Abstract Activation products of the early complement components C1, C4 and C3 can be found colocalized with diffuse and fibrillar β-amyloid ( β/A4) deposits in Alz- heimer’s disease (AD) brains. Immunohistochemically, C1-esterase inhibitor (C1-Inh) and the C1 subcomponents C1s and C1r can not, or only occasionally, be detected in plaques or in astrocytes. The present finding that C1q, C1s and C1-Inh mRNA are present in both AD and con- trol brains suggests that the variable immunohistochemi- cal staining results for C1r, C1s and C1-Inh are due to a rapid consumption, and that the inability to detect C1s, C1r or C1-Inh is probably due to the dissociation of C1s- C1-Inh and C1r-C1-Inh complexes from the activator- bound C1q into the fluid phase. Employing monoclonal antibodies specific for different forms of C1-Inh, no com- plexed C1-Inh could be found, whereas inactivated C1- Inh seems to be present in astrocytes surrounding β/A4 plaques in AD brains. These findings, together with our finding (using reverse transcriptase-polymerase chain re- action) that C1-Inh is locally produced in the brain, sug- gest that in the brain complement activation at the C1 level is regulated by C1-Inh. Immunohistochemically, no evidence for the presence of the late complement compo- nents C5, C7 and C9, or of the membrane attack compl (MAC), was found in β/A4 plaques. In contrast to the mRNA encoding the early components, that of the complement components appears to be hardly detectab (C7) or absent (C9). Thus, without blood-brain-barrier im pairment, the late complement components are probab present at too low a concentration to allow the formatio of the MAC, which is generally believed to be responsib for at least some of the neurodegenerative effects served in AD. Therefore, the present findings support th idea that in AD, complement does not function as an in- flammatory mediator through MAC formation, but throug the action of early component activation products. Key words Complement · C1 · C1 inhibition · Alzheimer’s disease Int r oduct ion The activation products of classical pathway compleme factors C1q, C4 and C3, but not the alternative pathway factor properdin, can be found in diffuse and class plaques in the cerebral cortex and hippocampus of heimer’s disease (AD) patients [7, 8, 15, 21, 26, 28]. Cla sical pathway activation of complement in AD brains pro ably occurs through an antibody-independent activa mechanism, because IgG or IgM are absent from β/A4 plaques [9, 28, 30]. In vitro, C1q, the recognition unit o C1, can bind to the β/A4 peptide [17, 28]. In addition, ag- gregated β/A4 peptides have been shown to activate the classical pathway of complement in vitro [17, 28]. More over, decreased C1q levels in the cerebrospinal flu AD patients may correlate with the degree of dem [32], indicating that C1 activation may be involved in th neurodegenerative mechanisms in vivo. Although the presence of C1q and of C4 and C3 acti- vation products in β/A4 deposits has been unequivocally shown, that of the other C1 subcomponents C1r and C1 and of the only known inhibitor of activated C1, C1-es- terase inhibitor (C1-Inh), is not clear. C1s can be found R. Veerhuis · I. Janssen · C. E. Hack · P. Eikelenboom Early complement components in Alzheimer’s disease brains Acta Neuropathol (1996) 91 : 53–60 © Springer-Verlag 1996 Received: 6 June 1995 / Revised: 21 July 1995 / Accepted: 2 August 1995 REGULAR PAPER R. Veerhuis (Y) · I. Janssen Department of Neuropathology, Free University Hospital, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands Tel.: 31-20-4444096; Fax: 31-20-4442964 R. Veerhuis Departments of Psychiatry and Pharmacology, Free University of Amsterdam, Amsterdam, The Netherlands R. Veerhuis · R. Eikelenboom Graduate School of Neurosciences Amsterdam, Research Institute of Neurosciences Vrije Universiteit, Amsterdam, The Netherlands C. E. Hack Department of Autoimmune Diseases of the Central Laboratory for Bloodtransfusion, Amsterdam, The Netherlands P. Eikelenboom Department of Psychiatry, Free University of Amsterdam, Amsterdam, The Netherlands