PSEN1 A431E (Jalisco)


Pathogenicity: Alzheimer's Disease : Pathogenic, Spastic Paraparesis : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73685885 C>A
dbSNP ID: rs63750083
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GCA to GAA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 12


This mutation was first identified in five individuals with Alzheimer’s disease in a large genetic screen. Clinical details and family history information were not reported (Rogaeva et al., 2001).

This mutation was found in numerous families with ancestry tracing to the state of Jalisco in Western Mexico and may be one of the most prominent AD mutations in people with Mexican heritage. Of 13 Mexican families affected by autosomal-dominant AD, nine were shown to carry the A431E mutation. Within these nine families, 13 individuals were clinically diagnosed with AD. The disease was transmitted in an autosomal-dominant manner. Haplotype analysis suggested that these individuals share a common ancestor, demonstrating a founder effect (Yescas et al., 2006).

An additional 20 patients from 15 putatively unrelated families were also reported to carry the A431E mutation (Murrell et al., 2006). The 15 families were from Guadalajara (two), Chicago (one), and Southern California (12). All but one of the families could trace their ancestry to Jalisco. The remaining A431E proband was from Arizona and identified as non-Hispanic Caucasian. Haplotype analysis showed that all A431E mutation carriers in this study descended from a common ancestor.

This mutation was also identified in a 46-year-old man clinically diagnosed with AD who had a family history consistent with AD. His father was from Jalisco and had died at the age of 32 from an accident. This proband is unusual in that he also carried a second missense mutation in presenilin-1, T354I. It is likely that the Jalisco mutation accounts for the disease in this individual; however, the significance of the T354I mutation is unclear and may be benign (Lee et al., 2006).

The average age of onset in these families was about 40 years of age, ranging from about 33 to 44. In addition to cognitive changes, especially memory problems, some individuals showed prominent depression and personality changes. Motor symptoms, such as spastic paraplegia, myoclonus, and pyramidal rigidity, were also noted among some. At least one proband had a history of partial seizures 20 years before the onset of AD symptoms (Yescas et al., 2006; Murrell et al., 2006). Psychological changes, and especially depression, may occur early in mutation carriers. In a study of 33 young Mexican women (average age about 31), mutation carriers (who were unaware of mutation status) were likelier to exhibit symptoms of depression than non-mutation carriers, and twice as likely to have sought psychiatric help (Ringman et al., 2004). In one case, a 35-year-old carrier presented with mutism, lack of spontaneous movement, and refusal to eat, resulting in a presumptive diagnosis of catatonia (Alakkas et al., 2020).

Interestingly, in one family, all affected members, spanning four generations, had initial motor symptoms and less- prominent, atypical cognitive impairment (Santos-Mandujano et al., 2019). Two of five mutation carriers in the most recent two generations presented with lower limb weakness. The one carrier who also had cognitive symptoms, had non-amnestic, very mild cognitive impairment, with visuospatial deficits and olfactory dysfunction at age 54, only a year younger than the mean age of death in his family. Moreover, as recounted by other family members, affected individuals in previous generations were cognitively unimpaired or became impaired at a late stage of disease.

Homozygosity for this mutation was reported in a 35- year-old man with childhood learning disability and onset of progressive cognitive deficits leading to dementia at age 33 (Parker et al., 2019). The patient suffered from chronic nighttime behavioral disturbance, possibly REM behavior disorder, as well as spastic paraparesis and pseudobulbar affect, a condition characterized by episodes of sudden uncontrollable laughing or crying.


At least five autopsied cases confirmed the diagnosis of AD (Murrell et al., 2006). Brain imaging showed mutation carriers were affected by cortical and subcortical atrophy (Yescas et al., 2006). In several mutation carriers, white matter abnormalities have been reported. In three carriers of the mutation with spastic paraparesis, widespread white-matter abnormalities were observed in the corpus callosum, occipital, parietal, and frontal lobes (Soosman et al., 2016). Consistent with this alteration, in one of the individuals, electrophysiological measurements revealed slowed motor and sensory conduction in the lower extremities. PiB-PET imaging, however, showed low amyloid burden in sensorimotor cortex. Moreover, three mutation carriers from another family, including one symptomatic, one presymptomatic, and one asymptomatic individual, had periventricular white- matter hyperintensities suggestive of early glial and vascular pathology that seemed to be consistent with the individuals’ clinical stage of disease and cortical atrophy pattern (Santos-Mandujano et al., 2019).

In the homozygous individual, MRI revealed a high level of cerebral atrophy. Also, chronic microhemorrhages were seen in occipital, temporal, and right frontal lobes (Parker et al., 2019).

Of note, one carrier was reported to have Lewy body pathology, as assessed by α-synuclein staining, in the amygdala, cingulate gyrus, and neocortex (Leverenz et al., 2020). However, no detectable staining was observed in another carrier from the same family, with the same age at onset (51) and similar disease duration (10 versus 9 years). 

Biological Effect

This mutation is associated with increased levels of Aβ42 in the plasma of presymptomatic individuals. In the cerebrospinal fluid, it is associated with a decline in Aβ42 levels and a reduced Aβ42/Aβ40 ratio (Ringman et al., 2008; Ringman et al., 2012). Further biomarker analysis suggested A431E mutation carriers may have lower CSF levels of Aβ37, Aβ38, and Aβ39, suggesting the mutation may modulate γ-secretase cleavage (Portelius et al., 2010). In vitro experiments using APP-C99 as a substrate indicated the mutation reduces both Aβ40 and Aβ42 production, but the effect is stronger for Aβ40 (Sun et al., 2017). Moreover, in silico analysis predicts a possibly damaging effect of the mutation (Yescas et al., 2006).

The A431E mutation may also alter monoamine oxidase-A (MAO-A) activity, as suggested by the enhanced MAO-A activity observed in hippocampal HT-22 cells expressing PSEN1 A431E (Pennington et al., 2011). This effect could help explain the frequently observed depression in patients carrying the mutation.

Last Updated: 08 Oct 2020


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Paper Citations

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  2. . Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing early-onset Alzheimer's disease in Mexican families. Neurogenetics. 2006 Jul;7(3):195-200. Epub 2006 Apr 21 PubMed.
  3. . The A431E mutation in PSEN1 causing familial Alzheimer's disease originating in Jalisco State, Mexico: an additional fifteen families. Neurogenetics. 2006 Nov;7(4):277-9. Epub 2006 Aug 5 PubMed.
  4. . The Thr354Ile substitution in PSEN1:: disease-causing mutation or polymorphism?. Neurology. 2006 Jun 27;66(12):1955-6. PubMed.
  5. . Female preclinical presenilin-1 mutation carriers unaware of their genetic status have higher levels of depression than their non-mutation carrying kin. J Neurol Neurosurg Psychiatry. 2004 Mar;75(3):500-2. PubMed.
  6. . Early-Onset Alzheimer's Disease Masquerading as Catatonia. Case Rep Neurol Med. 2020;2020:1493481. Epub 2020 Sep 12 PubMed.
  7. . Clinical Association of White Matter Hyperintensities Localization in a Mexican Family with Spastic Paraparesis Carrying the PSEN1 A431E Mutation. J Alzheimers Dis. 2020;73(3):1075-1083. PubMed.
  8. . Homozygosity for the A431E mutation in PSEN1 presenting with a relatively aggressive phenotype. Neurosci Lett. 2019 Apr 23;699:195-198. Epub 2019 Feb 1 PubMed.
  9. . Widespread white matter and conduction defects in PSEN1-related spastic paraparesis. Neurobiol Aging. 2016 Nov;47:201-209. Epub 2016 Aug 8 PubMed.
  10. . Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype. Arch Neurol. 2006 Mar;63(3):370-6. PubMed.
  11. . Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology. 2008 Jul 8;71(2):85-92. PubMed.
  12. . Cerebrospinal fluid biomarkers and proximity to diagnosis in preclinical familial Alzheimer's disease. Dement Geriatr Cogn Disord. 2012;33(1):1-5. PubMed.
  13. . Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease. Mol Neurodegener. 2010;5:2. PubMed.
  14. . 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.
  15. . Alzheimer disease-related presenilin-1 variants exert distinct effects on monoamine oxidase-A activity in vitro. J Neural Transm. 2011 Jul;118(7):987-95. PubMed.

Other Citations

  1. T354I

Further Reading


  1. . Current concepts of mild cognitive impairment and their applicability to persons at-risk for familial Alzheimer's disease. Curr Alzheimer Res. 2009 Aug;6(4):341-6. PubMed.

Protein Diagram

Primary Papers

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  2. . Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing early-onset Alzheimer's disease in Mexican families. Neurogenetics. 2006 Jul;7(3):195-200. Epub 2006 Apr 21 PubMed.


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