Alzheimer briefly reported the clinical and pathological findings in 51-year-old woman at a meeting held in 1906.1 In 1911, he described the precise pathology, senile plaques (Drusen) and neurofibrillary tangles, in a second case with onset at 54 years of age.2 Because Alzheimer used the Bielshowsky silver method, he clearly showed the process of neurofibrillary tangle formation in the AD brain (Fig. 1b–d). He described extracellular tangles that were penetrated by glial processes (Fig. 1d). Alzheimer proposed the independence of AD as an entity showing a special form of senile dementia. He described the difference between AD and senile dementia as follows: young onset in the 6th decade; focal symptoms, such as aphasia, apraxia and agnosia; severe psychosis and rapid progression; and serious neurodegeneration. In 1910, Kraepelin,3 who directed Alzheimer, described AD in his textbook including that AD may be ‘senium praecox’, a more or less age-independent unique disease process, because AD sometimes starts around the age of 40 years.
In 1989, Redlich4 described the presence of numerous senile plaques, miliare Sklerose, in the brains of two subjects with senile dementia (Fig. 2). This was the first report of senile plaques in senile dementia. In 1906, when Miyake5 visited Obersteiner's laboratory in Vienna, he examined the brains of 26 aged subjects and found numerous senile plaques, Gliarosetten, in two of three brains with senile dementia, although he found no senile plaques in 23 non-demented subjects. Miyake5 also reported a case of vascular dementia as Dementia arteriosklerotica. In 1911, Simchowicz6 examined a large number of aged brains: 40 with senile dementia, 11 non-demented subjects, six with dementia praecox, six with arteriosclerotic dementia, nine other forms of senile psychosis, two dogs (aged 12 and 17 years) and one horse (aged 22 years). Simchowicz6 showed the importance of the size, arrangement and number of plaques rather than the presence or absence of senile plaques for the pathological diagnosis of senile dementia, because senile plaques sometimes appear in non-demented brains or in other forms of senile psychosis. In 1907, 1910 and 1912, Fischer7–9 examined 158 brains and divided dementia into three groups: (i) PresbiophreneDemenz (senile dementia), with numerous senile plaques, in 72 cases (46%); (ii) Einfachen senilen Demenzen (simple dementia), without senile plaques, in 42 cases (27%); and (iii) arteriosklerotic dementia in 44 cases (28%). Fischer found senile plaques in two of 35 (6%) non-demented subjects. Based on these results, he proposed that the presence of massive senile plaques is a characteristic feature of senile dementia. Furthermore, he precisely examined the brains using the Bielschowsky silver method and classified senile plaques into eight forms.8 One of the eight forms, Diffuse Infiltration des nervösen Gewebes durch die fäedigen Massen (Fig. 3), is diffuse plaques, which was later found by β protein immunostaining.10 Diffuse plaques were lost from the history of AD neuropathology after that time, because the major method used to examine brains after World War II was Bodian silver staining on paraffin sections, which does not recognize small amounts of amyloid.11 In the 1970s, diffuse plaques found in aged brains using the Bielschwsky method were considered an artefact (i.e. a non-specific adhesion of silver particles). However, in the late 1980s, these plaques were found with β protein immunostaining and were termed ‘diffuse plaques’ because their morphology is quite similar to that of the Diffuse Infiltration des nervösen Gewebes durch die fäedigen Massen.10 Uyematsu12 examined 100 brains with senile psychosis in 1923, when he visited Boston. He also classified senile plaques and reported a ‘diffuse form without nuclear-like central mass’, which is just a diffuse plaque.