All in the Family: Alois Alzheimer’s Second Patient Came from Extended Disease Pedigree

During his lifetime, Alois Alzheimer described five cases of the “characteristic sickness of the cerebral cortex” that his boss, the eminent psychiatrist Emil Kraepelin, later would name in honor of his late colleague. Now, neurologists in Alzheimer’s home state of Bavaria are investigating how these early patients’ family members fared. Alzheimer’s dramatic account of the 51-year-old woman Auguste D. has become a widely cited milestone in the history of this dreaded disease. Yet it may be his second patient, Johann F., who has inspired the most extensive genealogical research to date of the original five.

In an upcoming issue of Annals of Neurology, currently available online, Hans Kluenemann and colleagues at the University Hospital for Psychiatry, Regensburg, describe the first results of their effort to identify all of the estimated 3,000 past and present members of Johann F’s family. Johann F. died in 1910 at the age of 57. He is of particular interest to science because he had a form of the disease whose pathology includes plaques but no tangles. The paper reports 16 probably affected relatives found in the church records, but Kluenemann says that by now they have identified 38. They are assembling the pedigree of this extended family to identify a gene underlying this version of AD. They already have blood samples from 20 living relatives, but Kluenemann expects his team will need to find and evaluate at least 100-200 individuals.

Kluenemann et al. combed through church records in villages east of Munich along the river Inn, where the family lived for generations. These records revealed genealogical information about Johann F.’s family going back to 1670 and list the cause of death in funeral entries. In their paper, the authors report that four maternal ancestors and three of Johann’s eight siblings also had had mental illness. They conclude that Johann F. belonged to a family with a predisposition to dementia that strikes between 30 and 60 years of age. Of the roughly 2,700 deceased family members, the paper reports information on 200, but the team’s detective work to date has yielded information on 800. Kluenemann estimates that 300 are currently alive, including, perhaps, some in the U.S.

To aid in the search for living relatives, Kluenemann invites researchers who have information on autopsy-confirmed cases of "plaque-only" or "plaque-dominated" presenile dementia with age of onset before age 65 to contact him. Cases from Germany, Austria and Switzerland would be ideal, Kluenemann says, but his search is now world-wide. Please contact Hans.Kluenemann@bkr-regensburg.de. (See also Desperately Seeking Collaborators.)—Gabrielle Strobe

Comments

  1. We are a research group from Bavaria and wondered what might have happened to the ancestors and descendants of Alzheimer’s patient Johann F. He is unique because his pathology showed plaques but no tangles, and we are interested in the genetics of "plaque-only" Alzheimer’s disease. Johann F’s brain pathology is typical of this subgroup. (Actually, 75 percent of cases of plaque-only AD turn out to be Lewy-body disease, but this case did not have Lewy bodies on hematoxylin-esosin stains. The original slides are extremely valuable so we did not re-stain them. We cannot completely rule out that Johann’s family does not have Lewy-body disease, though Alzheimer’s very detailed description of Johann F does not sound like it. Lewy body dementia is defined neuropathologically, so we need another autopsied case to be sure! In any event, the gene for Lewy-body dementia is not known, either.)

    Johann F. died childless but we are in contact with living family members, all descendants of his siblings. All descendants we know are young and/or still healthy, though some of their parents had been affected. The last affected family member died in the 1970s.

    Overall, we estimate that there are 3,000 family members between 1750 and 2002. We believe that at least 300 are alive. Of course, a considerable number of individuals are lost to follow up. There was one documented case of emigration to the United States and in other cases we do not know where family members went. Did they move to Munich or did they emigrate? Did me miss some hint in the church book? Was the name misspelled? We have to do a lot of double-checking. Germany’s strict privacy laws forbid us to simply ask a health insurance company to print out the names and addresses of everyone with early onset AD. Therefore, we have used regional newspapers, local radio, and TV to recruit affected Alzheimer patients from four counties in Lower Bavaria.

    This is very time consuming-work (informing the public, contacting families, getting consent, driving all over a mountain state). Sometimes, we spend one whole day to draw blood from a single proband! Unfortunately, church books are not based on individual records that cover the whole lifespan of a person. Instead they are based on parishes and document religious events. But starting in 1803, the law required that the cause of death for any funeral be listed. This goes back to Napoleon, who had occupied Bavaria at that time. If, for example, a church book mentions that a family member married into another parish 5 miles away, we have to go through the church books of all surrounding parishes to track this person’s eventual cause of death.

    The archives contain data of the subjects of the prince bishop of Passau, who ruled large swaths of Lower Bavaria. The subjects of the prince bishop were only allowed to marry other subjects of the prince bishop. Therefore, people and their descendants stayed were they were. Members of family F. still live on the same farm were there ancestors lived in 1670. A very stable population!

    We are working on having the church book data digitized. This will eventually be an enormous resource for Alzheimer research in the region—even in the US, considering that 50 million Americans are of German descent. It would be helpful if data on all relatives was only a mouse-click away. In 1997, the Bavarian State Cultural Fonds funded a pilot project to digitize one million of the six million data sets in the church books. This took six years. We estimate that a single man could digitize the other five million data sets in 32 years. Of course, we are applying for funding to get this done quicker.

    Why is this so valuable for Alzheimer’s research? Because there is a founder population. The bishops ruled over large parts of the Bavarian forests, which is still the largest wooded area in central Europe. Around 1,700, the bishop founded "islands in a sea of trees", settlements high up in a mountainous, isolated area. The winters are extremely harsh up there. Therefore the settlements were isolated in winter and did not sustain a large population nor was there any industrial growth. In the last 50 years the area stayed isolated because the villages lie along the former "iron curtain". Areas that were settled so late and contain a founder population that is so well documented are extremely rare in Europe. We know the names of the original settlers, and we want to do more Alzheimer's research looking at other genetic forms of AD up there. But for now we concentrate on "plaque-only" AD.

    The timing of this disease is not on the detectives’ side, however. Having fallen ill in his 50s, Johann F. was unsymptomatic for several decades and lived only a few more years after the disease hit. This means there is only a relatively short time window when we can examine affected descendants. For example, we came too late in at least two cases. One family member phoned to tell us that a relative had died from Alzheimer's disease in their 50's two years ago!

    The most interesting aspect in this family’s disease is the variable age of onset (30s to 60s). We would love to identify the factors that can shift the age of onset by decades!

    View all comments by Hans Kluenemann

  2. The second Alzheimer patient may well be a FAD case. It represents a "plaque only" case and I wonder if it's like the "cotton wool" plaques seen in some PS1 mutation. I hope someone can sequence the gene to find out.

    View all comments by Edward Koo

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References

Other Citations

  1. Alzheimer’s dramatic account

Further Reading

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Primary Papers

  1. Klünemann HH, Fronhöfer W, Wurster H, Fischer W, Ibach B, Klein HE. Alzheimer's second patient: Johann F. and his family. Ann Neurol. 2002 Oct;52(4):520-3. PubMed.

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