The effect of apolipoprotein E (ApoE) genotype on biomarkers of amyloidogenesis, tau pathology and neurodegeneration in Alzheimer's disease

The presence of the epsilon 4 allele in apolipoprotein E (ApoE) represents the most important genetic risk factor for late onset sporadic Alzheimer's disease (AD), together with age and mid-life hypercholesterolemia. ApoE4 is the most important lipid transporter between cells in the CNS and it was found that ApoE4 is involved in Amyloid beta (A beta) formation, fibrilisation, accumulation, in the aggregation and hyperphosphorylation of tau and in the metabolism of brain cholesterol and in neurodegeneration. Low cerebrospinal fluid (CSF) A beta 1-42 is a marker of A beta plaque load in the brain. High CSF t-tau and p-tau concentrations reflect axonal and neuronal damage and injury, which correlates with a neurofibrillary tangle stage and load, also reflecting the intensity of the disease process. Magnetic resonance imaging (MRI) brain atrophy is a biomarker of neurodegeneration and is the result of loss of neurons, synapses and dendritic arborization. ApoE genotype interacts with the AD biomarkers: epsilon 4 carriers were found to present with lower concentrations of Ab1-42, higher tau and p-tau, higher tau/A beta ratio and a higher degree of brain atrophy at any disease stage, changing the test performances and the ability to distinguish between the different cognitive condition. The presence of the epsilon 4 allele was also found to increase the power to predict further cognitive decline. Even if the presence of ApoE4 is not a deterministic factor for AD, it seems to shift the progression of the disease towards a younger age and faster progression. It is also likely that the epsilon 4 allele increases the intensity of the pathological process in several ways. In the study of cognitive impaired patients and in their follow-up, biomarkers should be interpreted in consideration of the ApoE genotype in order to better predict the progression of the disease.