Alzheimer's disease: diagnostics, prognostics and the road to prevention

Abstract

Alzheimer's disease (AD) presents one of the leading healthcare challenges of the 21st century, with a projected worldwide prevalence of >107 million cases by 2025. While biomarkers have been identified, which may correlate with disease progression or subtype for the purpose of disease monitoring or differential diagnosis, a biomarker for reliable prediction of late onset disease risk has not been available until now. This deficiency in reliable predictive biomarkers, coupled with the devastating nature of the disease, places AD at a high priority for focus by predictive, preventive and personalized medicine. Recent data, discovered using phylogenetic analysis, suggest that a variable length poly-T sequence polymorphism in the TOMM40 gene, adjacent to the APOE gene, is predictive of risk of AD age-of-onset when coupled with a subject's current age. This finding offers hope for reliable assignment of disease risk within a 5-7 year window, and is expected to guide enrichment of clinical trials in order to speed development of preventative medicines.

Fig. 1

Alzheimer’s disease age of onset curves by APOE genotype, based on the information available in 1994 (adopted from [28]). Age of onset for LOAD, sporadic AD and control subjects as published in 1994 [28]. The age-of-onset is scored as a function of the individual’s APOE genotype. Onset curves were estimated by Kaplan-Meier product limit distributions

Fig. 2

Hypothetical Alzheimer’s disease age of onset curves by TOMM40-APOE haplotype, based on the information available today (February 2010). We propose that each of the original AD age of onset curves is in fact a composite of sub-curves that are defined by TOMM40 genotype [70, 79]. The APOE4/4 curve would be unchanged, as the vast majority of APOE4 alleles carry the long (L) TOMM40 rs10524523 allele. There would be two curves for APOE3/4 individuals due to the presence of either a short (Sh) or a very long (VL) rs10524523 polymorphism linked to APOE3. There would likely be three curves for APOE3/3 individuals due to the possible combination of alleles at rs10524523, i.e. short/short (Sh/Sh), short/very long (Sh/VL), and very long/very long (VL/VL)