The association of APOE with inherited susceptibility to typical “spo-radic” late onset AD was uncovered by the concurrence of four lines of in-vestigation. First, genetic linkage studies in pedigrees with predominantly late-onset, familially aggregated AD provided suggestive evidence (z = +2.5) for an AD susceptibility locus on chromosome 19q12-q13 near the APOE gene. Second, analysis of proteins from the CSF that were capable of binding the Aβ peptide revealed that one of the proteins was apolipoprotein E (APOE). Third, APOE is a biochemical component of the senile plaque of AD. Finally, genetic association studies by the author and Allen Roses revealed that one allelic variant of APOE (ε4) was associated with a large (13x) increase in risk for “sporadic” late onset AD113.
The APOE gene in humans contains three common polymorphisms - ε2 (cysteines at codon 112 and codon 158); ε3 (cysteines at codon 112); and ε4 (arginine at codon 112). Analysis of these polymorphisms in normal control
DISCOVERIES ARISING FROM BASIC SCIENCE STUDIES OF SPECIFIC NEURODEGENERATIVE DEMENTIAS
populations and in patients with AD by Allen Roses’ group in collaboration with the author’s group113, led to the discovery that there is an increase in the frequency of the ε4 allele in patients with AD (allele frequency in AD is approximately 40%, compared to 15% in normals), and that there is a smaller reduction in the frequency of the ε2 allele (from 10% to about 2% in AD). More significantly, there is a dose-dependent relationship between the number of copies of ε4 and the age-of-onset of AD such that each copy of ε4 reduced age-of-onset by 10 years. Thus, ε4/ε4 subjects have an earlier onset than do heterozygous ε4 subjects. Subjects with the apparently protective ε2 allele, on the other hand, have a later onset. The association between ε4 and AD has been robustly confirmed in numerous studies and in several different ethnic groups. The association is weaker with advanced age of onset.
Although the association between APOE ε4 and AD is robust, it is not spe-cific. Observations in patients with head injury114, spontaneous intracerebral haemorrhage115, and in patients undergoing elective cardiac bypass surgery116, all suggest a poorer outcome for patients with the ε4 allele. There is a confirmed association between the ε4 allele and the Lewy body variant of AD117.
The mechanism by which the ε4 allele is associated with an earlier onset of AD, and by which the ε2 allele is associated with a later onset is unclear.
The most obvious hypothesis is that APOE might influence the production, distribution, or clearance of the Aβ peptide. This hypothesis is supported by observations by the author and118 others119 that the genotype at APOE modu-lates age-of-onset in subjects carrying the APP Val717Ile mutation (but not the APP692 mutation), suggesting a direct biochemical interaction between APOE and APP (or its metabolic products) (see Figure 30 and Section IV, 2b below). Second, subjects with one or more APOE ε4 alleles have a higher Aβ peptide plaque burden than do subjects with no ε4 alleles120. In vitro studies suggest that delipidated APOE ε4 binds Aβ more avidly than APOE ε3. There is also evidence that both APOE and Aβ may be cleared through the lipoprotein-related (LRP) receptor and/or via the LDL-receptor and that APOE ε4 and the Aβ peptide may compete for clearance through the LRP and LDL-R receptors. Finally, transgenic mice expressing the APPV717F
mutation (PDAPP mice) develop profound cerebral Aβ deposition when bred on an APOE+/+ background, but have very little Aβ deposition on an APOE-/- background.
TRANSLATING DISCOVERIES IN BASIC MOLECULAR BIOLOGY, CELL BIOLOGY, AND MOLECULAR GENETICS INTO TRANSFORMATIVE APPROACHES TO THE DIAGNOSIS AND TREATMENT OF CURRENTLY INCURABLE NEURODEGENERATIVE DEMENTIAS
However, the fact that APOE ε4 is not specifically associated with AD raises the possibility that it acts by some other non-specific “off pathway”
mechanism. Along this line of thinking, an alternate hypothesis relates to changes in cholesterol metabolism in AD and their effects on Aβ metabo-lism. Both epidemiological and direct experimental evidence in cell culture models suggests that cholesterol metabolism and APP metabolism are func-tionally intertwined. Specifically, reduction in cellular cholesterol availabil-ity results in significant changes in APP trafficking and processing, with the resultant reduction in Aβ formation121. In addition, epidemiological studies on patients who have taken statins for hypercholesterolemia appear to have a reduced incidence of Alzheimer Disease (although statins have no signifi-cant effect of the disease in patients with clinically diagnosed AD)122.
Finally, there is a good correlation between the degree of clinical de-mentia and the decrease in synaptic density in AD, and it has been suggested that APOE may be involved in synaptic plasticity during regeneration and repair, and that the ε4 allele is less efficient in this role. This is in accord with clinical epidemiological data suggesting that the presence of APOE ε4 is associated with: 1) lower pre-morbid IQ scores in young adults; and 2) with a poorer outcome after a variety of unrelated CNS injuries including head injury, stroke, and coronary artery bypass grafting. It has therefore been suggested that the association between APOE ε4 and AD may not determine whether AD occurs, but rather, the clinico-pathologic response to other caus-ative factors by modulating a variety of effects including Aβ processing and regeneration-repair etc123. Indeed, these putative effects of APOE on several different mechanisms need not be mutually exclusive.
Regardless of the underlying mechanisms, the discovery of the association of AD with APOE ε4 by the same author and colleagues113 has had a profound ef-fect on both the the understanding of late onset “sporadic“ AD, and increasingly on the management of patients with typical late-onset sporadic AD. Thus, APOE genotype can be used as an adjunctive clinical test. APOE Is routinely used to partition clinical trial cohorts into more homogenous (APOE- vs APOE+) sub-groups. And APOE has recently been used as a therapeutic target in preclinical drug trials. Specifically, bexarotene has been shown to upregulate APOE levels which then caused, with a few days, a dramatic clearance of A plaques and sig-nificant improvement in cognitive function in APP transgenic mice124.
DISCOVERIES ARISING FROM BASIC SCIENCE STUDIES OF SPECIFIC NEURODEGENERATIVE DEMENTIAS