Ž . Brain Research 843 1999 87–94 www.elsevier.comrlocaterbres Research report Apolipoprotein E and b-amyloid levels in the hippocampus and frontal cortex of Alzheimer’s disease subjects are disease-related and apolipoprotein E genotype dependent Uwe Beffert a,b , Jeffrey S. Cohn c , Caroline Petit-Turcotte a,b , Michel Tremblay c , Nicole Aumont b , Charles Ramassamy b , Jean Davignon c , Judes Poirier a,b, ) a Department of Neurology and Neurosurgery, McGill UniÕersity, Montreal, Quebec, Canada H4A 2B4 b Douglas Hospital Research Centre, 6875 BlÕd. LaSalle, Verdun, Quebec, Canada H4H 1R3 c Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal, 110 Pine AÕenue West, Montreal, Quebec, Canada H2W 1R7 Accepted 20 July 1999 Abstract Ž . Ž . The e 4 allele of apolipoprotein E apoE is associated with increased risk for the development of Alzheimer’s disease AD , possibly Ž . due to interactions with the b-amyloid Ab protein. The mechanism by which these two proteins are linked to AD is still unclear. To further assess their potential relationship with the disease, we have determined levels of apoE and Ab isoforms from three brain regions of neuropathologically confirmed AD and non-AD tissue. In two brain regions affected by AD neuropathology, the hippocampus and frontal cortex, apoE levels were found to be decreased while Ab levels were increased. Levels of apoE were unchanged in AD 1–40 cerebellum. Furthermore, levels of apoE and Ab were found to be apoE genotype dependent, with lowest levels of apoE and highest 1–40 levels of Ab occurring in e 4 allele carriers. These results suggest that reduction in apoE levels may give rise to increased deposition 1–40 of amyloid peptides in AD brain. q 1999 Published by Elsevier Science B.V. All rights reserved. Keywords: Apolipoprotein E; b-Amyloid; Alzheimer’s disease 1. Introduction Ž . Apolipoprotein E apoE is a polymorphic protein of growing interest in the central nervous system due to the association of one common allele, the e 4 allele, with Ž . w x Alzheimer’s disease AD 9,33,37 . Polymorphisms in the apoE gene at two different sites yield three common alleles in the general population: e 2, e 3 and e 4 which give rise to w x their respective proteins apoE2, apoE3 and apoE4 44,49 . These proteins can be distinguished by isoelectric focusing due to charge differences arising from amino acid substitu- tions at sites 112 and 158 of the 299 amino acid protein. apoE2 contains a cysteine at both sites, apoE3 contains AbbreÕiations: Ab, amyloid b peptide; AD, Alzheimer’s disease; apoE, apolipoprotein E; ELISA, enzyme-linked immunosorbent-assay; LRP, low density lipoprotein receptor related protein ) Corresponding author. Department of Neurology and Neurosurgery, McGill Centre for Studies in Aging, 6825 Blvd. LaSalle, Verdun, Que- bec, Canada H4H 1R3. Fax: q 1-514-888-4099; E-mail: mcjp@musica.mcgill.ca cysteine at site 112 and arginine at site 158 while apoE4 w x possesses arginine at both mutation points 36,45 . These specific amino acid changes in the apoE protein lead to various biochemical and functional changes which are currently being investigated in order to better explain the association of the e 4 allele of apoE with AD. Several hypotheses point toward an apoE isoform spe- cific effect related to the apoE protein which supports the genetic association with AD. Since apoE synthesis is in- creased following a number of different models of neu- ronal injury, one of these hypotheses concerns a direct role for apoE in neuronal remodelling and neurite outgrowth. Using a variety of models, several laboratories have now shown that apoE3 and apoE4 differentially modulate neu- rite outgrowth, generally with apoE3 demonstrating in- creased outgrowth while apoE4 either inhibits or is less w x efficient 6,10,13,17,31,32,34,42 . Another hypothesis involves a direct interaction of apoE with the neurotoxic b-amyloid protein, a protein directly implicated in AD by virtue of its isolation from the 0006-8993r99r$ - see front matter q 1999 Published by Elsevier Science B.V. All rights reserved. Ž . PII: S0006-8993 99 01894-6