Abstract To assess whether amyloid plaque accumulation in the monkey brain can account for age-related cognitive impairment that begins at about 20 years of age, we mea- sured plaque content in the brains of 14 rhesus monkeys aged 5–30 years. We used immunohistochemistry employ- ing the monoclonal antibody 6E10, which is specific to amino acids 1–17 of the amyloid β peptide to identify amy- loid plaques in serial coronal sections of the forebrain. Amy- loid plaques accumulate with age, starting at 25 years of age and escalating after 30 years. Until the age of 30, plaques are only found in a few monkeys and are relatively sparse. Re- sults from our group and others show that plaque content and the proportion of individuals afflicted with amyloid plaques increase with age. Although both cognitive dysfunc- tion and plaque content increase with age, amyloid plaque content does not correlate with the cognitive dysfunction ob- served in elderly monkeys since even in very old subjects some cognitively impaired animals have few amyloid plaques and others with abundant plaques show only minor cognitive impairments. In summary, amyloid plaques appear to accumulate significantly only in monkeys over 25 years of age but do not appear to be a causal factor in age-related cognitive decline of the normal aging rhesus monkey. Key words Aging · Rhesus · Macaca mulatta · 6E10 · Amyloid Introduction Aging deleteriously impacts cognition and the cellular in- tegrity of the brain. Some mechanisms that are considered relevant to normal aging in the brain include oxygen free radical formation [8, 12, 38], neurotrophin desensitization [41], loss of calcium homeostasis [26], mitochondrial mu- tations [11], blood-brain barrier changes [18, 28], and amine accumulation [42], among others. While aspects of the molecular mechanisms of these changes have been identified, little work has yet been done to determine how these are related to age-associated cognitive decline. Several histopathological features, such as accumula- tion of amyloid plaques, neurofibrillary tangles (NFTs), and the formation of dystrophic neurites, characterize the brains of aged human subjects, with much higher numbers of these structures occurring in Alzheimer’s disease (AD). A major component of amyloid plaques, the amyloid β peptide (Aβ), appears to be toxic to neurons and the prin- cipal etiological agent of AD. The Aβ is derived from a range of larger 115- to 140-kDa amyloid precursor pro- teins produced by alternative splicing. The Aβ peptide can be 40 or 42 amino acids long and the longer form pos- sesses high self-aggregating properties due to its greater hydrophobicity [44]. Although this longer form is com- mon in amyloid plaques found in late-onset AD, the shorter form is more abundant in monkeys [15, 19]. The rhesus monkey serves as a useful model of normal aging of the human central nervous system in which age- associated cognitive impairment can be compared to its as- J. A. Sloane · M. F. Pietropaolo · D. L. Rosene · M. B. Moss · A. Peters · T. Kemper · C. R. Abraham Lack of correlation between plaque burden and cognition in the aged monkey Acta Neuropathol (1997) 94 : 471–478 © Springer-Verlag 1997 Received: 17 June 1996 / Revised, accepted: 12 May 1997 REGULAR PAPER J. A. Sloane Department of Pathology, Boston University School of Medicine, 80 E. Concord Street, Boston, MA 02118, USA M. F. Pietropaolo · C. R. Abraham () Department of Biochemistry, Boston University School of Medicine, 80 E. Concord Street, Boston, MA 02118, USA Tel.: 1-617-638-4308; Fax: 1-617-638-5226; e-mail: cabraham@bu.edu C. R. Abraham Department of Medicine, Boston University School of Medicine, 80 E. Concord Street, Boston, MA 02118, USA M. B. Moss · T. Kemper Department of Neurology, Boston University School of Medicine, 80 E. Concord Street, Boston, MA 02118, USA D. L. Rosene · M. B. Moss · A. Peters · T. Kemper Department of Anatomy and Neurobiology, Boston University School of Medicine, 80 E. Concord Street, Boston, MA 02118, USA D. L. Rosene · M. B. Moss · A. Peters Yerkes Regional Primate Research Center, Emory University, Atlanta, GA 30322, USA