Using genetics to enable studies on the prevention of Alzheimer's disease - PubMed (original) (raw)

Using genetics to enable studies on the prevention of Alzheimer's disease

D G Crenshaw et al. Clin Pharmacol Ther. 2013 Feb.

Abstract

Curing Alzheimer's disease (AD) remains an elusive goal; indeed, it may even prove to be impossible, given the nature of the disease. Although modulating disease progression is an attractive target and will alleviate the burden of the most severe stages, this strategy will not reduce the prevalence of the disease itself. Preventing or (as described in this article) delaying the onset of cognitive impairment and AD will provide the greatest benefit to individuals and society by pushing the onset of disease into the later years of life. Because of the high variability in the age of onset of the disease, AD prevention studies that do not stratify participants by age-dependent disease risk will be operationally challenging, being large in size and of long duration. We present a composite genetic biomarker to stratify disease risk so as to facilitate clinical studies in high-risk populations. In addition, we discuss the rationale for the use of pioglitazone to delay the onset of AD in individuals at high risk.

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Figures

Figure 1

Figure 1. Frequencies of TOMM40 523 polyT lengths in different groups

PolyT length is in number of T residues. The Caucasian samples (n=463) in panel A were obtained from the Wisconsin Registry for Alzheimer’s Prevention. The Ghanaian samples (B, n=41) were from elderly, non-demented subjects. The Far Eastern samples (C–E, n=60 in each case) were from young, healthy subjects. 523 allele lengths were determined by sequencing. Blue bars, 523 alleles connected to APOE ε4; red bars, 523 alleles linked to APOE ε3 (or APOE ε2); green bars indicate when the linkage between 523 and an _APOE_allele could not be unambiguously assigned knowing only the genotypes at the two loci.

Figure 2

Figure 2. Age of onset of cognitive impairment as a function of TOMM40 523 genotype

The Bryan ADRC, Memory, Health and Aging cohort (n=508, 106 conversion events) was followed prospectively at the Bryan ADRC at Duke University. Cognitive status was determined using standard neuropsychological tests, . Age at which cognitive impairment occurred was retrospectively stratified by_TOMM40_ genotype and Kaplan-Meier curves were constructed.TOMM40 genotype was determined using sequencing-based genotyping method (Polymorphic DNA Technologies, Inc). _TOMM40_genotypes and the corresponding APOE genotypes are indicated on the figure. The red line corresponds to APOE ε4/4; the two green lines correspond to APOE ε3/4, and the three blue lines correspond to APOE ε3/3. Note that, within this cohort, there are 78 individuals who carry an _APOE_ε2 allele, but only 5 convert to cognitive impairment during the study (VL/L (APOE ε2/4), n=1; S/L (_APOE_ε2/4), n=2; VL/VL (APOE ε3/3), n=2 ). These individuals are indicated as points on the appropriate _TOMM40_genotype curve; open circles and closed diamonds indicate the age of symptom onset for the APOE ε2/4 and _APOE_ε2/3 cases, respectively. Number of subjects per 523 genotype and (number converted to case status): L/L, n=23(11); VL/L, n=54(24); S/L, n=72(23); S/S, n=100(20); S/VL, n=138(22); VL/VL, n=51(6).

Figure 3

Figure 3. Pharmacogenetically-enriched, primary prevention clinical trial design

Subject registries are established at a number of international sites that have resources for identifying an epidemiological population of the appropriate age range; competencies for neuropsychological testing are developed at each site. At the start of the trial, entry and exclusion criteria are reviewed for each subject and eligible subjects undergo a battery of neuropsychological tests. Those subjects with normal cognition (age-normed) proceed into the prevention study, are genotyped and segregated to the high and low risk strata of the study according to the risk algorithm (Table 1). Low risk subjects are treated with placebo and high risk subjects are randomized to placebo or PIO.

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