MEDICAL HYPOTHESES AND RESEARCH
VOL. 6, No. 1/2, July 2010
R. Perneczky, et al.  Med. Hypotheses Res. 6: 19-24.
Does the Apolipoprotein E Genotype Influence Amyloid
Precursor Protein Sorting by Sortilin-Related Receptor:
Implications for Alzheimer’s Disease?
Robert Perneczky†*, Panagiotis Alexopoulos†, Tamara Eisele,
Hans Förstl and Alexander Kurz
Department of Psychiatry and Psychotherapy, Technische Universität München, München,
Abstract. The amyloid hypothesis of Alzheimer’s disease (AD) argues that the cerebral
accumulation of amyloid is a primary driver of AD pathology, including amyloid plaque
deposition, neurofibrillary tangle formation, synapse loss and neuronal cell death. Many
lines of evidence support this hypothesis, and some major players of the cascade have been
identified, including the amyloid precursor protein (APP), apoliprotein E (APOE), the beta-
site APP cleaving enzyme (BACE1), and the sortilin- related receptor (SORL1). However, the
processes that finally lead to amyloid accumulation are still poorly understood. Recent
evidence suggests that SORL1 is able to switch away APP from the amyloidogenic cleavage
by BACE1. It has also been suggested that SORL1 activity is influenced by its ligand APOE.
Alterations in the three-dimensional structure and in the binding properties of APOE related
to the APOE4 genotype may cause changes in the interaction between SORL1 and APOE.
These changes could affect the capacity of SORL1 to bind to APP, resulting in a reduced
retention of APP by SORL1 in subcellular compartments. It appears promising to investigate
possible associations between distinct single nucleotide polymorphisms within the SORL1
gene and the cerebrospinal fluid products of the amyloid cascade, and to test if these
associations are modified by the APOE genotype. This may considerably enhance our
understanding of the pathological processes leading to AD.
† The first two authors contributed almost equally.
* Correspondence: Dr. Robert Perneczky, Department of Psychiatry and Psychotherapy,
Ismaninger St 22, 81675 München, Germany. Tel: + 49 89 4140-6055. Fax: + 49 89 4140-4888.