Alzheimer’s disease (AD) is the most common type of dementia in the United States, with a prevalence expected to increase dramatically in coming decades.1 Currently there are approximately 4.5 million persons with AD and the figure is anticipated to rise over 13 million by 2050 as the population ages.2 In Singapore, the prevalence rate of people with dementia aged 65 years and above is about 6.2% and this number is estimated to double every 20 years until 2050.3
The escalating cost of healthcare is expected to be dominated by care provided for the elderly. The need to keep health expenditure within affordable limits by focusing on disease prevention and health promotion, and containing the high costs of hospital care is being emphasised.4 Currently, there is no available pharmacologic intervention that can arrest the pathophysiologic deterioration in AD. Although efforts to develop disease-modifying drugs continue, resources are also being mobilised to delineate AD risk factors and implement preventive measures in a concerted effort to forestall the anticipated AD epidemic.5
Apolipoprotein E and Alzheimer’s Disease
Autosomal dominant genes — amyloid precursor protein (APP), presenilin 1 (PSEN 1), presenilin 2 (PSEN 2) — are strongly associated with the early onset forms of AD.6 Genetic testing already occurs for these rare familial forms of AD, with counselling procedures based on the Huntington’s disease [End Page 85] testing model.7 However, these mutations account for a very small proportion of AD cases.
For the far more common variant, there have been massive efforts to discover susceptibility genes. The only gene associated with AD that has been consistently replicated is Apolipoprotein E (APOE) gene which encodes a protein involved in cholesterol transport. APOE gene exists in three isoforms (ε2, ε3, ε4), differing by single amino acid substitutions.8 There have been many publications concerning the extent of increased risk of possessing APOE ε4 allele. The ε4 allele was found to be associated with an increased risk for the late onset AD (LOAD).9 The degree of risk varies depending upon whether the individual carries one or two ε4 alleles.10 Comparing with ε3/ε3 individuals, the odds ratios of developing the disease have been estimated in a seminal study to be 3.2 (95% confidence interval, 2.9–3.5) and 11.6 (95% confidence interval, 8.9–15.4) for carriers of one or two ε4 alleles, respectively.9 The lifetime risk of contracting AD may increase from 9% in ε4-negative persons to 29% for carriers of a single ε4 allele.11 Finally, the appearance of AD symptoms in ε4 carriers may be accelerated by one to two decades,9 and conversion from mild cognitive impairment (MCI) to incipient AD expedited.12 Several studies have also suggested that the presence of an ε2 allele may play a protective role against developing AD.13,14 Many studies about the effects of the ε4 allele suggest that it influences the age at which AD occurs, rather than the overall lifetime risk for AD.14–16
APOE Testing: Current Guidelines and Recommendations
Current practice guidelines do not recommend APOE genotyping in cases of dementia and MCI except within the context of clinical or epidemiological research. Moreover, APOE genotyping thus far is not recommended for prognostication in cognitively intact persons.17,18 Nevertheless, it is fairly routine for researchers to determine the APOE genotype of elderly people with cognitive impairment or dementia and in healthy individuals in the context of clinical and epidemiological research.19
The establishment of the Singapore Longitudinal Ageing Study (SLAS) by the Gerontology Research Programme (GRP) is an example of such a research programme.20 The general aims of this project are to track the transition from healthy ageing to functional impairment, illnesses and death, as well as to identify risk and protective factors for these outcomes. Patients and research volunteers of this research are not informed of the test results unless specifically requested for or if the results are deemed to be clinically important (i.e. obligate disclosure). [End Page 86]