alzheimer, alois

Alois Alzheimer (1864-1915)

Manuel B. Graeber

University Department of Neuropathology,Imperial College London and HammersmithHospitals Trust, London, UK

Alois Alzheimer (Fig. 1) was born on the 14th

of June 1864 in Marktbreit am Main(Germany) and died in Breslau (nowWroclaw, Poland) on December 19, 1915.Alzheimer’s most widely known contributionto the Neurosciences is the histologicaldescription of the disease that was namedafter him by Emil Kraepelin (1). However,research into this disease represents but asmall segment of Alzheimer’s clinico-pathological interests which were focused onthe histopathology of the cerebral cortex inthe mentally ill.

Figure 1 Alois Alzheimer. The original of thisprotrait is kept in the historical library of the Max-Planck-Institute of Neurobiology (formerly theTheoretical Institute of the Max-Planck-Institute ofPsychiatry, Munich), Martinsried, Germany

Through his early histopathological researchin psychiatry, Alzheimer became one of thefounding fathers of neuropathology,nurturing a unique brain research tradition in

Germany that lasted for almost a century1.Alzheimer always thought of himself as aphysician and was able to combine hisinnovative research with the demandingclinical duties of a psychiatrist.

The Man

His colleagues had a high esteem forAlzheimer’s work and also for hispersonality. In his obituary for Alzheimer,Robert Gaupp, then head of psychiatry atTübingen University and Alzheimer’spredecessor as Oberarzt2 in Kraepelin’sclinic in Munich, the Royal PsychiatricHospital, wrote: “… Alzheimer was a manwith a clear head and unusual creativepowers who took greatest pains over hiswork and had a strong sense for scientifictruth. The right training provided, thiscombination of talents had to result inoutstanding achievements in the field ofscience. This was complemented by hiswarmhearted interest in the fellow man, hismentality of a true physician, and the greatenjoyment from combining science andmedical practice. Although he mainly workedin a small, infinitely difficult specialist field,he always made sure that his research couldnot endanger the clinician and physician inhim” (4).

It was in Kraepelin’s clinic in Munich whereAlzheimer’s life as a scientist came to fullfruition. Alzheimer himself provides a shortaccount of his professional development untilhe moved to Munich in 1903. In hiscurriculum vitae, written in the same year, hestates: "The undersigned, Dr. med. AloisAlzheimer, catholic, born at Marktbreit inBavaria on the 14th of June 1864 as son ofthe Royal notary, Eduard Alzheimer,attended the elementary school atMarktbreit, the Gymnasium3 at Aschaffen-burg and the Universities of Berlin, Tübingenand Würzburg. In 1887, he passed thedoctoral exam in Würzburg (Fig. 2), and inthe following year the state examination.Subsequently, he continued working in

1 This tradition has become known as the “Munich School of Neuropathology”. Nissl, Alzheimer and Spielmeyer are credited for its creation (2). It ended with the closure of Georg Kreutzberg’s Department at the Max-Planck-Institute of Neurobiology in 2000; for additional historical information see ref. 3.2 Senior physician3 Secondary school

http://www.ibro.info/Pub/Pub_Main_Display.asp?LC_Docs_ID=3445


Würzburg for a few months in thehistological laboratory of Geheimrat4 vonKoelliker, and worked then for seven yearsas assistant physician and seven years assecond physician5 in the municipal mentalasylum in Frankfurt/Main. In order to be ableto devote more time to scientific studies, heleft this position in March 1903 after the

Figure 2 Alzheimer’s doctoral thesis on theearwax glands (Würzburg, 1888)

Hofrat6, Professor Kraepelin, promised him apost as scientific assistant in his clinic inHeidelberg. Together with ProfessorKraepelin he moved to Munich in October ofthis year." (5)7

While the decade in Munich brought out themaster of neurohistological technique inAlzheimer, his 14 years in Frankfurt (1888-1902) have to be considered foundationyears and three aspects seem of particular

4 Privy councillor5 Oberarzt, lead clinician under the Professor; from 1896, as successor to Franz Nissl who had left for Kraepelin’s clinic in Heidelberg to prepare his habilitation (see footnote 8)6 Privy Councillor, honorary7 This article contains a photo of Alzheimer’s Curriculum vitae written in “old German” (before Sütterlin)

importance: Firstly, after joining the clinicalservice run by Professor Emil Sioli at theFrankfurt Asylum, Alzheimer found himself ina unique position. He was, at the same time,able to contribute to the development of amodern clinical service while setting up ascientific patient database. In addition, hebuilt an archive of autopsy cases, on whichhe could rely during the rest of his scientificcareer. For instance, the brain of the firstAlzheimer disease patient, Auguste D., whodied in Frankfurt in 1906, was sent toAlzheimer when he was already in Munich,i.e. four years after he had left Frankfurt.Secondly, Alois Alzheimer met Franz Nissl inFrankfurt. Only four years older, Nissl hadalready established himself in the new field ofneurohistology. Nissl was widely known forhis revolutionary “Nissl staining” method fornerve cells (6) which is still in use in routineand experimental neurohistologylaboratories around the world. Nissl arrivedin Frankfurt shortly after Alzheimer andreceived an appointment as secondphysician5 in Sioli’s clinic. Alzheimer andNissl became close friends and spent muchtime together discussing findings over themicroscope. Nissl’s influence on Alzheimer’swork cannot be overestimated (7). Thirdly, in1894 Alzheimer married his beloved wifeCecilie Geisenheimer (neé Wallerstein) inFrankfurt. This marriage provided Alzheimerwith financial independence and put him in aposition to support his own research.

Immediately after his move to Munich,Alzheimer published his habilitation thesis8

on the histopathology of general paralysis ofthe insane (“Progessive Paralyse”, Fig. 3;and see ref. 8). This late complication of asyphilis infection was very common inAlzheimer’s time: about 10% of allhospitalised psychiatric patients sufferedfrom the disease. Alzheimer was able tostudy a series of 170 autopsy brainsproviding the histological knowledgeavailable on the disease today.

Alzheimer’s newly founded “neuro-anatomical laboratory” in Munich woninternational acclaim resulting in a largenumber of international visitors. The long listof names includes N. Achucarro (Spain), F.Bonfiglio (Italy), S. Casamajor (USA), U.

8 A habilitation thesis was a formal requirement for a promotion to the rank of professor in the German academic system

2


Cerletti (Italy), H.G. Creutzfeldt (Germany), B.Doinikow (Russia), A Farworsky (Russia), F.Fulci (Italy), A. Jakob (Germany), F. Lotmar(Switzerland), L. Merzbacher (Argen-tina), L.Omorokow (Russia), G. Perusini (Italy), St.Rosental (Poland) and T. Simchowicz(Poland) (5).

Figure 3 Alzheimer’s habilitation thesis ongeneral paralysis of the insane (Munich, 1904)

There are reports that Alzheimer’s laboratoryhad an unusually warm atmosphere that washighly conducive to learning and creativeresearch. As K. Kleist (5) described it,Alzheimer would return from his lunch breakat 2 pm every day, one hour earlier than hiscollaborators, and resume his work in thelaboratory. When his co-workers later joinedhim, he would walk by every seat smokinghis cigar and explain to them with greatpatience subtle neuromorphological detailsthrough the microscope. It is of note that F.H. Lewy, who discoveredthe Lewy bodies in Parkinson’s disease, wasone of Alzheimer’s visiting researchers. Lewypublished his seminal observations on Lewybodies under the Munich laboratory address.Alzheimer must have had a very high opinionof the young doctor as he selected the 27year old Dr Lewy to run his research

laboratory in Breslau. It was very unfortunatefor Lewy that Alzheimer died three years aftertaking up the chair in Breslau. Lewy paid theMunich laboratory another visit a number ofyears later when Walther Spielmeyer hadsucceeded Alzheimer as director of the worldfamous laboratory.

Alzheimer’s boss, Emil Kraepelin, was anearly founder of modern psychiatry and avisionary who propagated the idea of abiological cause of psychiatric diseases at atime when Freud was preachingpsychoanalysis. He is best known for hiswork on schizophrenia. Kraepelin created anenvironment where Alzheimer and otherbrain researchers could excel. Apart fromFranz Nissl, who even gave up his chair ofpsychiatry in Heidelberg to conduct basicresearch in Kraepelin’s institute, this grouplater also included Corbinian Brodman andEmil Jahnelt. Kraepelin was an astutepolitician who succeeded in raising fundingfor a new psychiatric research institute in themiddle of World War I. The foundation ofAlzheimer’s research laboratory was alogical consequence of Kraepelin’s originalconcept, but without Alzheimer’s successfulscientific work, Kraepelin would have hardlyhad a strong argument for the establishmentof his research institute. The lattersubsequently became the DeutscheForschungsanstalt für Psychiatry, Kaiser-Wilhelm-Institut and, after World War II, wasrenamed the Max-Planck-Institute ofPsychiatry.

The Work

Alzheimer’s work has been reviewed indepth by his successor, Walther Spielmeyer,in a very impressive obituary (7) whichappeared in a journal Alzheimer hadfounded9. The following text contains severaltranslated passages and excerpts from thisunique article.

According to Spielmeyer, Alzheimer’sresearch was characterised by a close co-operation between the anatomical sciencesand the clinic. His histological research wasguided by clinical aspects and clinicalexperiences, and, in turn, clarification of

9 See ref. 4, not to be confused with the journalshown in Figure 4

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clinical problems through scrutiny ofanatomical facts was a most importantscientific goal. Kraepelin saw this as a keyreason for Alzheimer’s importance and thegreat success of Alzheimer’s work. It is notsurprising that Alzheimer considered "casereporting" an important scientific activity. Heexplicitely stated that anatomical researchneeds to be guided by clinical experience.This concept is readily apparent from anumber of his publications (cf. Appendix).Alzheimer’s large study on general paralysisof the insane (8) is an excellent example.Starting out from clinically typical cases, thecharacteristic histological features aredetermined, novel histological observationsare compared with those in other diseases,and Alzheimer then demonstrates how thehistological differential diagnosis can be

Figure 4 The Journal founded and edited by Nissland later by Nissl and Alzheimer

used to answer clinical questions. Accordingto Spielmeyer, Nissl and Alzheimer won the“victory of anatomy in psychiatry” (7). Thescientific activity of both researchers had anemphasis on the pathology of the cerebralcortex in mental diseases quite in line withKraepelin’s concept for psychiatry (Fig. 4).

Alzheimer’s early research benefited fromthe fact that when he was a young doctor in

Professor Sioli’s asylum, experiencedcolleagues such as Weigert and Nissl werealso in Frankfurt. By 1884, Weigertpublished his technique for the visualisationof myelin sheaths, and Nissl developed hisfamous method for the detailedmorphological analysis of nerve cells.Spielmeyer emphasises the great influenceNissl had on Alzheimer. Alzheimer and Nissldid research together over many years inFrankfurt and extended their close friendshipand scientific collaboration in Heidelbergwhere Alzheimer worked as an assistant atKraepelin’s clinic between 1902 and 1903.Nissl’s strong influence on his work wasacknowledged by Alzheimer in the followingbeautiful manner (7): "I shall mention Nissl’sname as often as scientific works by him onthe topic under discussion are known to me.However, Nissl’s share in these studies doesnot end with that. The amicable scientificinteractions which I was allowed to entertainwith him over the last 15 years have givenme so much stimulation that I must concede– to give but one example – that none of thefollowing ideas that might enhance ourknowledge has been conceived without hisdirect or indirect participation."10

Alzheimer’s work on general paralysis of theinsane is among his best knownpublications. Spielmeyer suggests that anyresearch on cortical pathology has to startwith a review of Nissl’s studies but also ofthis basic publication (8) of Alzheimer’s. Forthe latter study, Alzheimer had examined 170cases of general paralysis of the insane,illustrating how common the disease was atthe time. Importantly, in this study Alzheimerrealised that the degenerative process whichunderlies this devastating illness takes placerather independently from the inflammatoryreactions. However, the exact nature of thedisease process has remained enigmatic. AsSpielmeyer pointed out (7), very little ofAlzheimer’s teachings had to be revised and,though 100 years old today, they have notbeen corrected or amended but onlyconfirmed.

10 This is from a footnote on page 20 of ref. 8. There isone more sentence in the original: “This does notpreclude the fact that Nissl may well disagree withsome views expressed here.” (“Das hindert nicht, daßvielleicht Nissl manche Auffassungen, die hierwiedergegeben sind, nicht teilen dűrfte”.)

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Working on general paralysis as a “model”cortical disease, Alzheimer delineated seniledementia, cerebral atherosclerosis, damagecaused by chronic alcoholism and acutesyphilitic infections of the brain.Furthermore, lyssa, trypanosomiasis and theanatomical basis of idiocy11 were among hisinterests. Alzheimer further recognised theneoplastic nature of the tumourous "gliamasses" in tuberous sclerosis, and he alsoworked on the anatomical basis ofHuntington’s chorea and the choreaticmovements in general. In hepatolenticulardegeneration, Alzheimer described glialchanges which now carry his name,Alzheimer type 1 and 2 astrocytes12.Atherosclerosis had been of interest toAlzheimer since the start of his scientificwork. Between 1894 and 1902, he acquireddetailed knowledge on the subject.

Figure 5 Alzheimer’s disease. Amyloid plaquespredominantly in the upper cortical layers ofAuguste D.’s (9) brain as described by Alzheimer(10) (from ref. 11)

Alzheimer went on to demonstrate thatBinswanger’s "Encephalitis subcorticalischronica" was not inflammatory in nature.His studies on atherosclerosis led Alzheimerto investigate other senile processes and

11 Extreme mental retardation12 See neuropathological textbooks for further

explanation

notably dementia. Alzheimer’s studies on thepathology of the cerebral cortex culminatedwith the publication of his now famous shortarticle providing the first description of theneurofibrillary tangles in the first Alzheimerpatient, Auguste D. (10) (Figs. 5-8). In a later,more comprehensive review article that waspublished in 1911, Alzheimer discussesvarious aspects of the disease (12). It maycome as a surprise to many today that it wasalready clear at Alzheimer’s time that there

Figures 6 and 7 Amyloid plaques at highermagnification (from ref. 13)

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are no fundamental differences between thehistological substrate of the classical(presenile) form of Alzheimer’s disease andsenile dementia. Alzheimer himself viewedclassical (presenile) Alzheimer’s disease asan atypical form of senile dementia (7).Alzheimer’s work answered the importantquestion of whether the senile dementingprocess depends on atherosclerosis or otherregressive vascular changes. It became clearthat cerebral atherosclerosis and seniledementia are fundamentally differentdiseases.

Epilepsy forms part of another large diseasegroup Alzheimer worked on to defineanatomical subtypes. He stated: "If we aim tounderstand the nature of a disease, topredict its prognosis, to elucidate its courseand finally treat it prophylactically ortherapeutically, we must have clear,precisely defined disease entities before us.What we call epilepsy today, however, doesnot represent such an entity but apparentlyencompasses a whole group of differentdisorders." Alzheimer correctly pointed outthat many cases of epilepsy show scleroticchanges of the “Ammonshorn”. He alsoemphasised the importance of studying thebreakdown of nervous tissue and the types ofacute neuroglial responses in epilepticbrains.

A review of his life’s work reveals that therewere two main periods of Alzheimer’sscientific activity. The first period ended withhis habilitation in 1904 and the publication ofthe corresponding article on generalparalysis (8). After he had moved to Munich,Alzheimer wrote that in a few promising earlyinstances, pathological anatomy hadsuccessfully demonstrated that diseasescharacterised by dementia and paralysis,respectively, may be caused by differenttissue processes (7). This was important asWernicke had proposed that "mentaldiseases with an anatomical correlate" maybe caused by essentially the same diseaseprocess. Thus, the responses of theneuroglia would differ only in quantitativeterms and disease-associated changes of theneurons would also not show alterationstruly characteristic of the respective diseaseprocess. Alzheimer, however, demonstratedclearly that neither the pathologicalphenotype profile of a case nor theaccompanying glial response manifest

themselves as simple quantitativephenomena. Therefore, Alzheimer believedit to be a prime task of the "corticalanatomist" to determine theneuromorphological specifics of a diseaseprocess and to document all subtledifferences in comparison to other corticalpathologies. Fortunately, Alzheimer’sextensive histological material of his twopublished Alzheimer cases is now accessibleand will be made freely available to thegeneral public in due course13.

Figure 8 A neurofibrillary tangle, first describedby Alzheimer in Auguste D.’s brain (from ref. 13)

This original research material beautifullydemonstrates that the histological stainsproduced by Alzheimer’s laboratory were ofthe highest quality, a prerequisite, in fact, forhis meticulous tissue analyses. In particular,Alzheimer realised that the responses of theneuroglia are strongly dependent on the typeand intensity of a disease process.Furthermore, he was aware of the diagnosticdifficulties surrounding a claimed “specifichistopathology” associated with schizo-phrenia and warned against anyoverinterpretation.

13 http://www.microglia.net/AD_100yrs_Book.html

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Like many great scientists, Alzheimer hadproblems with the academic establishment ofhis time. Rumoured to be "only ananatomist", it was an inordinately long timebefore he was awarded a full professorship inrecognition of his achievements. Looking athis published works (see Appendix) therumour was obviously wrong. The synergiesbetween Alzheimer’s anatomical and clinicalstudies have fostered the development ofpsychiatry and notably neuropathology likevery few other research programmes.Alzheimer is rightly considered a foundingfather of neuropathology and his life’sachievements exemplify the strong roots thisdiscipline has, and needs to have, in theclinical neurosciences.

Figure 9 Alzheimer’s research motto14

Alzheimer was an optimist. Difficultiesstimulated him to find novel ways in newterritories. He formulated his approach toresearch on the occasion of the 25th

anniversary of Prof. Dr. Emil Sioli’sdirectorship of the Frankfurt mental asylum(Fig. 9.; cited in ref. 7, originally from ref. 49in the Appendix). Alzheimer was ameticulous worker and never publishedprematurely. During one of his rare visits tothe neuroanatomical laboratory, Kraepelincommented that Alzheimer’sneuroanatomical “mills would grind ratherslowly” (5). Spielmeyer comments onAlzheimer’s publication policy: “Alzheimernever had to fight for recognition for hisresearch work. The clarity of his oralpresentations and writings convinced even adistant observer about the importance of hisresults. At these times [!]15 of prolific

14 “(Denn) nicht übermässige Bedenken und lähmendeVerzagtheit helfen den Wissenschaften vorwärts undhaben ihnen vorwärts geholfen, sondern eingesunder Optimismus, der in froher Zuversicht nachneuen Wegen der Erkenntnis sucht, da er überzeugtist, dass sie zu finden sein werden”.

15 Spielmeyer wrote this in 1916 (7)

publishing16 where everyone believes to havesomething of importance to say and wheremany advertise the little things they find overand over again, Alzheimer never took thefloor unless he had something trulyimportant to say." The scientific enterprisehas continued to move forward since thenand the result speaks for itself: as ofSeptember 2003, a search of the Medlinedatabase retrieves > 40,000 entriescontaining the term “Alzheimer”, and aGoogle search yields 2,070,000 hits. Acomplete list of Alzheimer’s published worksis attached to this article (see Appendix).

Acknowledgements

I am indebted to Karin and the late JohannaStöltzing for their help with decipheringAlzheimer’s handwritten Curriculum vitae.Special thanks go to Ingrid Holzinger and DrJames Chalcroft, Max-Planck-Institute ofNeurobiology, Martinsried, Germany, for ascan of Alzheimer’s portrait (Figure 1) and forhelp (I.H.) with obtaining several ofAlzheimer’s publications. Furthermore, I amgrateful to Emilie M. Croisier, London,Professor Richard B. Banati, Sydney, and DrStephen Gentleman, London, for commentson the manuscript. I would also like to takethis opportunity to thank the OpenSourcecommunity for making the OpenOfficesoftware package freely available, which wasused for the preparation of this manuscripton a computer running GNU/Linux. The textof this publication is published under theICDNS GPL (general public license, seewww.ICDNS.org for further information).

I would like to dedicate this article toProfessor Georg W. Kreutzberg, Munich, andto the memory of the “Munich School ofNeuropathology”.

Web links

1. A current international neuropathologicalconsensus definition of Alzheimer’s diseasecan be found at

www.ICDNS.org,

a web site of the International Society of

16 Original: Vielschreiberei

7

"EXCESSIVE RESERVATIONS ANDPARALYSING DESPONDENCY HAVE NOTHELPED THE SCIENCES TO ADVANCE

NOR ARE THEY HELPING THEM TOADVANCE, BUT A HEALTHY OPTIMISM THAT CHEERFULLY SEARCHES FOR NEW

WAYS TO UNDERSTAND, AS IT ISCONVINCED THAT IT WILL BE POSSIBLE

TO FIND THEM."


Neuropathology.

2. A book, "100 Years of Alzheimer’sDisease", is scheduled to appear in 2006 andwill be published under a general publiclicense. The book will illustrate all (>400)histological tissue sections used byAlzheimer for his research into the diseasethat was named after him, see

http://www.microglia.net/AD_100yrs_Book.html

Favourite Sentences

"Excessive reservations and paralysingdespondency have not helped the sciencesto advance nor are they helping them toadvance, but a healthy optimism thatcheerfully searches for new ways tounderstand, as it is convinced that it will bepossible to find them."

References

1. Kraepelin E (1910) Psychiatrie. Ein Lehrbuchfür Studierende und Ärzte. II. Band, KlinischePsychiatrie. Verlag Johann Ambrosius Barth,Leipzig

2. Spatz H (1961) Franz Nissl. In: Scholz W (ed)50 Jahre Neuropathologie in Deutschland(1885-1935). Thieme, Stuttgart, pp 43-66

3. Graeber MB (1999) No man alone: Therediscovery of Alois Alzheimer’s original cases.Brain Pathology 9:237-240

4. Gaupp R (1916) Alois Alzheimer. MünchenerMedizinische Wochenschrift 6:195-196

5. Meyer JE (1961) Alois Alzheimer. In: Scholz W(ed) 50 Jahre Neuropathologie in Deutschland(1885-1935). Thieme, Stuttgart, pp 67-78

6. Kreutzberg GW (1984) 100 years of Nisslstaining. Trends in Neurosciences 7: 236-237

7. Spielmeyer W (1916) Alzheimer’s Lebenswerk.Zeitschrift fűr die gesamte Neurolologie undPsychiatrie 33:1-44

8. Alzheimer A (1904) Histologische Studien zurDifferentialdiagnose der progressivenParalyse. Nissl’s histologische undhistopathologische Arbeiten 1: 18-314

9. Maurer K, Volk S, Gerbaldo H (1997) AugusteD. and Alzheimer’s disease. Lancet 349:1546-1549

10. Alzheimer A (1907) Über eine eigenartigeErkrankung der Hirnrinde. AllgemeineZeitschrift fűr Psychiatrie 64:146-148

11. Graeber MB, Mehraein P (1999) Reanalysis ofthe first case of Alzheimer’s disease. EuropeanArchives of Psychiatry and ClinicalNeuroscience 249 Suppl 3:10-13

12. Alzheimer A (1911) Über eigenartige

Krankheitsfälle des späteren Alters. Zeitschriftfűr die gesamte Neurologie und Psychiatrie4:356-385

13. Graeber MB, Kosel S, Grasbon-Frodl E,Moeller HJ, Mehraein P (1998) Histopathologyand APOE genotype of the first Alzheimerdisease patient, Auguste D. Neurogenetics1:223-228

Address of the author:

Manuel B. Graeber MD PhD MRCPathProfessor of Neuropathology Honorary Consultant, HammersmithHospitalsTrustUniversity Department of NeuropathologyNeurosciences Division, Faculty of MedicineImperial College London, Charing Cross CampusFulham Palace Road, London, W6 8RF, [email protected]/manuel.html

Appendix

Publications of Alois Alzheimer (translatedtitles in italics)

1. Alzheimer A (1888) Ueber dieOhrenschmalzdruesen [On the earwax glands].Inaugural-Dissertation [Medical doctoralthesis], Koenigliche Julius-Maximilians-Universitaet Wuerzburg; 20 pages17 and 2plates with illustrations

2. Alzheimer A (1891) Ueber einen Fall vonspinaler progressiver Muskelatrophie mithinzutretender Erkrankung bulbaerer Kerneund der Rinde [On a case of spinal progressivemuscular atrophy with additional disease ofbulbar nuclei and the cortex]. Archiv fuerPsychiatrie 23, 459; 27 pages and 1 plate withillustrations

3. Alzheimer A (1894) Die Paralysis progressivader Entwicklungsjahre [Progressive paralysisof adolescence]. Neurologisches Centralblatt13, 732; 1 page

4. Alzheimer A (1894) Die arteriosklerotischeAtrophie des Gehirns [The arterioscleroticatrophy of the brain]. NeurologischesCentralblatt 13, 765; 3 pages

5. Alzheimer A (1895) Kolloide Entartung desGehirns [Colloid degeneration of the brain].Neurologisches Centralblatt 14, 886; 1 page

6. Alzheimer A (1895) Ueber die durch Druck aufden Augapfel hervorgerufenen Visionen [Onvisual phenomena caused by pressure appliedto the eye bulb]. Centralblatt fuer

17 Page and plate numbers are provided wherepossible

8


Nervenheilkunde und Psychiatrie 6, 473; 6pages

7. Alzheimer A (1896) Die Fruehform derallgemeinen progressiven Paralyse [The earlyform of general progressive paralysis].Allgemeine Zeitschrift fuer Psychiatrie 52, 533;62 pages

8. Alzheimer A (1896) Ein „geborener Verbrecher“[A „born criminal“]. Archiv fuer Psychiatrie undNervenkrankheiten 28, 327; 27 pages

9. Alzheimer A (1896) Ueber die anatomischeAusbreitung des paralytischen Degene-rationsprozesses [On the anatomical spreadingof the paralytic degeneration process].Neurologisches Centralblatt 15, 1007; 1 page

10. Alzheimer A (1896) Fuenf Faelle, in welchensich neben einer hochgradigen Arterio-skleroseder Gefaesse disseminierte Herde in derRinde, den Markleisten und im tiefen Markfinden [Five cases in which, in addition tosevere arteriosclerosis of the blood vessels,disseminated foci are found in the cortex, thecortical and the deep white matter]. Ref.18

Centralblatt fuer Nervenheilkunde undPsychiatrie 7, 549; 1 page

11. Alzheimer A (1897) Ueber rueckschreitendeAmnesie bei der Epilepsie [On retrogradeamnesia in epilepsy]. Centralblatt fuerNervenheilkunde und Psychiatrie 8, 316; 2pages

12. Alzheimer A (1897) Das Delirium acutum [Theacute delirium]. Monatsschrift fuer Psychiatrieund Neurologie 2, 64; 2 pages

13. Alzheimer A (1897) Beitraege zurpathologischen Anatomie der Hirnrinde und zuranatomischen Grundlage einiger Psychosen[Contributions to the pathological anatomy ofthe cerebral cortex and the anatomical basis ofsome psychoses]. Monatsschrift fuerPsychiatrie und Neurologie 2, 82; 39 pagesand 3 plates with illustrations

14. Alzheimer A (1897) Ein Fall von luetischerMeningomyelitis und –encephalitis [A case ofluetic meningomyelitis and –encephalitis].Archiv fuer Psychiatrie 29, 63; 17 pages and 1plate with illustrations

15. Alzheimer A (1897) Ueber perivasculaereGliose [On perivascular gliosis]. AllgemeineZeitschrift fuer Psychiatrie und psychisch-gerichtliche Medicin 53, 863; 3 pages

16. Alzheimer A (1898) Die Colloidentartung desGehirns [The colloid degeneration of the brain].Archiv fuer Psychiatrie 30; 37 pages and 1plate with illustrations

17. Alzheimer A (1898) Ein Beitrag zurpathologischen Anatomie der Epilepsie [Acontribution on the pathological anatomy ofepilepsy]. Monatsschrift fuer Neurologie undPsychiatrie 4, 345; 25 pages and 2 plates withillustrations

18. Alzheimer A (1898) Neuere Arbeiten ueber dieDementia senilis und die auf atheromatoeserGefaesserkrankung basie-renden

18 Referat

Gehirnkrankheiten [Newer studies on seniledementia and brain diseases caused byatheromatous vascular disease]. Monatsschriftfuer Psychiatrie 3, 101; 15 pages

19. Alzheimer A (1899) Beitrag zur pathologischenAnatomie der Seelen-stoerungen desGreisenalters [Contribution on the pathologicalanatomy of the disturbances of the soul at highage]. Neurologisches Centralblatt 18, 95; 2pages

20. Alzheimer A (1900) Einiges zur pathologischenAnatomie der chronischen Geistesstoerungen[On the pathological anatomy of chronic mentaldisturbances]. Allgemeine Zeitschrift fuerPsychiatrie und psychisch-gerichtliche Medizin57, 597; 3 pages

21. Alzheimer A (1902) Die Seelenstoerungen aufarteriosklerotischer Grundlage [Disturbances ofthe soul caused by arteriosclerosis].Allgemeine Zeitschrift fuer Psychiatrie undpsychisch-gerichtliche Medizin 59, 695; 17pages

22. Alzheimer A (1902) Ueber atypische Paralysen[On atypical paralyses]. Allgemeine Zeitschriftfuer Psychiatrie und psychisch-gerichtlicheMedizin 59, 170; 5 pages

23. Alzheimer A (1904) Histologische Studien zurDifferentialdiagnose der progressiven Para-lyse [Histological studies on the differentialdiagnosis of progressive paralysis]. Nissl’shistologische und histopathologische Arbeiten1; 297 pages and 14 large plates withillustrations

24. Alzheimer A (1904) Histologische Studien zurDifferentialdiagnose der progressiven Para-lyse [Histological studies on the differentialdiagnosis of progressive paralysis]. Ludwig-Maximilians-Universitaet Muenchen [Habili-tation thesis]

25. Alzheimer A (1904) Einiges ueber dieanatomischen Grundlagen der Idiotie [Somefindings on the anatomical basis of lunacy].Centralblatt fuer Nervenheilkunde undPsychiatrie 15, 497; 9 pages

26. Alzheimer A (1904) Das Delirium alcoholicumfebrile Magnan’s [The alcoholic febrile deliriumof Magnan]. Centralblatt fuer Nervenheilkundeund Psychiatrie 15, 437; 5 pages

27. Alzheimer A (1905) Haben wir bei denverschiedenen Geisteskrankheiten mitanatomischem Befund einen histologischannaehernd gleichen Krankheitsprozessvorauszusetzen? [Do we have to postulate ahistologically very similar disease process indifferent mental diseases with anatomicalfindings?] Neurologisches Centralblatt 24, 680;3 pages

28. Alzheimer A (1905) Progressive Paralyse undendarteriitische Hirnlues [Progressive para-lysis and endarteritic lues cerebri]. Centralblattfuer Nervenheilkunde 16, 443; 3 pages

29. Alzheimer A (1906) Ueber den Abbau desNervengewebes [On the degradation of thenervous tissue]. Allgemeine Zeitschrift fuer

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Psychiatrie und psychisch-gerichtliche Medi-zin 63, 568; 5 pages

30. Alzheimer A (1906) Ueber einen eigenartigen,schweren Erkrankungsprozess der Hirnrinde[On a peculiar, severe disease process of thecerebral cortex]. Neurologisches Centralblatt25, 1134 [reference to the lecture only, noabstract]

31. Alzheimer A (1906) Zur pathologischenAnatomie der Paralyse und derparalyseaehnlichen Erkrankungen [On thepathological anatomy of paralysis andparalysis-like diseases]. Muenchenermedizinische Wochenschrift 53, 1643; 1 page

32. Alzheimer A (1907) Ueber eine eigenartigeErkrankung der Hirnrinde [On a peculiardisease of the cerebral cortex]. Zeitschrift fuerPsychiatrie 64, 146; 3 pages

33. Alzheimer A (1907) Einige Methoden zurFixierung der zelligen Elemente derCerebrospinalfluessigkeit [Several methods offixation for cellular elements of thecerebrospinal fluid]. Centralblatt fuerNervenheilkunde und Psychiatrie 18, 449; 3pages

34. Alzheimer A (1907) Die Gruppierung derEpilepsie [The categorisation of epilepsy].Allgemeine Zeitschrift fuer Psychiatrie undpsychisch-gerichtliche Medizin 64, 418; 4pages

35. Alzheimer A (1907) Ueber die Indikationen fuereine kuenstliche Schwanger-schaftsunterbrechung bei Geisteskranken [Onindications for an induced abortion in lunatics].Muenchner Medizinische Wochenschrift 54,1617; 5 pages

36. Alzheimer A (1907) Die stationaere Paralyse[The stationary paralysis]. AllgemeineZeitschrift fuer Psychiatrie und psychisch-gerichtliche Medizin 64, 670 (656); 8 pages

37. Gaupp R, Alzheimer A (1907) Die Frage derstationaeren Paralyse der Irren [The questionof stationary paralysis of the lunatics].Centralblatt fuer Nervenheilkunde undPsychiatrie 245; 18 pages

38. Alzheimer A (1909) Die syphilitischenGeistesstoerungen [The syphilitic mentaldisturbances]. Allgemeine Zeitschrift fuerPsychiatrie und psychisch-gerichtliche Medizin66, 920; 10 pages

39. Alzheimer A (1910) Ueber Degeneration undRegeneration an der peripheren Nervenfaser[On degeneration and regeneration at theperipheral nerve fibre]. Zeitschrift fuer diegesamte Neurologie und Psychiatrie Ref. 1,654; 2 pages

40. Alzheimer A (1910) Beitraege zur Kenntnissder pathologischen Neuroglia and ihrerBeziehungen zu den Abbauvorgaengen imNervengewebe [Contributions on theunderstanding of the pathological neurogliaand their relationships to the breakdownprocesses in nervous tissue]. (Nissl’s-Alzheimer’s) Histologische und

Histopathologische Arbeiten. Band 3, 401; 162pages and 8 plates with illustrations

41. Alzheimer A (1910) Die diagnostischenSchwierigkeiten in der Psychiatrie [Thediagnostic difficulties in psychiatry]. Zeitschriftfuer die gesamte Neurologie und Psychiatrie 1,1

42. Alzheimer A (1911) Ueber die anatomischeGrundlage der Huntingtonschen Chorea undder choreatischen Bewegungen ueberhaupt[On the anatomical basis of Huntington’schorea and the choreatic movements ingeneral]. Zeitschrift fuer die gesamteNeurologie und Psychiatrie 3, 566; 2 pages

43. Alzheimer A (1911) Ist die Einrichtung einerpsychiatrischen Abteilung im Reichs-gesundheitsamt erstrebenswert? [Is theestablishment of a psychiatric department atthe central (“Reichs”) health authoritydesirable?]. Zeitschrift fuer die gesamteNeurologie und Psychiatrie 6, 242; 5 pages

44. Alzheimer A (1911) Ueber eigenartigeKrankheitsfaelle des spaeteren Alters [Onpeculiar cases of disease at higher age].Zeitschrift fuer die gesamte Neurologie undPsychiatrie 4, 356; 30 pages and 2 plates withillustrations

45. von Hoesslin C, Alzheimer A (1912) EinBeitrag zur Klinik und pathologischenAnatomie der Westphal-StruempellschenPseudosklerose [A contribution on the clinicalfeatures and the pathological anatomy of thepseudosclerosis Westphal-Struempell]. Zeit-schrift fuer die gesamte Neurologie undPsychiatrie 8, 183; 27 pages and 1 plate withillustrations

46. Alzheimer A (1912) Ergebnisse auf demGebiete der pathologischen Histologie derGeistesstoerungen [Results in the field of thepathological histology of mental distur-bances].Zeitschrift fuer die gesamte Neurologie undPsychiatrie 5, 753; 28 pages

47. Alzheimer A (1912) Die Bedeutung derSymptomenkomplexe in der Psychiatrie,besonders im Hinblick auf das manisch-depressive Irresein [The importance ofsymptom complexes in psychiatry, especiallywith respect to manic-depressive disease].Zeitschrift fuer die gesamte Neurologie undPsychiatrie Ref. 5, 806; 5 pages

48. Alzheimer A (1913) Ueber noch nicht genauerbekannte paralyseaehnliche Krankheitsbilder[On paralysis-like disorders that are not yetknown in detail]. Zeitschrift fuer die gesamteNeurologie und Psychiatrie Ref. 6, 1074; 2pages

49. Alzheimer A (1913) 25 Jahre Psychiatrie. EinRueckblick anlaesslich des 25jaehrigenJubilaeums von Prof. Dr. Emil Sioli als Direktorder Frankfurter Irrenanstalt [25 years inpsychiatry. A look back on the occasion of the25th anniversary of Prof. Dr. Emil Sioli’sdirectorship of the Frankfurt mental asylum].Archiv fuer Psychiatrie und Nervenkrankheiter

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52, 853; 14 pages50. Alzheimer A (1913) Ueber die

Abbauvorgaenge im Nervensystem [On thedegradation processes in the nervous system].Zeitschrift fuer die gesamte Neurologie undPsychiatrie Ref. 8, 81; 2 pages

51. Alzheimer A (1913) Beitraege zurpathologischen Anatomie der Dementiapraecox [Contributions on the pathologicalanatomy of the dementia praecox]. Zeitschriftfuer die gesamte Neurologie und Psychiatrie,Ref. 7, 621; 2 pages

52. Alzheimer A (1913) Ueber zwei verschiedeneTypen von Entwicklungshemmungen desGehirns [On two types of developmentalmalformations of the brain]. Zeitschrift fuer diegesamte Neurologie und Psychiatrie, Ref. 8,289; 2 pages

53. Alzheimer A (1914) Ueber einen Fall vonPoliomyelitis bulbi et cerebelli [On a case ofpoliomyelitis bulbi et cerebelli]. Zeitschrift fuerdie gesamte Neurologie und Psychiatrie, Ref.8, 534; 1 page

54. Alzheimer A (1914) Ueber einen Fall von„hysterischer Bulbaerparalyse“ [On a case of„hysterical bulbar palsy“]. Zeitschrift fuer diegesamte Neurologie und Psychiatrie, Ref. 8,534; 2 pages

55. Alzheimer A (1914) Ueber den gegenwaertigenStand der Lehre von der Epilepsie [On thecurrent status of the teaching on epilepsy].Deutsche medizinische Wochenschrift 40,1451; 1 page

56. Alzheimer A (1915) Faelle vonMethylalkoholvergiftung [Cases of methylalcohol intoxication]. Deutsche medizinischeWochenschrift 41, 635; 1 page

57. Alzheimer A (1916) Ueber eine eigenartigeErkrankung des zentralen Nervensystems mitbulbaeren Symptomen und schmerzhaftenspastischen Krampfzustaenden der Extremi-taeten [On a peculiar disease of the centralnervous system with bulbar symptoms andpainful spastic cramps of the extremities].Zeitschrift fuer die gesamte Neurologie undPsychiatrie 33, 45; 15 pages and 1 page withillustrations [posthumous, edited by W.Spielmeyer]

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