Alois Alzheimer
The encounter that conferred medical immortality on Alois Alzheimer took place in the city mental asylum of Frankfurt in December 1901, when he met the woman who became the first known case of Alzheimer’s disease. On November 25, Auguste D., age 51, had been admitted with “delerium and frenzied jealousy of her husband.” Her symptoms included cognitive and language deficits, auditory hallucinations, delusions, paranoia, and aggressive behavior. She had become unable to care for herself at home and had rejected all attempts to help her. Given her relatively young age, she was diagnosed with what we would today call “presenile dementia.”
Alzheimer had joined the staff of the asylum in 1888, after completing his medical studies in Würzburg the previous year. In Frankfurt, he began his education in psychiatry and devoted himself to his greatest interest, neuropathology. In 1895, Alzheimer was appointed director of the asylum in Frankfurt, and he continued his research on a wide range of subjects, including clinical studies of manic depression and schizophrenia. In 1889, the distinguished neurologist Franz Nissl came to work in the same asylum, and the two scientists began a long and productive collaboration, studying in particular the normal and pathological anatomy of the cerebral cortex. This work resulted in a major six-volume work (Histologic and Histopathologic Studies of the Cerebral Cortex), published between 1906 and 1918.
In 1902, the leading German psychiatrist of the time, Emil Kraepelin, invited Alzheimer to work with him at the university psychiatric clinic in Heidelberg. A year later, Kraepelin was called to the new university psychiatric clinic in Munich, and asked Alzheimer to join him. In Munich, Alzheimer established his famous anatomical laboratory, which became a mecca for students from all over the world who were interested in the clinical and anatomical correlates of diseases of the brain.
As carried out by Alzheimer and Nissl, neuropathology was as much art as science. In their studies, they took advantage of the new artificial dyes being produced by German dye makers. Nissl’s method of staining nerve cell bodies is still used today. According to one of Alzheimer’s students, Gaetano Perusini, “the chief purpose for Alzheimer’s laboratory research is the study of the pathological anatomy of psychoses: Alzheimer has the students examine the brains in the most exhaustive fashion.”
Alzheimer would spend time with each student—there were 20 microscope workstations in the laboratory—explaining things as they shared a microscope. Those who attended have described the sight of Alzheimer bowing his large head over the microscope, his pince nez dangling from a string, always with a cigar. As he commenced his explanations, he would put down the cigar. At the end of the day, his tour of the laboratory would be marked by a cigar stump at each workstation.
When Auguste D. died in June 1906, Alzheimer obtained access to her medical records, and her brain was sent to him for analysis. The pathological-anatomical investigation revealed thinning of the cerebral cortex and two further abnormalities, which remain the neuropathological hallmarks of the disease that bears his name. The first, senile plaque (“miliary foci”) had been described previously in the brains of elderly people. The second, however, was novel—neurofibrillary tangles (“dense bundles of fibers”) in the cerebral cortex. Alzheimer presented his findings at a meeting of psychiatrists in Tübingen on November 3, 1906. In his presentation, Alzheimer made the then bold assertion that her dementia was intimately related to gross neuropathological lesions in her autopsied brain. The talk was published the following year.
Alzheimer’s second case was a demented 56-year-old man, Johann F., who was admitted to the university psychiatric clinic in Munich on September 12, 1907, and died there on October 3, 1910. Like Auguste D., he had extensive plaques, but no neurofibrillary tangles in the cerebral cortex. In 1911, Alzheimer published his findings in this case together with an extensive description of the cellular pathology of Alzheimer’s disease (AD), along with several figures, mainly drawings, including several examples of the histopathology of his first case.
Alzheimer probably did not intend to define a new disease, and there has been considerable discussion on whether he thought the two cases he reported constituted a new clinical and pathological entity. The term Alzheimer’s disease was first used by his mentor, Emil Kraepelin, in the 1910 edition of his famous textbook, Handbook of Psychiatry. In his 1911 paper, Alzheimer used the term without comment, and it was adopted almost immediately by researchers in the field of dementia. However, Alzheimer seemed to believe that “his” disease might be a particularly severe form of senile dementia with an early onset.
During his years in Frankfurt, Alzheimer conducted microscopic analyses of several other conditions. He described brain changes associated with arteriosclerosis and a loss of nerve cells, most pronounced in the corpus striatum, in Huntington’s disease. He also studied brain changes in epilepsy, noting for example, a comprehensive loss of nerve cells in the hippocampus of many epileptic patients. As early as in 1907, he suggested—correctly as it turned out—that the cellular loss might be caused by the attack itself.
In 1912, Alzheimer was appointed professor of psychiatry at the University of Breslau (now Wroclaw, Poland). On the train from Munich, he became ill and had to be hospitalized upon arrival. Despite deteriorating health, he devoted the last three years of his life to research and clinical work, but never was able to begin his university duties in Breslau as intended. In 1915, at the age of 51, he died of cardiac failure.
Remarkably, AD is still diagnosed in much the same way it was a century ago. Considering the many advances in the diagnosis of other diseases over the past century, this says a lot about the quality of Alzheimer’s clinical-pathological research.
The Amyloid Hypothesis of AD
Studies of the etiology of AD were “not particularly fruitful over most of the 20th century,” according to Tanzi and Bertram, and most cases displayed no discernable mode of inheritance. In 1981, an increased incidence of dementing illness was found in the relatives of 125 patients with autopsy-confirmed AD, suggesting genetic transmission. An increased incidence of Down’s syndrome was also noted, suggesting a connection with chromosome 21. Middle-aged patients with Down’s syndrome have a high incidence of Alzheimer-type neuropathology.
Research on AD got a big boost with the 1984 report, by George Glenner and Caine Wong, of the amino acid sequence of the main component of β-amyloid—a 4-kDa peptide they called “amyloid β protein (Aβ). This study, based on an analysis of cerebrovascular amyloid from patients with Down’s syndrome, marks the beginning of the “amyloid hypothesis” of AD. According to this hypothesis, the accumulation of AΒ, as determined by the balance between its generation and clearance in the brain, is the primary driver of AD-related pathology, including neurofibrillary tangle formation, synapse loss, and neuronal cell death.
The Αβ sequence reported by Glenner and Wong and a sequence found later in amyloid-β from senile plaques led to the identification of the gene encoding amyloid precursor protein (APP). Mutations in APP were subsequently linked to early-onset familial AD (FAD). However, these mutations accounted for only a small fraction of cases, prompting a search for other FAD genes. In 1995, genes encoding presenilins 1 and 2 were reported as novel early-onset FAD genes.
In 1993, the ε4 allele of apolipoprotein E4 (apoE4) was found to increase the risk for late-onset FAD and lower the age of onset. This association was corroborated in hundreds of independent studies worldwide, and meta-analyses showed that APOE is a major susceptibility factor for AD. Much of the groundwork for the explosion of research on apoE and AD was laid at Gladstone, where apoE has long been studied for its involvement in heart disease. Gladstone investigators have also been involved in discovering roles for apoE in nervous system biology. An early example, from 1995, was the finding that neurite extension in neuronal cell is enhanced by apoE3 and inhibited by apoE4.
The link between apoE and Alzheimer’s disease prompted Gladstone to establish a “molecular neurobiology” program at Gladstone, and Lennart Mucke was recruited to head up that effort. The success of the program led to the establishment of the Gladstone Institute of Neurological Disease in 1998, with Lennart as founding director.
Sources
Alois Alzheimer. http://www.whonamedit.com/doctor.cfm/177.html. [accessed August 25, 2006].
Bick KL (1999) The early story of Alzheimer’s disease. In: Alzheimer’s Disease, 2nd ed. (Terry RD, Katzman R, Bick KL, Sisodia SS, eds) Lippincott Williams & Wilkins, Philadelphia, pp 1–9.
Graeber MB, et al. (1997) Rediscovery of the case described by Alois Alzheimer in 1911: Historical, histological and molecular genetic analysis. Neurogenetics 1:73–80.
Tanzi RE, Bertram L (2005) Twenty years of the Alzheimer’s disease amyloid hypothesis: A genetic perspective. Cell 120:545–555.
