ApoE genotyping as a progression-rate biomarker in phase II disease-modification trials for Alzheimer's disease

Stone, David J.; Molony, Cliona; Suver, Christine; Schadt, Eric E.; Potter, William Z.

doi:10.1038/tpj.2009.58

Cited by 19 publications

(15 citation statements)

References 16 publications

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“…In a similar vein, it must be recognized that participants in clinical trials and ADNI are samples of convenience with their own prevailing characteristics, so that trends observed in population studies (such as the effect of genotype on disease progression or as a prognostic biomarker) may differ from trends observed in clinical trials. Particularly for trials with small sample sizes, trends contradictory to population studies may be seen [48]. …”

Section: Discussionmentioning

confidence: 99%

Effect of APOE genotype status on targeted clinical trials outcomes and efficiency in dementia and mild cognitive impairment resulting from Alzheimer's disease

Kennedy

Cutter

Schneider

2013

Alzheimer's & Dementia

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Background Apolipoprotein ε4 genotype has been recommended as a potential inclusion or exclusion criterion in targeted clinical trials for Alzheimer disease and MCI due to AD, and implemented in trials of immunotherapeutic agents. Methods We tested this recommendation with clinical trials simulations using participants from a meta-database of 19 studies to create trials samples with APOE ε4 proportions ranging from 0% (all noncarriers) to 100% (all carriers). For each percentage of APOE ε4 carriers, we randomly resampled the database for 1000 trials for each trials scenario, planning for 18 or 24 month trials with samples from 50 to 400 patients per treatment or placebo group, up to 40% dropouts, outcomes on the AD Assessment Scale – cognitive subscale (ADAS-cog) with effect sizes from 0.15 to 0.75, and calculated statistical power. Findings Enrichment of clinical trials participants based on APOE ε4 carrier status resulted in minimal increases in power compared to enrolling participants with APOE ε3 genotype only or enrolling patients without regard to APOE genotype. Increased screening requirements to enhance the sample would offset gains in power. Interpretations Although samples enriched for APOE ε4 carriers in AD or MCI clinical trials showed slightly more cognitive impairment and greater decline using number APOE ε4 alleles as an inclusion criterion most likely would not result in more efficient trials; and trials would take longer because fewer patients would be available. APOE ε4/εX (where x= 2, 3 or 4) genotype could be useful however as an explanatory variable or covariate if warranted by a drug’s action.

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Section: Discussionmentioning

confidence: 99%

Effect of APOE genotype status on targeted clinical trials outcomes and efficiency in dementia and mild cognitive impairment resulting from Alzheimer's disease

Kennedy

Cutter

Schneider

2013

Alzheimer's & Dementia

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“…Although there are ethnic and demographic differences in allele frequencies, around 25% of the world’s population carries at least one copy of the ε4 risk allele, and each copy of this risk allele is associated with an approximate threefold increase in the odds of developing AD (Bertram et al, 2007). The ApoE-ε4 allele increases not only the risk of developing LOAD but also the rate of dementia progression both in terms of cognitive decline (Stone et al, 2010) and temporal lobe atrophy (Lehtovirta et al, 1995; Filippini et al, 2009b; Hua et al, 2010). …”

Section: Introductionmentioning

confidence: 99%

The apolipoprotein E epsilon 4 allele is associated with ventricular expansion rate and surface morphology in dementia and normal aging

Roussotte

Gutman

Madsen

et al. 2014

Neurobiology of Aging

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The apolipoprotein E epsilon 4 allele (ApoE-ε4) is the strongest known genetic risk factor for late onset Alzheimer’s disease. Expansion of the lateral ventricles occurs with normal aging, but dementia accelerates this process. Brain structure and function depend on ApoE genotype not just for AD patients but also in healthy elderly, and even in asymptomatic young individuals. Therefore, we hypothesized that the ApoE-ε4 allele is associated with altered patterns of longitudinal ventricular expansion, in dementia and normal aging. We tested this hypothesis in a large sample of elderly participants, using a Linear Discriminant Analysis-based approach. Carrying more ApoE-ε4 alleles was associated with faster ventricular expansion bilaterally and with regional patterns of lateral ventricle morphology at 1- and 2-year follow up, after controlling for sex, age, and dementia status. ApoE genotyping is considered critical in clinical trials of AD. These findings, combined with earlier investigations showing that ApoE is also directly implicated in other conditions, suggest that the selective enrollment of ApoE-ε4 carriers may empower clinical trials of other neurological disorders.

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“…A number of genetic risk factors for AD have been proposed [9], [10], [11], [12], however only the apolipoprotein E ( APOE ) ε4-allele, which lowers the age of onset and accelerates the cognitive decline, has a large effect [13], [14]. Pathologically AD is characterized by the presence of two insoluble protein aggregates, senile plaques formed from the peptide β-amyloid (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau protein [15].…”

Section: Introductionmentioning

confidence: 99%

“…A number of biological processes have been associated with AD, including cholesterol metabolism, inflammation, and response to misfolded proteins such as increased expression of heat shock proteins [20]. The link with lipid metabolism is supported for example by the essential role of APOE in lipid transport in the brain [13], [14]. However, these processes have not been unequivocally ordered into a pathogenic cascade, and the molecular mediators and correlates of each are largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Molecular Insights into the Pathogenesis of Alzheimer's Disease and Its Relationship to Normal Aging

et al. 2011

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Alzheimer's disease (AD) is a complex neurodegenerative disorder that diverges from the process of normal brain aging by unknown mechanisms. We analyzed the global structure of age- and disease-dependent gene expression patterns in three regions from more than 600 brains. Gene expression variation could be almost completely explained by four transcriptional biomarkers that we named BioAge (biological age), Alz (Alzheimer), Inflame (inflammation), and NdStress (neurodegenerative stress). BioAge captures the first principal component of variation and includes genes statistically associated with neuronal loss, glial activation, and lipid metabolism. Normally BioAge increases with chronological age, but in AD it is prematurely expressed as if some of the subjects were 140 years old. A component of BioAge, Lipa, contains the AD risk factor APOE and reflects an apparent early disturbance in lipid metabolism. The rate of biological aging in AD patients, which cannot be explained by BioAge, is associated instead with NdStress, which includes genes related to protein folding and metabolism. Inflame, comprised of inflammatory cytokines and microglial genes, is broadly activated and appears early in the disease process. In contrast, the disease-specific biomarker Alz was selectively present only in the affected areas of the AD brain, appears later in pathogenesis, and is enriched in genes associated with the signaling and cell adhesion changes during the epithelial to mesenchymal (EMT) transition. Together these biomarkers provide detailed description of the aging process and its contribution to Alzheimer's disease progression.

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ApoE genotyping as a progression-rate biomarker in phase II disease-modification trials for Alzheimer's disease

Cited by 19 publications

References 16 publications

Effect of APOE genotype status on targeted clinical trials outcomes and efficiency in dementia and mild cognitive impairment resulting from Alzheimer's disease

Effect of APOE genotype status on targeted clinical trials outcomes and efficiency in dementia and mild cognitive impairment resulting from Alzheimer's disease

The apolipoprotein E epsilon 4 allele is associated with ventricular expansion rate and surface morphology in dementia and normal aging

Molecular Insights into the Pathogenesis of Alzheimer's Disease and Its Relationship to Normal Aging

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