Based on molecular genetic data, researchers in Seattle proposed last year that Alois Alzheimer’s first patient likely carried the same familial AD mutation common to Volga Germans (ARF related news story on Yu et al., 2010). The evidence was circumstantial, and a study in this month’s Archives of Neurology definitively disproves the hypothesis. Sequencing DNA from century-old brain tissue of Alzheimer’s quintessential case, researchers led by Ulrich Mueller of the Institute for Human Genetics in Giessen, Germany, report that Auguste Deter did not, in fact, carry the presenilin-2 N141I mutation.

Senior author Manuel Graeber rediscovered Auguste D.’s original slides in the basement of the Institute of Neuropathology at the University of Munich while finishing his clinical training and habilitation thesis there in the 1990s (Graeber, 1999). Graeber, now at the University of Sydney in Australia, did not contribute to the Seattle study, and told ARF he has “always argued against carrying out single-gene tests on this precious material.” However, Mueller “convinced me on this one occasion.” Mueller and Graeber worked together on the original analysis (Graeber et al., 1997), Graeber wrote.

Thomas Bird and Chang-En Yu of the University of Washington, who led the Seattle analysis, wrote in response to Mueller’s findings: “We thank Dr. Mueller and colleagues for their careful molecular analysis of this valuable tissue. The etiology and biological pathogenesis initiating the early onset of neuritic plaques and neurofibrillary tangles in Auguste D. remains a mystery today, just as it was for Alzheimer more than 100 years ago.”

Having ruled out the PS2 N141I mutation, Graeber’s team plans to eventually sequence other portions of Auguste D.’s DNA to find which mutations or known AD risk variants she might have had. “But I think one should wait until technology is so mature that a complete genome scan can be done on a minute portion of this archival material,” Graeber noted. “The slides are valuable not only from a historical point of view, but their quality is such that they can serve as an inspiration for anyone with an interest in brain research (see examples here, see photos in Alois Alzheimer biographical story).”—Esther Landhuis

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  1. Was the first step of any genetic investigation, namely the study of the family history of the proband, undertaken in the case of Auguste D. beyond the succinct notes in her clinical record? Her father died aged 45 (no diagnosis given), her mother aged 64 of pneumonia, her three brothers are "healthy" (their ages not given) and "there is no mental illness in the family." Given the high "a priori" probability of dominant inheritance in instances of what is now called early-onset Alzheimer's disease (EOAD), the age at death of both her parents is within two standard deviations for affected EOAD family members (1). Incidentally, we found "pneumonia" as the registered cause of death for a number of EOAD patients in our Calabrian study. There is a 0.8 probability for at least one of her brothers and 0.5 for her daughter to have been a carrier, and a non-negligible one for contemporary descendants to be affected.

    A family reconstruction along the lines of what we did for family N (FAD1), which later came to be the index for the PS1 M146L mutation, would certainly be feasible, and interesting, and could resolve the problems raised by Mueller, Winter, and Graeber.

    References:

    . Alzheimer's disease: a model from the quantitative study of a large kindred. J Geriatr Psychiatry Neurol. 1992 Jul-Sep;5(3):126-31. PubMed.

  2. Has anyone studied the descendants of Auguste Deter?

References

News Citations

  1. Research Brief: Auguste D.'s Mutation Identified?
  2. Tuebingen: The Man Behind the Eponym

Paper Citations

  1. . The N141I mutation in PSEN2: implications for the quintessential case of Alzheimer disease. Arch Neurol. 2010 May;67(5):631-3. PubMed.
  2. . No man alone: the rediscovery of Alois Alzheimer's original cases. Brain Pathol. 1999 Apr;9(2):237-40. PubMed.
  3. . Rediscovery of the case described by Alois Alzheimer in 1911: historical, histological and molecular genetic analysis. Neurogenetics. 1997 May;1(1):73-80. PubMed.

External Citations

  1. habilitation
  2. see examples here

Further Reading

Papers

  1. . Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift fur Psychiatrie und Psychisch-gerichtliche Medizin. 1907 Jan;64:146-8.

Primary Papers

  1. . Alois Alzheimer's case, Auguste D., did not carry the N141I mutation in PSEN2 characteristic of Alzheimer disease in Volga Germans. Arch Neurol. 2011 Sep;68(9):1210-1, author reply 1211. PubMed.
  2. . Alois Alzheimer's Case, Auguste D., Did Not Carry the N141I Mutation in PSEN2 Characteristic of Alzheimer Disease in Volga Germans—Reply. Arch Neurol. 2011;68(9):1211.