Should the ApoE genotype be a covariate for clinical trials in Alzheimer disease?

Should the apolipoprotein E (ApoE) genotype be a covariate for clinical trials in Alzheimer disease (AD)? ApoE is a transport protein for lipids, amyloid-beta proteins, and the different phenotypes differentially affect amyloid-beta deposition, neurofibrillary tangle formation, and microglial activation. The ApoE genotype has not affected efficacy in short symptomatic AD trials. ApoE4 has been associated with greater efficacy in at least two mild cognitive impairment studies. Vasogenic edema was more frequent in ApoE4 AD patients treated with a monoclonal antibody to amyloid beta. Since there is evidence that the ApoE genotype may differentially affect disease mechanisms, efficacy, and adverse effects in both AD and mild cognitive impairment trials, the ApoE genotype should be included as a covariate in future studies.

In clinical drug trials, it is appropriate to include as a covariate (a) any factor that is likely to diff erentially aff ect underlying rates of disease progression or (b) factors that are likely to diff erentially aff ect potential known mechanisms of action of the drug being studied or (c) both. With regard to therapeutic drug trials in Alzheimer disease (AD), a frequent and appropriate concern is whether the apolipoprotein E (ApoE) genotype should be taken as a covariate in statistical analyses regarding effi cacy or adverse eff ects. Th e ApoE ε4 genotype is the major genetic risk factor identifi ed for AD. Th e ApoE ε4 genotype is associated with earlier age of onset for the disease, with heterozygous patients having a 50% chance of dementia in their mid to late 70s and homozygous patients having a 50% chance of dementia in their mid to late 60s. Th e odds ratio for developing dementia also goes up signifi cantly with gene dose. Th ese associations hold true for both sporadic and familial forms of the illness. Pathologically, inheritance of the E4 genotype has been associated with greater total amyloid deposition in the brain, both in cortical plaques and in the vessels, and increased neurofi brillary tangles [1,2]. In mild cognitive impairment (MCI) or very-early-stage AD, the E4 genotype is asso ciated with greater defi cits on the New York Paragraph Recall test, Auditory-Verbal Learning Test, and Buschke test at baseline. On magnetic resonance imaging, there are increases in both hippocampal atrophy and global atrophy at baseline [3], and on positron emission tomo graphy using FDG (fl uorine-18fl uorodeoxy glucose), there are greater defi cits in glucose metabolism in the posterior parietal and parahippocampal regions. In MCI subjects with the E4 genotype, cerebrospinal fl uid analyses typically have shown decreased levels of the protein amyloid beta (Aβ) 1-42 and increased levels of Tau and pTau [4].
With regard to mechanisms of action with potential relevance to AD, the ApoE protein has been demonstrated to have several functions, which include its roles as a major cholesterol-carrying protein in plasma and as the primary lipid-carrying transport protein in the central nervous system [5]. Th e ApoE protein also functions as a major transporter for the Aβ proteins [6]. Th e ApoE2, E3, and E4 protein phenotypes have diff erential affi nities for lipids and Aβ and consequent variable effi ciencies in these transport roles. Th ere is evidence in neuropathological studies of AD patients of greater microglial activation around Aβ plaques in patients with the ApoE 4 genotype [7]. Th ese patients also demonstrate greater abnormal phosphorylation of Tau. In summary, the diff erent ApoE2, E3, and E4 genotypes code for diff erent ApoE protein phenotypes, which result in functional variation in the actions of this protein as it plays roles that virtually span known and theorized disease mechanisms involved in the pathogenesis or progression (or both) in AD.
With regard to the infl uence of the ApoE genotype on clinical factors of potential importance in AD clinical trials, there may be diff erential eff ects related to disease stage, trial length, and the specifi c eff ects of the drug Abstract Should the apolipoprotein E (ApoE) genotype be a covariate for clinical trials in Alzheimer disease (AD)? ApoE is a transport protein for lipids, amyloid-beta proteins, and the diff erent phenotypes diff erentially aff ect amyloid-beta deposition, neurofi brillary tangle formation, and microglial activation. The ApoE genotype has not aff ected effi cacy in short symptomatic AD trials. ApoE4 has been associated with greater effi cacy in at least two mild cognitive impairment studies. Vasogenic edema was more frequent in ApoE4 AD patients treated with a monoclonal antibody to amyloid beta. Since there is evidence that the ApoE genotype may diff erentially aff ect disease mechanisms, effi cacy, and adverse eff ects in both AD and mild cognitive impairment trials, the ApoE genotype should be included as a covariate in future studies.
regarding symptomatic actions versus eff ects on longerterm biological progression of the disease. In the original 12-to 26-week symptomatic trials of tacrine in mild to moderate AD, post hoc statistical analyses using the ApoE genotype to defi ne subgroups of patients suggested that patients with the ApoE4 genotype progressed more rapidly on placebo and conversely were more likely to respond to treatment with tacrine [8]. However, later studies looking at the ApoE genotype as a factor in other cholinesterase inhibitor trials in mild to moderate AD (donepezil, rivastigmine, and galantamine) failed to confi rm this hypothesized association [9][10][11].
Other short-term trials (6 weeks to 6 months) in mildto moderate-stage AD with drugs believed to benefi cially aff ect mitochondrial function, energy metabolism, and/ or insulin resistance (caprylidene and rosiglitazone) were not positive overall, but subanalyses suggested that the subgroups with the ApoE2 or ApoE3 genotypes did signifi cantly benefi t [12]. However, with rosiglitazone, three later double-blind placebo-controlled studies of 1-year duration failed to reproduce or demonstrate benefi cial eff ects in either the general AD population or the ApoE2 or ApoE3 genotype subgroups [13]. Overall, the infl uence of the ApoE genotype in shorter symptomatic studies in AD has been preliminary, negative, or equivocal.
Increased attention is being focused on an earlier stage of AD, MCI, in which several longer-duration trials have evaluated candidate drugs for delaying or preventing conversion from MCI to AD. Th e ApoE genotype does appear to play a more signifi cant role in at least some of the longer MCI trials. In the Alzheimer Disease Cooperative Study group's MCI double-blind placebocontrolled trial (duration of 3 to 4 years) of donepezil or vitamin E versus placebo, MCI patients with the ApoE4 genotype on placebo were much more likely to progress and convert to AD [14]. Patients with the ApoE4 genotype showed signifi cantly lower rates of conversion from MCI to AD versus placebo when treated with donepezil. Similar fi ndings were seen in a large comparably designed double-blind placebo-controlled trial of rivastigmine in MCI. Th us, substantial evidence suggests that ApoE4related diff erences in brain and disease progression may be observed in association with ApoE4 in MCI and that these eff ects may diff erentially infl uence detectable treatment eff ects.
Th e ApoE genotype also appears to have had diff erential infl uence on adverse eff ects in a phase II AD treatment trial of a monoclonal antibody against Aβ (bapineuzumab). In this trial, subjects with the ApoE4 genotype were much more likely to develop vasogenic brain edema at lower doses of this antibody [15]. Th e known greater Aβ deposition in cerebral vasculature in AD patients with the ApoE4 genotype may or may not play a role in this phenomenon.
In summary, there is evidence that, through a variety of interactions and functional eff ects, variation in the ApoE genotype and the coded-for, diff erent resultant polymorphic proteins may aff ect rates of disease progression in AD and potentially responses to therapies (with regard to both effi cacy and safety). It therefore would seem prudent to stratify or include the ApoE genotype as a covariate in most AD therapeutic trials. Inclusion of the ApoE genotype should decrease variance in future studies, increasing the likelihood of successfully determining whether the drug under study benefi ts patients or is safe in treating AD.