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.
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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!
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.