Apolipoprotein E and ALzheimer's Disease: The Tip of the Susceptibility Iceberg

Abstract

Apolipoprotein E (APOE) is a true susceptibility polymorphism of the common form of Alzheimer's disease (AD). There are three APOE alleles (epsilon 2, epsilon 3, epsilon 4) that are universally distributed in the population with some variation in allele frequency due to racial and ethnic differences, and are associated with different risks and age of onset distributions. In multiple studies, the positive predictive value for symptomatic possible or probable AD patients who carry at least one epsilon 4 allele was consistently > 95%. Thus, early in the clinical course of dementia, when diagnoses are only 60-70% accurate, the presence of an epsilon 4 allele raises the diagnostic accuracy of AD to 95%. With the anticipation of a second major late-onset AD susceptibility locus on chromosome 12, a matrix of relative susceptibility risks in the population raises many ethical and social questions associated with preclinical prediction. The metabolism of apoE (protein) in the brain is a new and exciting area of neurobiology research made relevant by the association with AD. We have constructed transgenic animals using large human genomic fragments containing human APOE on an APOE-deficit mouse background as well as homologous recombination experiments replacing mouse APOE with human APOE promoter elements. The APOE tissue elements, NOT the human APOE gene coding sequence, is associated with the human pattern of intraneuronal apoE immunoreactivity.

Effect of COMT Val 108/158 Met genotype on frontal lobe function and risk for schizophrenia

“…In some respects, our results with COMT and schizophrenia are similar to the calpain-10 association with diabetes (63), and the association of the APO e4 allele with Alzheimer's disease, although the APO e4 effect is much greater (64). The calpain-10 allele is found in 75% of the general population and in 80% of diabetics, a weak association that is not easily replicated across populations, and the biologic effect of the polymorphism is unknown.…”

Association of late-onset Alzheimer's disease with genetic variation in multiple members of the GAPD gene family

“…It follows that genetic mutations affecting various steps of the A␤ pathway, such as A␤ production, degradation͞ clearance, deposition, and neuronal apoptosis, could be associated with AD. Indeed, a number of such candidate genes have been reported to be risk factors for late-onset AD (LOAD), although so far only apolipoprotein E (APOE) has been confirmed by multiple independent studies (6). However, only Ϸ50% of AD cases carry an APOE4 allele, ‡ ‡ and genetic studies have predicted that at least four other genes modify age of disease onset (7).…”

Apolipoprotein E4 Forms a Molten Globule

“…One of the common human apoE isoforms, apoE4, is a major risk factor for Alzheimer's disease (3)(4)(5) and atherosclerosis (6 -8). ApoE4 is also associated with poor recovery from head injury and stroke (9 -11), cognitive decline associated with coronary bypass surgery (12), increased severity of tissue damage in multiple sclerosis (13), shortening of survival after the onset of amyotrophic lateral sclerosis (14), and a poor response to other forms of central nervous system stress (15).…”