Familial plaque-only Alzheimer’s disease
|Art der Förderung:||Standard Projekt|
|Institution:||Universität Regensburg, Universitätsklinik für Psychiatrie|
|Projektleitung:||Dr. Hans-Hermann Klünemann|
|Laufzeit:||01. Mai 2004 - 31. Oktober 2004|
Introduction: One of five cases described by Alois Alzheimer belonged to the rare ‘plaque-only’ subtype of Alzheimer disease. The brain of this patient, Johann F., showed an abundance of unusually large plaques, but not the other hallmark of Alzheimer’s disease, tangles. One remarkable clinical sign was the loss of language in this patient in addition to his memory deficit.
Hypothesis: Plaque-only AD is inherited and is caused by a so far unknown genetic alteration in an unidentified gene. The variable penetrance of this genetic factor leads to variable age of onset between the fourth and seventh decade of life.
Preliminary results: According to our genealogical data there is a familial predisposition to dementia with variable age of onset (thirties to sixties) in this family from villages in the counties Passau and Rottal-Inn. We have documented a predisposition to dementia in this Bavarian family as far back as 1750 and possess genealogical data of 1247 members of this kindred. The total number of family members between 1750 and today is estimated to be circa 3000 persons. In deceased 53 individuals we found disease descriptions indicating possible dementia. So far we have identified 22 living adult family members, one of these 22 is affected by dementia. The genetic work-up of this patient is in progress. The counties Passau and Rottal-Inn have about 301,034 inhabitants (Source Bavarian Statistical Yearbook 2000).
Specific aims: To make sure to identify all living affected members of this kindred we will recruit 300 AD patients with symptom onset before age 70.
Methods: The search for living affected family members is still in progress. We are cooperating with other Bavarian neurology and psychiatry hospitals, but patient recruitment will also be through primary care physicians, local neuropsychiatrists, Alzheimer care centers, reports in local Radio and TV stations as well as newspaper articles in the local press. We already produced a TV documentary about this project.
Long-term goal: to identify the gene causing plaque-only Alzheimer’s disease as rational basis for therapeutic strategies.
We have been following the kindred of Alois Alzheimer`s 2nd patient Johann F for the last five years. The Munich physician Alois Alzheimer published the autopsy of this man in 1911 because of the unusually large and numerous plaques found in this brain. The early-onset of dementia at 54-years made a genetic component to his disease quite likely. However, data about the family history were not mentioned in the original 1911 article. In 1997 the results of a genetic analysis of Johann F. ruled a mutation in the APP gene and a causative ApoE4 genotype out (Graeber et al. 1997).
Four diseases show plaques on histological brain sections and could have been the cause of dementia in Johann F.: Alzheimer disease, Dementia with Lewy-Bodies, Familial British Dementia and Creutzfeldt-Jakob disease (CJD). We therefore tested DNA samples from the affected family members with a positive family for mutations in associated genes (Alzheimer: PS1,PS2 and APP), Familial British Dementia (BRI) and CJD (PRNP). Mutations in these five genes are being be ruled out.
In 2000 we set out to initially establish the genealogy of Johann F. and found description of mental illness in several maternal ancestors of Johann F. as well as in the death records of half of his eight siblings indicating dementia with onset before age 70y in a fashion that affects about half of the members in each generation. We send letters to about 2000 former in-patients of four mental hospitals and asked to return our survey when they came from the region. Several families returned our survey and some of the probands were related to the family of Johann F. Most these probands had the earliest signs of dementia before age 70, but were between 70 and 80 years of age when we drew blood samples. We modified our strategy and teamed up with the GSF, the Göttingen Institute of Anthropology and the Munich Institute of Neuropathology in addition to the CRND (Toronto) to solve this medical mystery. We sent letters to more than 300 phsyicians in two counties and asked for help. Twenty-four physicians returned our survey who care for several hundred dementia sufferer, but only few patients fulfilled our inclusion criteria. The main reasons were later onset of dementia and a history of alcohol abuse.
We also collected blood samples from the healthy spouses of dementia patients from and asked for the family history of the so called “spousal controls”: almost half of the dementia patients with age of onset before age 70y with regional ancestors had 1st degree relatives with dementia, while none of the spousal controls reported a dementia in their first degree relatives. In addition, we started feed our data and blood samples into the system of the Danubian Biobank Initiative www.danubianbiobank.de that will store the samples and make them available to other researchers.
We then wanted to know who good the genealogical data are. We asked the Institute of Anthropology of Göttingen University to analyze the Y-Chromosome of seven men who carry the same family name as Johann F. and the tissue of Johann F. Preliminary genetic data indicate that the genealogies are quite accurate We also needed better data about the degree of inbreeding in the Passau region. Inclusion citeria were a) absence of mental illness and b) probands as well as both parents had to be born in the region. However, the blood samples of more than 100 healthy volunteers from a soccer club and members of the local genealogical society are still being analysed at the GSF research center in München-Neuherberg.
Wissenschaftliche Publikationen auf Basis des geförderten Projekts
Klünemann, H.H., Ridha, B.H., Magy, L., Wherrett, J.R., Hemelsoet, D.M., Keen, R.W., De Bleecker, J.L., Rossor, M.N., Marienhagen, J., Klein, H.E., Peltonen, L., Paloneva, J. (2005). The genetic causes of basal ganglia calcification, dementia and bone cysts: DAP12 and TREM2. Neurology, 64:1502-1507.
Klünemann, H.H., Kloiber, S., Wurster, H., Klein, H. (2004). Familiäre plaque-only Alzheimerkrankheit in den Landkreisen Rottal-Inn und Passau. Psychiatrische Praxis, 31(1):61-63.
Klünemann, H.H., Rogaeva, E., Neumann, M., Kretzschmar, H.A., Kandel, M., Toulina, A., Sato, C., Salehi-Rad, S., Pfister, K., Klein, H.E., St George-Hyslop, P.H. (2004). Novel PS1 Mutation in a Bavarian Kindred. Alzheimer Dis Assoc Disorders,18:256-258.