2019 news; Del-Aguila et al., 2019). All three women had AD pathology when they died in their 80s. The carrier and one sibling had severe dementia at death, while the other sibling had mild dementia. Sequencing analyses revealed a reduced proportion of excitatory neurons in the carrier compared with the non-carriers.

In silico algorithms to predict the effects of this variant on protein function (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Cruchaga et al., 2012, gnomAD v2.1.1Xiao et al., 2021).


Alzheimer's Disease : Likely 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. A79V: Although results from different assays were mixed, two in-depth studies probing production of multiple Aβ peptides indicated a pathogenic effect and all studies showed an increase in the Aβ42/Aβ40 ratio.


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. A79V: At least one family with >=3 affected carriers and >=1 unaffected noncarriers, but 1 noncarrier had LOAD with age at onset within the range of onset of carriers.


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)

Research Models

An iPSC cell line has been generated from skin fibroblasts of a 48-year-old presymptomatic woman carrying the mutation (Li et al., 2016). An isogenic control line, in which the mutation has been corrected, is also available (Pires et al., 2016).

Last Updated: 09 Nov 2022


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News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?
  2. When It Comes to Alzheimer’s Disease, Do Human Microglia Even Give a DAM?

Paper Citations

  1. . Generation of induced pluripotent stem cells (iPSCs) from an Alzheimer's disease patient carrying an A79V mutation in PSEN1. Stem Cell Res. 2016 Mar;16(2):229-32. Epub 2016 Jan 14 PubMed.
  2. . Generation of a gene-corrected isogenic control cell line from an Alzheimer's disease patient iPSC line carrying a A79V mutation in PSEN1. Stem Cell Res. 2016 Sep;17(2):285-288. Epub 2016 Aug 7 PubMed.
  3. . Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet. 1998 Jan;7(1):43-51. PubMed.
  4. . 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.
  5. . Extreme cerebrospinal fluid amyloid beta levels identify family with late-onset Alzheimer's disease presenilin 1 mutation. Ann Neurol. 2007 May;61(5):446-53. PubMed.
  6. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  7. . Genetic mutations associated with presenile dementia. Neurobiol Aging. 2002 Jul-Aug; 23(S1):322.
  8. . Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. PLoS One. 2012;7(2):e31039. PubMed.
  9. . Phenotypic Similarities Between Late-Onset Autosomal Dominant and Sporadic Alzheimer Disease: A Single-Family Case-Control Study. JAMA Neurol. 2016 Sep 1;73(9):1125-32. PubMed.
  10. . Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.
  11. . Pleiotropic Effects of Variants in Dementia Genes in Parkinson Disease. Front Neurosci. 2018;12:230. Epub 2018 Apr 10 PubMed.
  12. . DLB and PDD: a role for mutations in dementia and Parkinson disease genes?. Neurobiol Aging. 2012 Mar;33(3):629.e5-629.e18. PubMed.
  13. . Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimers Res Ther. 2020 Sep 11;12(1):108. PubMed.
  14. . A single-nuclei RNA sequencing study of Mendelian and sporadic AD in the human brain. Alzheimers Res Ther. 2019 Aug 9;11(1):71. PubMed.
  15. . Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations. Mol Neurodegener. 2008;3:20. PubMed.
  16. . 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.
  17. . Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
  18. . Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40. Hum Mutat. 2006 Jul;27(7):686-95. PubMed.
  19. . Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. Transl Psychiatry. 2021 Nov 3;11(1):558. PubMed.
  20. . 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.
  21. . 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 Jan-Jun;296:100393. Epub 2021 Feb 8 PubMed.
  22. . 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

Protein Diagram

Primary Papers

  1. . Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet. 1998 Jan;7(1):43-51. PubMed.


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