Alzheimer’s Second Patient: Johann F. andHis Family

Hans H. Klunemann, MD,1 Wolfgang Fronhofer,2 Herbert Wurster, PhD,2 Wolfgang Fischer, MD,3

Bernd Ibach, MD,1 and Helmfried E. Klein, MD1

Alois Alzheimer evaluated five cases of Alzheimer’s disease in the early 20th century. We focused on the family of“Johann F.,” Alzheimer’s second patient, who died in October 1910 at age 57 years, and whose brain pathology is typicalof a subgroup of Alzheimer’s disease, the so-called “plaque-only type.” It was perhaps Emil Kraepelin’s personal knowl-edge of this patient and the histological data of the other four cases that influenced Kraepelin to coin the term Alzhei-mer’s disease. The church archive in Passau has a genealogical database drawn from sacramental registers dating fromapproximately 1580 to 1900. The genealogical data of the “Johann F.” family, which comes from villages in LowerBavaria, extends as far back as 1670. We found documentation starting around 1830 about cause of death in the churchrecords, which shows a familial predisposition to dementia. Affected family members include the mother, maternalgrandfather, maternal great-aunt, maternal great-grandfather as well as three of Johann F.’s eight siblings. The offspring(children and grandchildren) of these affected siblings also were affected by mental illness. We conclude that “Johann F.”represents the index case of a family with a predisposition to presenile dementia with variable age of onset (30s to 60s).

Ann Neurol 2002;52:520–523

Alzheimer’s first patient, the 51-year-old Auguste D.initially was presented by Alois Alzheimer in 1906;then, a small series of patients was published by Alz-heimer’s pupil, Gaetano Perusini, in 1910.1–5 One yearlater, Alois Alzheimer published a report about anotherpatient, “Johann F.,” whose brain showed plaques butno neurofibrils.6–8

Auguste D. and Johann F. were the patients whomAlois Alzheimer clinically examined, whereas in theother three cases only the brains were analyzed at Alz-heimer’s laboratory. It was probably the autopsy resultsof the other cases and his clinical experience with thepatient, “Johann F.,” that convinced Emil Kraepelin tocoin the term Alzheimer’s disease in 1910.9 “Johann F.”was the only one of the five patients who actually spentany time at Kraepelin’s hospital in Munich.2 Tissuefrom this 90-year-old case of “plaque-only” Alzheimer’sdisease was rediscovered in 1994, and analysis hasshown that exon 17 of the amyloid precursor proteinhas no mutations.7 We hypothesized that establishingthe genealogy of Johann F. might yield insights intothe inheritance pattern of “plaque-only” Alzheimer’sdisease.

Subjects and MethodsThe name of Johann F. and his place of birth had been pub-lished previously. However, we chose not to publish this in-formation again. The ethics commission of the University ofRegensburg approved this study in 2000.

Records were obtained from the Munich City Archive,and sacramental registers were collected at the Catholic Ar-chives in Passau. Only the previously published first namesof the brothers, Jakob and Johann F., are used, in accordancewith Alzheimer’s convention. The other family memberswere numbered; the first number indicates the generation,and the second number identifies the individual within thatgeneration.

ResultsAlthough we traced the family back to 1670, usefuldata regarding medical illness begin to appear in thechurch records only in the early nineteenth century.The pedigree therefore begins with Johann F.’s great-grandfather (1:1) (Fig). We documented 256 individ-uals over eight generations; 79 of those 256 individualsdied before age 20 years, and for 87 other individuals adeath certificate could not be located. For 73 of the 90remaining individuals, a cause of death was recorded.

From the 1Universitatsklinik fur Psychiatrie, Regensburg; 2Archivdes Bistums Passau, Passau; and 3Bezirksklinikum Mainkofen,Deggendorf, Germany.

Received Apr 2, 2002, and in revised form May 21. Accepted forpublication May 21, 2002.

Published online Aug 19, 2002, in Wiley InterScience(www.interscience.wiley.com). DOI: 10.1002/ana.10309

Address correspondence to Dr Klunemann, University of Regens-burg School of Medicine, Department of Psychiatry, Universi-tatsstrasse 84, 93053 Regensburg, Germany.E-mail: hans.kluenemann@bkr-regensburg.de

HISTORY OF NEUROLOGY

520 © 2002 Wiley-Liss, Inc.

Of the 38 individuals who died between the ages of 40and 70 years, for whom a disease or a cause of deathwas recorded, we found disease descriptions indicatingpossible dementia in 18. The informative maternal sideof the family is shown because we found data indicat-ing possible mental illness in 16 of these maternal rel-atives of Johann F. (5:3) and in his siblings. On thepaternal side, only two mentally ill individuals weredocumented (not shown in the family tree). The re-maining individuals are not shown to enhance the clar-ity of the pedigree diagram.

There was definite consanguinity because JohannF.’s father (4:1) and mother (4:2) shared the samegreat-grandfather (1:1, see family tree). Obviously, thefamily was aware of this consanguinity because “a dis-pens in tertia gradu affinitatis” was obtained from theCatholic Church.10,11 Johann F. (5:3) was born onMarch 8, 1853, and not in 1851 as incorrectly re-corded on the admission papers of Kraepelin’s Insti-tute.9 He initially moved to Simbach/Bavaria and later,in 1889, to Munich. At first, he tried to work as awagon driver, a janitor, and a firewood salesman with-out much success. He married a 39-year-old woman

(not shown in the pedigree) on April 23, 1895 andobtained Munich citizenship in 1903. There werenever any children recorded in the various documents.Two years after his wife’s death on June 4,1905, hewas brought to Kraepelin’s new psychiatric hospital byhis brother, Jakob (5:1).

Jakob (5:1) died in 1917, 2 years after Alois Alzhei-mer’s death. Documents show that the innkeeper Ja-kob F. (5:1) himself had been “mentally incapacitatedfor 3 years” before his death at age 66 years from ap-oplexy. There is a possible autosomal dominant patternof inheritance originating from the maternal side thatcan be constructed from the church records. The ma-ternal great-grandfather (2:3) died at age 67 years frominsanity in 1832. Subject 3:2, who was the maternalgrandfather of the index patient, Johann F., died in1867 at age 66 years with a diagnosis of “hydrocepha-lus.” His sister (3:3) died at age 42 years from insanityin 1831. Subject 4:2, who is the mother of Johann F.,was diagnosed as suffering from “insolitio” before herdeath at age 49 years. The Latin term insolitus can betranslated as “unaccustomed to a thing” or “unusual.”Several of Johann F.’s siblings (5:1–Jakob F.; 5:2; and

Fig. Pedigree of Family F. Squares indicate men and circles indicate women. Deceased persons are indicated by diagonal linethrough the icon. Filled icons stand for autopsy-confirmed early-onset Alzheimer’s disease. Those cases in whom early-onset AD is apossibility are symbolized by half-filled icons. Deceased individuals in line of descent who are presumed to have transmitted theearly-onset Alzheimer’s disease trait are indicated by a dot within the icon. Icons without additional symbols stand for living familymembers who are disease free so far. Consanguineous mating is indicated by a double horizontal line. The position of the indexpatient “Johann F.” is indicated by an arrow.

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5:6) were also showing signs of mental illness. JohannF.’s second oldest brother (5:2) died at age 45 yearsalso from a severe mental illness that was not furtherdescribed at his death in 1896. The daughter (6:1) ofthe second oldest brother (5:2) died from tuberculosisat age 31 years without any recorded signs of mentalillness. Her sister (6:2) committed suicide at age 60years. The grandson (7:1) of 5:2 committed suicide atage 49 years. Finally, Subject 5:6, a sister of Johann F.,died at age 69 years after “having been mentally inca-pacitated for 2 years due to old age.” Her son (6:3)died at age 57 years from “brain disease.” A grand-daughter (7:2) of 5:6 died at age 47 years at the Main-kofen State Mental Hospital in 1976.

Case 7:2This woman was admitted to the university mental hos-pital in Munich from 1955 until 1959 and again fromNovember 25, 1974 until February 27, 1975, with adiagnosis of “paranoid-hallucinatory schizophrenia.” Shestarted to run away from her home because of “men” inher house and “got lost in the woods for hours” severaltimes in 1976. On her last admission to the Mainkofenstate mental hospital, she was disoriented, incontinent,and unable to take care of herself but had no neurolog-ical deficits. Diagnosis of dementia and “cerebral degen-eration” was made. She died of pneumonia at age 47years. Her brother (7:4) was “forgetful” and “disorderly”before he died at age 64 years in 1999. The father (6:4)of 7:2 and 7:4 had died at age 82 years; his mental sta-tus before his death is unknown. However, her grand-mother (5:6) was mentally incapacitated for 2 years be-fore her death at age 69 years.

Case 6:5Case 6:5 who was a man from the maternal side of thefamily died in 1960 at age 46 years with a diagnosis of“cerebral degeneration.” His illness had started at age 36years with “progressive memory loss” according to theMainkofen hospital file. A pneumoencephalogram at theMunich hospital showed massive cerebral atrophy at age42 years in 1956. He had been married but had no chil-dren. His father (5:10) died at age 81 years 9 monthsfrom “apoplexia cerebri” in 1953, but we have norecords regarding the cognitive status of Subject 5:10.However, the grandfather (4:3) of that patient (6:4) andJohann F.’s mother (4:2) had been siblings. Subject 4:3had been mentally ill (mente captus) for several yearsand finally “without a mind” before he died from “apo-plexie” at age 57 years in 1892. Patient 6:4 and JohannF. shared the same ancestors 3:2 and 2:3.

Finally, Johann F.’s (5:3) maternal aunt (Subject4:4) also died at age 69 years from “mental illness” dueto “brain softening” in 1905. Her married son (5:11)died from a dementing illness at age 52 years in 1910.

The living family members, 7:3 as well as 8:1 and8:2, are without symptoms thus far.

DiscussionIn Johann F.’s family, the disorder seems to follow anautosomal dominant pattern of inheritance with vari-able penetrance and variable age of onset between the30s and mid to late 60s. Looking at the genealogy ofthis family might seem to be of historical interest only.However, because the genetic cause of “plaque-only”AD is still unknown, tracing all branches of this kin-dred eventually might yield new insights into the ge-netic and nongenetic factors, which influence pen-etrance and age of onset in “plaque-only” AD.However, because we have not looked at PS1 or PS2yet, or the rest of APP, we cannot really say that thecause of “plaque-only” AD must be a new gene.7

Other AD kindreds have been reported from Ger-many.12–15 The family described by Lauter has beentraced to a founder who was born in 1771 in a villagein the Upper Palatine region of Bavaria. Several mem-bers of this family and the family reported by vonBraunmuehl died at our hospital; both families havebeen lost for follow-up, and the mutations are un-known.12,13 Another large kindred reported by PeterFrommelt and colleagues was used, among others, todefine PS1 as a gene causing Alzheimer’s disease.14,15

This kindred was traced to a couple living in Westfaliain West Germany between 1850 and 1880.14 TheVolga German families described by Bird and col-leagues originated from villages in many parts of Ger-many, but mostly from around Frankfurt and theRhineland/Hesse area.16 There are no connections ofany of these kindreds to Family F genealogically. Neu-ropathologically, the autopsy in members of these kin-dreds showed plaques and tangles.12,13,14,17 Most ofthe neuropathology in Volga German cases is typicalAD plaques and tangles. However, a few cases are pre-dominantly amyloid pathology with few tangles, in-cluding a case with mostly amyloid angiopathy.17

PS1 and APP mutations were documented in 24(71%) of 34 families with autosomal dominant early-onset AD.18 A German study looked at 16 preseniledementia patients with onset before age 60 years and apositive family history.19 Genetic analysis of the genesPS1, PS2, APP and PrP (prion protein) yielded muta-tions in 9 of the 16 patients (56%).19 In other words,there is approximately a 56 to 71% chance of finding amutation in these four genes in cases of presenile de-mentia with a positive family history. It is unlikely thatthe disorder in Johann F.’s family could be caused by amutation in the prion protein gene, because the histol-ogy of this “plaque-only” case was typical of that of Alz-heimer’s disease and spongiform changes are absent (per-sonal communication with M. Graeber, Imperial College,Faculty of Medicine, London, United Kingdom).7,20

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A minority of neuropathologically confirmed ADbrains either lack or have very few neocortical neurofi-brillary tangles, constituting a form of “plaque-only”AD. Twenty-five percent of 147 consecutive cases ofneuropathologically confirmed AD in one series wereplaque-only AD. Of the plaque-only AD cases, 75%were Lewy body variant, and only 25% were pure AD.These results indicate that most plaque-only AD isLewy body variant.21 The original 1910 glass slides of“Johann F.” were rediscovered in Munich in 1997. Re-lying on the stains from Alzheimer’s time, Lewy bodieswere not detected in the tissue sections of JohannF.7,20

One possible mutation carrier (5:10) survived untilthe age of 81 years, when he died from apoplexy. Wedo not know whether this man (5:10) was cognitivelynormal before his death or whether his stroke wascaused by a hemorrhage associated with amyloid angi-opathy. Interestingly, his father also had died from astroke after a long mental illness. Another possible mu-tation carrier survived until age 83 years (6:4). Unfor-tunately, nothing is known about the cognitive statusof 6:4. A few cases of decreased penetrance in autoso-mal dominant early-onset AD have been noted.22,23

One special problem is posed by the diagnosis “in-solitio” used to describe Johann F.’s mother. The termis most likely deduced from the term insolitus, whichcan be translated as “unusual, uncommon.” The otherpossible translation of being “unaccustomed to a thing”might be a description of apraxia. It is unlikely that theterm was confused with “insolatio” (sunstroke) becausethe highest recorded temperature in the nearby townsPassau and Eggenfelden was only 23.5 and 22.2°C, re-spectively, on the day of her death and because she hadalready passed away at 10:30 in the morning.

A possible criticism of this study is that genealogicalrecords are “soft” data, because the only informationavailable is the cause of death and, sometimes, one lineregarding any mental illness. The final proof can onlybe to compare a mutation in a living relative withDNA from Johann F.’s tissue. Hence, we will attemptto link individual patients with this large family.

We thank Drs T. Bird, P. Frommelt, M.Gerst, M.Graeber, R.W.Hamill, D. Kuprel, A. Kurz, H. Lauter, C. Lubbers, H. J. Moller,and P. St. George-Hyslop for discussions of the case and also U.Frisch from the German National weather service for the data from1880.

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