Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, BP4
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73186898 T>C
Position: (GRCh37/hg19):Chr14:73653606 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTT to CTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was reported in the DNA of Auguste Deter, Alois Alzheimer's famous patient. The discovery of this novel presenilin-1 mutation offered an explanation to the longstanding question regarding the genetic basis of Deter's disease; however, the strength of this finding has since been called into question by a conflicting report.

Auguste D., as she is known to neuroscientists, was a German woman examined by Alzheimer in 1901 for symptoms of "presenile dementia." Her condition, characterized by memory loss and severe behavioral changes, including extreme jealousy, aggression, hallucinations, and delusions, led to her institutionalization in Frankfurt at the age of 51. She declined rapidly and died in 1906. Alzheimer examined her brain, and he reported his clinical and neuropathological findings in the landmark paper "A Characteristic Disease of the Cerebral Cortex" (Alzheimer, 1907).

In the 1990s, slides of Deter's sectioned cortex were rediscovered in the basement of the Institute of Neuropathology at the University of Munich (Graeber, 1999). Examination of the cortex confirmed the original diagnosis (Graeber et al., 1998; Enserink et al., 1998). DNA extracted from the century-old specimen showed that Deter had been homozygous for APOE ε3 (Graeber et al., 1998). Partial sequencing of PSEN1 and PSEN2, specifically exons 5 and 6 of PSEN1 and exon 5 of PSEN2, revealed a novel T>C change in PSEN1 at codon 176 (Müller et al., 2013). However, a later study was not able to validate the presence of this variant in Deter's DNA (Rupp et al., 2014). The later study also analyzed PSEN1 (exons 4-12), APP (exons 16-17), and PSEN2 (exons 4-12), but found no non-synonymous variants that could account for her disease, concluding that an as-yet-unknown mutation may be to blame.

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

Neuropathology

According to a translation of Alzheimer's 1907 paper, Deter's autopsy showed "an evenly affected atrophic brain without macroscopic foci." Alzheimer also noted neurofibrillary tangles and neuronal loss, observing that, "Eventually the nucleus and cytoplasm disappeared, and only a tangled bundle of fibrils indicated the site where once the neuron had been located." He also observed amyloid plaques that he called "miliary foci" or the "deposition of a peculiar substance in the cerebral cortex." Modern-day neuropathological analysis has confirmed the diagnosis, finding abundant amyloid plaques and neurofibrillary tangles in the cortex (Graeber et al., 1998; Enserink et al., 1998). Interestingly, Alzheimer's original preparations did not include the hippocampus or entorhinal cortex.

Biological Effect

Different assays have yielded variable results, but a comprehensive survey of Aβ peptides generated by this variant in a cell-based assay suggests it is damaging, reducing the Aβ37/Aβ42 ratio, despite its lack of an effect on the more commonly measured Aβ42/Aβ40 ratio (Liu et al., 2022; Apr 2022 news). Consistent with this finding, a previous study showed that mouse neuroblastoma cells expressing the variant secreted similar amounts of Aβ42 and Aβ40 compared with cells expressing wild-type PSEN1, and had a similar Aβ42/Aβ40 ratio (Hsu et al., 2020). In contrast, in an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate, the protein abrogated the production of Aβ40 and dramatically reduced that of Aβ42, resulting in an increase in the Aβ42/Aβ40 ratio (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).

Interestingly, cryo-electron microscopy studies of the atomic structure of γ-secretase bound to Notch or APP fragments indicate F176 directly interacts with residues from Notch, but not APP (Zhou et al., 2019; Yang et al., 2019; Jan 2019 news). The CADD-PHRED tool, which integrates diverse information about the variant, gave it a relatively low deleteriousness score, below 20 (CADD v.1.6, Sep 2021). Hsu and colleagues classified this variant as not pathogenic (Hsu et al., 2020).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because only one affected carrier has been reported and was not validated by a subsequent study. Moreover, cosegregation data are lacking, and the variant is absent, or very rare, in the gnomAD database.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

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References

News Citations

1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40? 20 Apr 2022
2. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019

Paper Citations

1. Alzheimer A. Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift fur Psychiatrie und Psychisch-gerichtliche Medizin. 1907 Jan;64:146-8.
2. Graeber MB. No man alone: the rediscovery of Alois Alzheimer's original cases. Brain Pathol. 1999 Apr;9(2):237-40. PubMed.
3. Graeber MB, Kösel S, Grasbon-Frodl E, Möller HJ, Mehraein P. Histopathology and APOE genotype of the first Alzheimer disease patient, Auguste D. Neurogenetics. 1998 Mar;1(3):223-8. PubMed.
4. Enserink M. First Alzheimer's diagnosis confirmed. Science. 1998 Mar 27;279(5359):2037. PubMed.
5. Müller U, Winter P, Graeber MB. A presenilin 1 mutation in the first case of Alzheimer's disease. Lancet Neurol. 2013 Feb;12(2):129-30. PubMed.
6. Rupp C, Beyreuther K, Maurer K, Kins S. A presenilin 1 mutation in the first case of Alzheimer's disease: revisited. Alzheimers Dement. 2014 Nov;10(6):869-72. Epub 2014 Aug 15 PubMed.
7. Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
8. Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
9. Sun L, Zhou R, Yang G, Shi Y. 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.
10. Liu L, Lauro BM, Wolfe MS, Selkoe DJ. 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;296:100393. Epub 2021 Feb 8 PubMed.
11. Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
12. Yang G, Zhou R, Zhou Q, Guo X, Yan C, Ke M, Lei J, Shi Y. Structural basis of Notch recognition by human γ-secretase. Nature. 2019 Jan;565(7738):192-197. Epub 2018 Dec 31 PubMed.

External Citations

1. gnomAD v2.1.1
2. CADD v.1.6

Further Reading