Mild cognitive impairment (MCI) refers to cognitive impairment without dementia (Morris 2001). It is a heterogeneous condition that has been operationalised in several ways. Matthews (Matthews 2008) has categorised MCI into age-related cognitive change, pathological decline, category systems, and the Mayo Clinic criteria. Under age-related cognitive change are age-consistent memory impairment (ACMI) and age-related cognitive decline (ARCD). Pathological decline encompasses the conditions of cognitive impairment no dementia (CIND), age-associated memory impairment (AAMI), age-associated cognitive decline (AACD), mild cognitive disorder (MCD), questionable dementia (QD), minimal dementia (MD), mild neurocognitive disorder (MNCD), limited cognitive disturbance (LCD), and benign senescent forgetfulness (BSF). The category systems cover subjective memory complaint (SMC) and MCI defined as a score of 22 to 26 on the 30-item Mini-Mental State Examination (MMSE). The Mayo Clinic criteria differentiate MCI into three subtypes: non-amnestic MCI (N-MCI), amnestic MCI (A-MCI), and multiple MCI (M-MCI). A-MCI refers to objective memory impairment with generally preserved cognitive functioning, or subjective memory complaints corroborated by an informant (Petersen 2004). Throughout this review, we will use the term 'MCI' to refer to any of the abovementioned conditions. In addition, we will include in our definition of MCI impairment on a cognitive test with an overall Clinical Dementia Rating (CDR) score of 0.5, or based on an equivalent measure (Morris 2001).
People with MCI are at increased risk of Alzheimer's disease (AD). About 35% of those with MCI have been reported to progress to AD over a follow-up period of 4.5 years, with a rate of progression that was thrice faster compared to cognitively healthy individuals (Bennett 2002). AD is a neurodegenerative disorder characterized pathologically by neuritic plaques and neurofibrillary tangles; and clinically by progressive memory loss, impairments in activities of daily living, and behavioural and neuropsychiatric symptoms. AD is the most common cause of dementia (Blennow 2006) and accounts for the majority of dementia cases worldwide (World Health Organization 2012).
There is currently no cure for AD dementia, although previous studies have shown some benefits of drug treatments in delaying cognitive decline and slowing disease progression (Peters 2012; Rountree 2012). Identifying those who are at an increased risk of developing AD dementia is therefore important for prognosis purposes and early intervention, when and if a treatment for reducing incident AD dementia is found.
Among the known risk factors for AD dementia is the ε4 allele of the apolipoprotein (APOE) gene. The APOE gene transports cholesterol and lipids in the brain, and is involved in neuronal repair (Bu 2009). APOE has three polymorphic alleles (ε2, ε3, and ε4), the combinations of which result in the six genotypes ε2ε2, ε2ε3, ε2ε4, ε3ε3, ε3ε4, and ε4ε4 (Leoni 2011). The APOE-ε4 allele has been shown to have high-avidity binding to amyloid beta (Strittmatter 1993), which is the main constituent of neuritic plaques.
About 15% of the general population has been reported to be APOE-ε4 allele carriers (Bu 2009). In Europe, APOE-ε4 prevalence has been reported to follow a north-south gradient, which was highest in northern Europe (˜60%), followed by middle Europe (˜40%), and southern Europe (˜30%) (Norberg 2011). An estimated 40% of those with AD dementia in the general population carry the ε4 allele (Bu 2009). APOE-ε4 has been associated with a ˜3.7-fold increased risk of AD dementia in case-control studies (Bertram 2007), while carriership of two ε4 alleles has been reported to increase the risk to as high as ˜15-fold (Farrer 1997). Although other genetic risk factors for AD dementia have been identified in genome-wide association studies in recent years, these genes usually show a much weaker effect (odds ratio of < 1.5) compared to APOE-ε4. In a meta-analysis, we found the APOE-ε4 allele to be a moderately strong predictor of progression from MCI to AD dementia (odds ratio of ˜2.3) (Elias-Sonnenschein 2011). The review, therefore, has useful implications for stratifying participants of clinical trials.
The purpose of the current review is to (1) assess through meta-analysis the diagnostic accuracy of the APOE-ε4 allele for identifying AD and predicting progression to AD dementia and other dementia among people with MCI; and (2) update and expand our previous meta-analysis. It differs from our earlier study in the following aspects. First, the period that will be covered is from 1993, when the first publication on the relationship between the APOE-ε4 allele and AD appeared (Strittmatter 1993), to 2013. Second, the definition of MCI will include the concepts of Matthews (Matthews 2008). Third, the methodological quality of the studies that will be included in the review will be assessed using the revised quality assessment of diagnostic accuracy studies (QUADAS-2) (Whiting 2011). Fourth, in the statistical analyses, we will be taking into account correlations between outcome measures, which are ideally assessed using a bivariate model. Fifth, no language restriction will be imposed on the search for relevant literature. And sixth, as the diagnostic accuracy of the APOE-ε4 allele in one setting may be different from other settings, we will be including in this review only studies in a primary care setting. We have prepared a similar review protocol for studies in secondary care and in community settings. We will be evaluating the accuracy of the APOE-ε4 allele at baseline in relation to (1) progression from MCI to AD dementia; and (2) progression from MCI to other types of dementia.
Target condition being diagnosed
The two target conditions in this review are (1) AD dementia; and (2) other types of dementia, which will be assessed at follow-up. We will be comparing the results of the index test obtained at baseline with the results of the reference standards at follow-up (delayed verification).
The index test is a genetic marker, that is, presence of APOE-ε4 allele as assessed by genotyping. A person is either a carrier or a non-carrier of the APOE-ε4 allele.
Dementia develops over several years. There is a presumed period when people are asymptomatic and when pathology is accumulating. Individuals or their relatives may then notice subtle impairments of recent memory. Gradually, more cognitive domains become involved and difficulty in planning complex tasks becomes increasingly apparent. In the Netherlands, people usually present to their general practitioner, who may administer a cognitive screening test and refer them to a hospital memory clinic. However, many people with dementia do not consult their general practitioner until much later in the disorder and will follow a different pathway to diagnosis, for example being identified during an admission to a general hospital for a physical illness. Thus, the pathway influences the accuracy of the diagnostic test. The accuracy of the test will vary with the experience of the administrator, and the accuracy of the subsequent diagnosis will vary with the history of referrals to the particular healthcare setting. Diagnostic assessment pathways may vary in other countries and diagnoses may be made by a variety of specialists, including neurologists and geriatricians.
Standard assessment of dementia includes history taking, clinical examination (including neurological, mental state, and cognitive examinations), and informant interview. Prior to diagnosis of dementia, the clinician normally rules out, and if possible treats, other physical or mental conditions that may be causing the cognitive impairment. Neuroimaging (computed tomography or magnetic resonance imaging) is recommended in most recent guidelines (McKhann 2011; NICE 2006). Most neuroimaging tests, and also recently cerebrospinal fluid sampling, are performed after a cognitive deficit is noted. However, individuals with abnormalities on brain imaging, which may be performed for any number of reasons, are more likely to be tested subsequently for cognitive impairment.
Dementia as diagnosed is defined by a deficit in more than two cognitive domains of sufficient degree to impair functional activities of daily living. The different diagnostic criteria for dementia are presented in the 'Reference standards' section and in Appendix 1.
An increasing number of studies suggest genetic susceptibility to AD dementia (Hollingworth 2011; Lambert 2009; Naj 2011; Seshadri 2010). TheAPOE-ε4 allele is the strongest known genetic risk factor for AD dementia. As a diagnostic tool, APOE genotyping might aid in:
identifying individuals with MCI at high risk of developing AD dementia;
increasing the accuracy of dementia diagnostics, in addition to the reference standards;
selecting candidates for trials with drugs that aim to slow down the progression of AD dementia.
Particular advantages of APOE genotyping are that it is safe and relatively inexpensive to perform.