Neurotoxic Fragments of Apolipoprotein E4 as a Biomarker for Alzheimer’s Disease and Other Neurodegenerative Disorders. INVENTORS

Apolipoprotein E (apoE) is the main transporter of cholesterol in the central nervous system (CNS) and is essential for neuronal maintenance and repair. ApoE polymorphisms in humans profoundly affect the structure and function of apoE and interfere with normal cellular metabolism. These polymorphisms arise from single-amino-acid substitutions at residues cys-112 and arg-158; among the three isoforms produced, apoE4 assumes a unique conformation resulting from an intramolecular domain interaction. This makes apoE4 more susceptible to misfolding and instability, leading to proteolysis and the generation of neurotoxic apoE fragments. These fragments, in turn, cause mitochondrial dysfunction, cytoskeletal alterations, and ultimately neuronal death. ApoE4 is a well-recognized genetic risk factor for Alzheimer’s disease (AD), while the proteolytic activity driving fragment production is another potential parameter of AD risk. Longitudinal studies of AD patients and age-matched controls indicate a marked association between apoE fragments and disease. Moreover, this extends beyond apoE4 since apoE3 can also be cleaved to the same fragments, but this normally occurs to a much lesser extent. However, in patients with high proteolytic activity, toxic fragment levels in apoE3 carriers can reach those of their apoE4-expressing counterparts. This might account for why some apoE3 carriers develop AD. Importantly, it demonstrates that the measurement of fragment levels can provide important diagnostic information beyond that achieved with simple apoE genotyping. The apoE4 allele also negatively impacts clinical outcomes following traumatic brain injuries and has been associated with the pathogenesis of multiple sclerosis, fronto-temporal dementia and stroke. It appears that an apoE4 genotype sets the stage and that a variety of second hits determine the exact nature of the manifested pathology. Recognition of the importance of apoE4 to AD has resulted in patients being genotyped for apoE4, and, in drug trials, segregated into a separate group. Furthermore, scientists at the Gladstone have recognized that apoE genotype is only part of the story, with proteolytic fragment quantitation providing another key indication of AD risk.