Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73683890 G>A
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GCC to ACC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 11


This mutation was first detected in a man of mixed Turkish and Bulgarian ancestry. He developed symptoms of Alzheimer’s disease, starting with apathy and behavioral disturbances affecting activities of daily living, at the age of 43. He developed significant cognitive decline along with intermittent visual hallucinations.

At least three additional members of this family (AD-46) were affected by dementia. The proband’s mother and maternal aunt had died with dementia in their 60s (onset at age 35 and 56, respectively). The proband’s maternal grandmother was also affected and died at age 70 (Lohmann et al., 2012).

The mutation was also found in a family spanning three generations with early-onset AD from the Dominantly Inherited Alzheimer Network (DIAN) Extended Registry (Hsu et al., 2018). The proband and the proband’s parent had ages at symptomatic onset of 50 and 57 years, respectively. In the parent, AD was confirmed at autopsy at age 67 years.  The mutation was absent in two population-based exome sequencing databases, EVS and ExAC.

The mutation was also reported in a man diagnosed with AD whose cognitive impairment first manifested at 56 years of age and who died at 67 (Gondim et al., 2019).


Neuropathology in one case was consistent with AD, including widespread tau and Aβ pathologies, but also included widespread α-synuclein inclusions, suggesting diffuse Lewy body disease (Gondim et al., 2019). Tau and α-synuclein aggregates were found co-existing in the same neuron. MRI brain scans of another case showed atrophy of the frontal lobes (Lohmann et al., 2012).

Biological Effect

Cells expressing PSEN1 A396T produced significantly more Aβ42 than cells expressing wild-type PSEN1 (Hsu et al., 2018). In an in vitro assay using isolated proteins, Aβ42 production was similar to that of the wild-type protein, but Aβ40 production was reduced, resulting in an approximately two-fold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017). In silico, this mutation is predicted probably damaging by PolyPhen-2. 

Last Updated: 06 Jun 2019


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Paper Citations

  1. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.
  2. . Discovery and validation of autosomal dominant Alzheimer's disease mutations. Alzheimers Res Ther. 2018 Jul 18;10(1):67. PubMed.
  3. . Diffuse Lewy Body Disease and Alzheimer Disease: Neuropathologic Phenotype Associated With the PSEN1 p.A396T Mutation. J Neuropathol Exp Neurol. 2019 Jul 1;78(7):585-594. PubMed.
  4. . 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.


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