Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
Position: Chr14:73637667 A>G
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATG to GTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4


This mutation was first reported in a genome-wide analysis of family-based AD samples from the National Institute of Mental Health Alzheimer’s Disease Genetics Initiative Study (Hooli et al., 2014). Two carriers were confirmed to have had AD at autopsy with ages at onset of 70 and 72 years.

The mutation was subsequently identified in three members of an Italian family with an early onset dementia showing an autosomal dominant pattern of inheritance (Gallo et al., 2017). The reported pedigree contains 14 affected family members over three generations. Mean age of symptom onset in this family is earlier, 52.7 years (range 49–58 years).

Detailed descriptions were available for three affected family members in the third generation. Although all three suffered from an early onset dementia, the pattern of cognitive and behavioral symptoms varied among them. The proband was clinically diagnosed with AD according to the criteria of McKhann et al., 2011. Symptoms, in the form of spatial disorientation and deficits in short-term memory and attention, appeared at 53 years of age. As disease progressed, in addition to worsening memory deficits, he also displayed loss of insight, disinhibition, apathy, and psychotic symptoms. The sister of the proband began exhibiting symptoms of memory loss and depression at 57 years of age. At age 69, she was clinically diagnosed with AD, displaying spatial disorientation, loss of episodic and working memory, planning impairment, dressing apraxia, dysgraphia, and insomnia. She also suffered from frequent falls, and clinical examination revealed spastic paraparesis as well as ideomotor apraxia. In the third patient, a cousin of the proband, disease appeared earlier and progressed more rapidly. At 49 years of age, she began showing symptoms of memory loss, depression, and apathy. Cognition rapidly declined, and she was diagnosed with dementia at age 52. However, the clinical phenotype of this patient was more suggestive of frontotemporal dementia than typical AD.

An unaffected sister of the proband did not carry the M84V mutation. The mutation was not found in 100 familial AD patients or 100 healthy Italian controls, nor is it present in the gnomAD variant database (May 2021).

The mutation was also found in a study of six pedigrees with early-onset AD from the Dominantly Inherited Alzheimer Network (DIAN) Extended Registry (Hsu et al., 2018). The proband was identified in a family with three generations of early-onset AD and with a mean age at onset of 59 years. The mutation was absent from two population-based exome sequencing databases, EVS and ExAC, and from more than 1700 AD and control samples. In one presymptomatic mutation carrier, the levels of AD CSF biomarkers (Aβ, total tau, and phospho-tau) were moderately altered 11 years prior to parental age of onset, consistent with observations in other autosomal dominant AD mutation carriers.


Neuropathology in two cases was consistent with AD (Hooli et al., 2014). In addition, MRI showed diffuse cortical atrophy (most prominent in mesial temporal structures) and atrophy of the cerebellar cortex (mainly involving Crus I) in the Italian proband and his sister (Gallo et al., 2017). In their cousin, atrophy of the frontal and temporal lobes was revealed by MRI. In an asymptomatic individual, 15 and 11 years prior to parental age of onset, PiB-PET revealed a progressive increase in cortical Aβ pathology (Hsu et al., 2018).


Biological Effect

In cells transfected with PSEN1 M84V, Aβ42 levels were greater than in those expressing the wild-type protein, and the Aβ42/Aβ40 ratio was increased (Hsu et al., 2018). Although the M84V mutation is highly conserved between PSEN1 and PSEN2, was predicted to be probably damaging by PolyPhen and to be disease-causing by MutationTaster (Gallo et al., 2017; Hsu et al. 2020), and the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021), inconsistent predictions were reported by others using several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) (Xiao et al., 2021). Raptor X predicted a significant change in protein structure (Gallo et al., 2017). Based on their pathogenicity guidelines, Hsu et al. classified M84V as probably pathogenic (Hsu et al., 2020).

Last Updated: 16 Sep 2021


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Paper Citations

  1. . Rare autosomal copy number variations in early-onset familial Alzheimer's disease. Mol Psychiatry. 2014 Jun;19(6):676-81. Epub 2013 Jun 11 PubMed.
  2. . The novel PSEN1 M84V mutation associated to frontal dysexecutive syndrome, spastic paraparesis, and cerebellar atrophy in a dominant Alzheimer's disease family. Neurobiol Aging. 2017 Aug;56:213.e7-213.e12. Epub 2017 Apr 27 PubMed.
  3. . The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):263-9. PubMed.
  4. . Discovery and validation of autosomal dominant Alzheimer's disease mutations. Alzheimers Res Ther. 2018 Jul 18;10(1):67. PubMed.
  5. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
  6. . 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 variant database
  2. Hooli et al., 2014
  3. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Rare autosomal copy number variations in early-onset familial Alzheimer's disease. Mol Psychiatry. 2014 Jun;19(6):676-81. Epub 2013 Jun 11 PubMed.

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