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  • Clinical Implications
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Clinical Implication

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

The Pharmacogenomics Journal volume 10, pages 161–164 (2010)Cite this article

Current studies suggest that apolipoprotein E (apoE) genotype influences the rate of progression in Alzheimer's disease (AD), with patients carrying the ɛ4 allele progressing faster than non-carriers. Results from some clinical trials show trends for apoE status and disease progression that disagree with trends in epidemiological studies however, raising questions as to whether populations defined for phase II clinical trials conform to the results seen in epidemiological studies, and raising concerns over the use of apoE genotyping as a progression-rate pharmacogenetic biomarker in AD disease-modification trials. We examined the cognitive subset of the Alzheimer's Disease Assessment Scale (ADAS-Cog) from 436 placebo-treated patients who had been genotyped for the apoE ɛ4 allele in two phase II clinical trials. In one trial ɛ4 carriers showed a faster rate of decline (P<0.001) that was evident by 9 months after baseline; in the second trial ɛ4 carriers showed worse cognitive scores at enrollment (P<0.05) and a trend towards a faster rate of cognitive decline, which reached borderline significance at 12 months (P=0.041). These results suggest that populations defined for clinical trials do in fact conform to the results seen in epidemiological studies, and studies showing a slower rate of disease progression in ɛ4 carriers probably represent chance finding because of low power. Furthermore, we propose that apoE genotyping may be only useful as a disease-progression/stratification biomarker in larger studies, where one could expect >219 ɛ4 carriers per treatment group.

Clinical trials for disease-modification strategies in AD are necessarily long term, requiring patient follow-up for ⩾1 year. In addition to the expense, patient drop-out and other problems associated with long-term follow-up, researchers designing these trials must deal with issues concerning the rate of cognitive decline, which differs substantially among individuals.1 Pharmacogenetic biomarkers for AD, especially those predicting the rate of cognitive deterioration, are therefore of high interest in this area. If applied properly, these markers can increase the power of any given trial, and potentially reduce the number of subjects necessary. The ApoE ɛ4 allele is the most obvious candidate, being both the most common and conferring the highest risk of any known genetic factor for late-onset AD.2, 3 The literature is conflicting as to the effect of ɛ4 on rate of cognitive decline; some studies show slower4, 5, 6 whereas others faster rates.7, 8, 9, 10, 11 This discrepancy may reflect chance findings because of a lack of power in smaller studies. Studies with over 200 AD subjects have consistently shown a more aggressive course of disease with the ɛ4 allele,7, 8, 10 and in the PROSPER trial (a large prospective study in the elderly with 5804 subjects) the ɛ4 allele was associated both with poorer memory performance at baseline and with more rapid cognitive decline.11

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Acknowledgements

We thank Chris Assaid, Yahong Peng and Michael Nessly for help with data retrieval and analysis.

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Author notes

  1. C Molony

    Present address: 4Current address: Molecular Profiling and Research Informatics, Merck Research Laboratories, Boston, MA, USA,

  2. C Suver

    Present address: 5Current address: Sage Bionetworks, Seattle, WA, USA,

  3. E E Schadt

    Present address: 6Current address: Pacific Biosciences, Menlo Park, CA, USA,

Authors and Affiliations

  1. Molecular Profiling and Research Informatics, Merck Research Laboratories, West Point, PA, USA

    D J Stone

  2. Genetics, Rosetta Inpharmatics LLC, a wholly owned subsidiary of Merck & Co, Seattle, WA, USA

    C Molony, C Suver & E E Schadt

  3. Department of Neuroscience & Ophthalmology, Merck Research Laboratories, North Wales, PA, USA

    W Z Potter

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Correspondence to D J Stone.

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Stone, D., Molony, C., Suver, C. et al. ApoE genotyping as a progression-rate biomarker in phase II disease-modification trials for Alzheimer's disease. Pharmacogenomics J 10, 161–164 (2010). https://doi.org/10.1038/tpj.2009.58

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