A characteristic feature of the parvopyramidal layer of the presubiculum of 6 individuals with Alzheimer disease (AD) was the presence of large, evenly distributed amyloid-β (Aβ) deposits, which in the end stage of the disease occupy 80.9 ± 12.2 % of the parvopyramidal layer. The strong reaction of Aβ deposits with antibodies 4G8 (17–24 amino acids, aa), 6E10 (1–17 aa), and R165 (32–42 aa), and their weak reaction with antibody R162 (32–40 aa) indicate that potentially highly fibrillogenic Aβ1–42 is a major constituent of presubicular amyloid. However, Aβ deposits in the presubiculum are thioflavin-S- and Congo red-negative—and thus, nonflbrillar—even after 11 to 19 years of AD. The unique properties of presubicular amyloid appear to be related to their origin; amyloid-associated proteins such as apolipoproteins E, and AI, α1-antichymotrypsin, and heparan sulfate proteoglycan, which are promoters of fibrillization or stabilizers of Aβ in neuritic plaques, are absent; activated astrocytes, which are the source of these proteins, are also absent. The unchanged number and distribution and the resting appearance of microglial cells revealed with RCA-I histochemistry suggest that they do not respond to diffuse Aβ deposits. The source of nonflbrillar presubicular Aβ is probably local neurons or neuronal projections to the parvocellular layer of the presubiculum. Neuronal, lake-like Aβ deposition appears to be characteristic of AD pathology. The presubiculum is most likely the model brain structure for the study of amyloid of exclusively neuronal origin. The parvopyramidal layer of the presubiculum reveals only a small population of the neurons (2.5 ± 2%) affected by neurofibrillary pathology.