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A presenilin 1 mutation in the first case of Alzheimer's disease

2012; Elsevier BV; Volume: 12; Issue: 2 Linguagem: Inglês

10.1016/s1474-4422(12)70307-1

1474-4465

Ulrich Müller, Pia Winter, Manuel B. Graeber,

Dementia and Cognitive Impairment Research

Auguste Deter is undoubtedly one of the most famous patients in medical history. She was the middle-aged woman in whom Alois Alzheimer first reported on “eine eigenartige Erkrankung der Hirnrinde” (a peculiar disorder of the cerebral cortex) more than a century ago.1Alzheimer A Über eine eigenartige Erkrankung der Hirnrinde.Allg Zeitschr Psychiatr. 1907; 64: 146-148Google Scholar The patient came to Alzheimer's attention when she was admitted to his psychiatric service at age 51 years, because of substantial forgetfulness accompanied by hallucinations. Dementia progressed rapidly and she died 5 years later, in 1906, at age 56 years. Neuropathological analysis of her cerebral cortex revealed many amyloid plaques and neurofibrillary tangles. Plaques and tangles—of which tangles were first discovered by Alzheimer in the brain of this patient2Graeber MB History of neuroscience: Alois Alzheimer (1864–1915). IBRO History of Neuroscience.http://www.ibro.info/Pub/Pub_Main_Display.asp?LC_Docs_ID=3445Date: 2003Google Scholar—are the neuropathological hallmarks of Alzheimer's disease as we now understand it. Originally, the term Alzheimer's disease referred to presenile dementia as reported by Alzheimer in Auguste Deter and in another patient. The use of the term is now broader than the original definition and includes the much more common senile form of dementia of the Alzheimer type.3Terry RD Davies P Dementia of the Alzheimer type.Ann Rev Neurosci. 1980; 3: 77-95Crossref PubMed Scopus (288) Google Scholar The neuropathological changes are indistinguishable between classic presenile Alzheimer's disease (now referred to as early-onset Alzheimer's disease), which occurs in patients younger than 65 years, and senile or late-onset Alzheimer's disease, which occurs in patients aged 65 years or older. Most cases of Alzheimer's disease have a multifactorial cause—ie, both genetic variants and environmental factors contribute to disease. The ɛ4 allele of the apolipoprotein E gene (APOE) is the most important predisposing genetic variant4Roses AD A model for susceptibility polymorphisms for complex diseases: apolipoprotein E and Alzheimer's disease.Neurogenetics. 1997; 1: 3-11Crossref PubMed Scopus (74) Google Scholar and the most important environmental factor is advanced age. In a small percentage (<2%) of cases, Alzheimer's disease is inherited as an autosomal dominant trait. Mutations in any of three genes can cause autosomal dominant Alzheimer's disease. These are the genes for amyloid precursor protein (APP) on chromosome 21, presenilin 1 (PSEN1) on chromosome 14, and the closely related presenilin 2 (PSEN2) on chromosome 1. Patients with autosomal dominant disease usually have an early onset. Both the patient records of Auguste Deter and the histological slides prepared from her brain in Alzheimer's laboratory have been rediscovered.5Maurer K Volk S Gerbaldo H Auguste D and Alzheimer's disease.Lancet. 1997; 349: 1546-1549Summary Full Text Full Text PDF PubMed Scopus (257) Google Scholar, 6Graeber MB Kösel S Grasbon-Frodl E Möller HJ Mehraein P Histopathology and APOE genotype of the first Alzheimer disease patient, Auguste D.Neurogenetics. 1998; 1: 223-228Crossref PubMed Scopus (64) Google Scholar Neuropathological reanalysis confirmed the original diagnosis.6Graeber MB Kösel S Grasbon-Frodl E Möller HJ Mehraein P Histopathology and APOE genotype of the first Alzheimer disease patient, Auguste D.Neurogenetics. 1998; 1: 223-228Crossref PubMed Scopus (64) Google Scholar, 7Enserink M First Alzheimer's diagnosis confirmed.Science. 1998; 279: 2037Crossref PubMed Scopus (14) Google Scholar Her APOE genotype was ɛ3/ɛ3.6Graeber MB Kösel S Grasbon-Frodl E Möller HJ Mehraein P Histopathology and APOE genotype of the first Alzheimer disease patient, Auguste D.Neurogenetics. 1998; 1: 223-228Crossref PubMed Scopus (64) Google Scholar The early disease onset and the absence of the genetic risk allele ɛ4 suggested that she might have had an autosomal dominant form of the disorder. This notion also fitted with her aggressive histopathology—characterised by an abundance of cortical tangles in addition to numerous amyloid plaques.6Graeber MB Kösel S Grasbon-Frodl E Möller HJ Mehraein P Histopathology and APOE genotype of the first Alzheimer disease patient, Auguste D.Neurogenetics. 1998; 1: 223-228Crossref PubMed Scopus (64) Google Scholar Because mutations in PSEN1 are the most common cause of autosomal dominant Alzheimer's disease,8Alzheimer Disease & Frontotemporal Dementia Mutation Databasehttp://www.molgen.ua.ac.be/ADMutationsGoogle Scholar we analysed PSEN1 in DNA extracted from a histological section of Auguste Deter's brain (appendix p 1). In exon 6 we found a T→C substitution at position 526 (c.526T→C; figure). This change is predicted to result in a Phe176Leu aminoacid substitution in the protein. Exon 6 mainly codes for the third transmembrane domain of presenilin 1.9Alzheimer's Disease Collaborative GroupThe structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families.Nat Genet. 1995; 11: 219-222Crossref PubMed Scopus (465) Google Scholar The findings were confirmed in independent DNA extractions. As negative control, the same region of exon 6 of PSEN1 was sequenced in DNA extracted from paraffin-embedded control tissue (appendix p 2). A sequence artifact was ruled out by confirmation of the results in different DNA preparations, the sequencing of both DNA strands, the absence of sequence changes in other parts of exon 6 and in exons 5 of both PSEN1 and PSEN2, and the absence of the observed sequence change in the paraffin-embedded control tissue. Several findings suggest that the c.526T→C substitution caused the disease in Auguste Deter: first, no single nucleotide polymorphism has been reported at this nucleotide position; second, the phenylalanine at position 176 and flanking aminoacids have been conserved during evolution (appendix p 3), which suggests an important function; and third, the mutation affects an aminoacid within the third transmembrane domain. The adjacent aminoacid (phenylalanine at position 177) has previously been shown to be changed in autosomal dominant Alzheimer's disease (Phe177Leu);10Rogaeva EA Fafel KC Song YQ et al.Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations.Neurology. 2001; 57: 621-625Crossref PubMed Scopus (191) Google Scholar this finding emphasises the importance of this domain of presenilin 1 for the normal function of the protein. In summary, the PSEN1 mutation in Auguste Deter is consistent with the clinical findings and uncovers the cause of disease in this important historical case. We declare that we have no conflicts of interest. UM was supported by the Bundesministerium für Bildung und Forschung (BMBF; Brain Net grant 01GI0299). Download .pdf (.23 MB) Help with pdf files Supplementary appendix