“Choosing Wisely”: Apolipoprotein E Genetic Testing for the Diagnosis of Alzheimer’s Disease in Dementia Clinics

Abstract

Background:

Apolipoprotein E (APOE) ɛ4 allele carriers have an increased risk of late-onset Alzheimer’s disease (AD). However, in the “Choosing Wisely” campaign for avoiding unnecessary medical tests, treatments, and procedures, APOE genetic testing is not recommended as a predictive test for AD.

Objective:

The aim of this study was to investigate the potential value of APOE genetic testing in a specific clinical context.

Methods:

Subjects with poor performance in the Korean version of the Mini-Mental Status Examination for dementia screening (MMSE-DS) with a Z-score of less than –1.5 were recruited from the public health centers. All participants underwent APOE genetic testing. Family history of dementia (FHx) was confirmed if one or more first-degree relatives had dementia.

Results:

Among 349 subjects, 162 (46.4%) were diagnosed with AD. APOE ɛ4 allele carriers had a much higher risk of AD in the group with FHx than in the group without FHx (OR = 15.81, 95% CI = 2.74–91.21 versus OR = 1.82, 95% CI = 1.00–3.27, z = 2.293, p = 0.011). The sensitivity, specificity, positive predictive value, and negative predictive value for the APOE ɛ4 allele were 47.7%, 90.9%, 91.3%, and 46.5% in the group with FHx.

Conclusion:

It would be a wise choice to perform the APOE genetic testing for the diagnosis of AD in subjects with poor performance in a screening test and a family history of dementia.

Keywords

Alzheimer’s disease apolipoprotein genetic testing odds ratio sensitivity specificity

INTRODUCTION

Alzheimer’s disease (AD) is the most important cause of dementia and affects 1 in 10 individuals over the age of 65 years. According to a recent World Health Organization (WHO) estimate, in April 2012, there were more than 35 million people with dementia worldwide. This number is expected to increase by more than thrice and reach 115 million by 2050 as a result of global population aging [1]. AD, the most common cause of dementia, accounts for 60–80% of dementia cases and represents a substantial economic burden [2]. Thus, the early detection and treatment of AD in the community-dwelling elderly population can be cost-effective. However, a majority of the patients are not diagnosed in a timely manner, presenting a major challenge.

The apolipoprotein E (APOE) ɛ4 allele on chromosome 19 is a perfect example for this challenge. Genetic studies found that the APOE ɛ4 allele is associated with the common form of AD beginning after the age of 60 years [3]. The APOE ɛ4 allele increases the risk and lowers the age of onset for late-onset familial and sporadic AD in a dose-dependent manner [3, 4]. In general, APOE ɛ4 allele carriers have an approximately 3- to 15-fold higher risk of late-onset AD than that of non-carriers, in a gene dose-dependent manner [5]. With respect to the cost-worthiness of screening tests for dementia, the APOE ɛ4/ɛ4 genotype is associated with AD occurring at a much younger age than average, the APOE ɛ3/ɛ4 genotype is associated with AD development at a slightly younger age than average, and the APOE ɛ3/ɛ3 genotype is associated with late-onset disease [6]. However, APOE genetic testing is not recommended for routine clinical assessments for the diagnosis of AD [7 –9].

The “Choosing Wisely” campaign, launched in 2012, is a United States-based health educational campaign led by the American Board of Internal Medicine (ABIM) foundation focused on reducing unnecessary health care. “Choosing Wisely” lists were created by national medical specialty societies and represent specific, evidence-based recommendations [10]. Each list provides a spur conservation about appropriate and necessary treatments, and lists are not used to establish coverage decisions or exclusion criteria. In accordance with the American College of Medical Genetics and Genomics (ACMG) guideline [11], “Choosing Wisely” announced that the APOE genotype for AD risk prediction has limited clinical utility and poor predictive value. This might be explained by the fact that the presence of the APOE ɛ4 allele is neither necessary nor sufficient for the development of AD.

APOE genetic testing has been covered by the National Health Insurance service in the Republic of Korea since 2017. It has become a popular genetic test and can be easily implemented in dementia clinics without a large burden on patients and caregivers in Korea. Doctors, physicians, and patients are wondering which one is “Choosing Wisely” with respect to APOE genetic testing. The perspective of “Choosing Wisely” and the clinical potential value of APOE genetic testing for the diagnosis of AD in dementia clinics are ongoing issues.

A family history of dementia (FHx) is a recognized risk factor for the development of late-onset AD [12, 13]. Although AD has no recognizable Mendelian pattern of inheritance, close relatives (first-degree relatives) with dementia have a higher risk of developing AD [14]. Although a number of studies have shown that FHx is a significant risk factor for AD, independent of APOE [14], several studies have suggested that susceptibility to AD is determined by the interaction of the APOE ɛ4 allele with other genetic and environmental factors that could affect FHx [15, 16].

In 2006, Korea launched a program at public health centers for the early detection of dementia in community-dwelling elderly people (>60 years old). This study focused on community-dwelling elderly individuals already assessed by dementia screening at a public health center using the Korean version of the Mini-Mental Status Examination for dementia screening (MMSE-DS) [17]. Subjects with poor performance in MMSE-DS with a Z-score of less than –1.5 were used to investigate the potential value of APOE genetic testing in a specific clinical context and to recommend subgroup expected to benefit from APOE genetic testing in clinical settings.

METHODS

Subjects

A community-based early detection program for dementia was initially started at 15 regional public health centers of Korea in 2006. Since then, the program has gradually expanded and is now implemented in 253 regions across Korea, under the support of the Ministry of Health & Welfare. The program aims to improve the quality of life of elderly people with dementia and their families by conducting early screening in individuals over 60 years old with a high risk of dementia and by early detection and management. The first step is dementia screening using MMSE-DS. The second step is diagnosis by a dementia specialist based on the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease Assessment Packet (CERAD-K) [18]. In the final step, a blood test and brain imaging are performed for the differential diagnosis of dementia.

In this study, subjects who already underwent the first and second steps at a public health center were recruited for the final step (i.e., differential diagnosis) at the dementia clinic of Jeju National University Hospital (Jeju-do, Korea; JNUH) between March 2017 and October 2017. Patients were initial visitors to the hospital who needed to be evaluated for dementia and had not taken or were not taking anti-dementia medications or antidepressants. Subjects with poor performance in a screening test who had MMSE-DS with a Z-score of less than –1.5 (converting raw scores from the MMSE-DS into age-, education-, and sex-standardized Z-scores) were selected. Subjects were then evaluated by a standardized neuropsychological test in addition to psychiatric, general physical, and neurological examinations. Subjects with other major psychiatric illness, including schizophrenia, bipolar disorder, and substance abuse, were excluded. All subjects were fully informed about the study protocol and written statements of informed consent were signed by either the subjects or their legal guardians. The study protocol was approved by the Institutional Review Board of JNUH.

Assessment

The severity of global cognitive impairment was examined by the MMSE-DS at each public health center. For the neuropsychological evaluation, the CERAD-K was used. Dementia was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorder-IV-TR (DSM-IV-TR) diagnostic criteria [19], and AD was diagnosed according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer‘s Disease and Related Disorders Association criteria (NINCDS-ADRDA criteria) [20]. Subjects with probable AD and possible AD were included in the AD group, and subjects with normal cognition and mild cognitive impairment (MCI) were included in the non-dementia group. All available information was reviewed by a panel of two experienced neuropsychiatrists specializing in dementia research to determine the Clinical Dementia Rating (CDR) index and diagnosis. Information about the history of dementia among first-degree relatives (i.e., parents and siblings, not children) was collected. For most subjects, multiple informants were sought to supplement and verify the responses. Dementia in family members was only established if both memory deficits and behavioral disturbances or time or space disorientation were reported [13]. Genomic DNA was extracted from the venous blood. APOE genotyping was performed according to the methods described by Wenham et al. [21]. APOE polymorphisms were in Hardy–Weinberg equilibrium. The APOE genotype was determined for all 349 subjects.

Statistical analysis

The subtypes of dementia were compared with respect to age, sex, education level, MMSE-DS, and CDR index. Continuous variables were analyzed by an analysis variance (ANOVA), and chi-squared tests were used to examine differences in categorical variables. Subjects were divided into AD and non-dementia groups. A logistic regression analysis was used to calculate the odds ratios (ORs) for the association between the APOE genotype and AD. In the comparison of two ORs, standard statistical tests of the logarithms of the OR were performed to calculate z-scores, using the sum of the variances of the logarithms of the ORs as the variance of the difference. Differences were considered significant if the p-value was less than 0.05. All statistical analyses were performed using IBM SPSS version 24.0.

RESULTS

Three hundred and forty-nine poor performance elderly subjects were enrolled in the present study. In total, 46.4% of subjects (n = 162) had AD, 2.0% (n = 7) had vascular dementia, 5.7% (n = 20) had mixed dementia, 3.7% (n = 13) had other types of dementia, 22.3% (n = 78) had MCI, and 19.8% (n = 69) had normal cognition. Other types of dementia included Lewy body dementia (n = 3), Parkinson’s disease dementia (n = 3), frontotemporal dementia (n = 2), alcohol-related dementia (n = 3), and dementia due to other general medical conditions (n = 2). Table 1 shows the baseline characteristics and APOE genotype distributions by the subtype of dementia. The higher proportion of APOE ɛ4 allele carriers was higher in the AD group than in the non-dementia group (38.3% versus 21.8%, p = 0.002).

Table 1

Baseline characteristics and APOE genotype distributions by the subtypes of dementia in subjects with poor performance in screening tests¹

	AD	VaD	MIXED	Other type	NC	MCI	Total	p ^*
Number of subjects (n, %)	162 (46.4)	7 (2.0)	20 (5.7)	13 (3.7)	69 (19.8)	78 (22.3)	349 (100)
Age (mean±SD, y)	80.0±7.5	77.6±5.9	79.8±8.4	77.2±7.0	74.4±6.4	77.0±8.0	78.1±7.7	<0.001
Gender (n, %, Female)	105 (64.8)	4 (57.1)	11 (55.0)	5 (38.5)	36 (52.2)	51 (65.4)	212 (60.7)	0.222
Education (mean±SD, y)	5.6±4.7	7.0±3.7	5.5±5.4	8.6±4.9	7.6±3.9	6.5±4.4	6.3±4.6	0.020
MMSE-DS (mean±SD)	15.4±5.6	14.7±5.1	14.6±4.3	17.2±5.4	20.1±4.1	18.9±4.9	17.1±5.5	<0.001
MMSE-DS Z-score (mean±SD)	–3.4±1.8	–4.7±1.0	–3.7±2.1	–4.1±1.3	–2.8±0.9	–2.6±1.3	–3.2±1.6	<0.001
CDR-SOB (mean±SD)	5.3±2.3	7.1±3.5	5.3±2.4	5.2±2.6	0.35±0.8	1.1±0.8	3.4±3.0	<0.001
Family history of dementia (n, %)	44 (27.2)	1 (14.3)	5 (25.0)	3 (23.1)	12 (17.4)	10 (12.8)	75 (21.5)	0.178
APOEɛ4 allele frequency (n, %)	62 (38.3)	3 (42.9)	4 (20.0)	3 (23.1)	16 (23.2)	16 (20.5)	104 (29.8)	0.035

¹Z-score of MMSE-DS < –1.5; APOE, Apolipoprotein E; NC, normal cognition; MCI, mid cognitive impairment; AD, Alzheimer’s disease; VaD, vascular dementia; MIXED, mixed dementia; Other type, other type of dementia; CDR, Clinical Dementia Rating; MMSE-DS, Korean version of the Mini-Mental Status Examination for dementia screening; CDR-SOB, Clinical Dementia Rating scale sum of boxes score; Results are expressed as total numbers (%) or means (standard deviation) for all variables. ^*ANOVA for continuous variables and chi-square tests for categorical variables were used to evaluate significance (level of significance: p < 0.05).

The frequency of AD increased with age (dividing subjects into three groups, <70 years, 70–79 years, and ≥80 years). Even within the same age group, the frequency of AD was higher in subjects with the APOE ɛ4 allele or FHx than in those without the APOE ɛ4 allele or FHx. The frequency was highest in the group with the APOE ɛ4 allele and FHx (Table 2).

Table 2

Frequency of AD with respect to the APOE ɛ4 allele and family history of dementia according to age

Age group (y)	APOEɛ4 allele+			APOEɛ4 allele –			Overall (%)
	FHx+ (%)	FHx – (%)	Total (%)	FHx+ (%)	FHx – (%)	Total (%)
<70	80.0	37.5	53.8	14.3	15.4	15.2	26.1
70–79	90.9	53.3	63.4	55.6	42.9	45.7	51.6
≥80	100	66.7	72.5	66.7	55.4	57.4	61.7
Total	84.0	51.9	59.6	46.0	39.5	40.8	52.4

APOE, Apolipoprotein E; AD, Alzheimer’s disease; FHx+, positive family history of dementia; FHx–, negative family history of dementia; Results are expressed as percentages (%) for all variables.

The age-adjusted ORs for the APOE ɛ3/ɛ4 and APOE ɛ4/ɛ4 genotypes relative to the ɛ3/ɛ3 genotype, were 2.31 (95% CI = 1.30–4.12) and 7.84 (95% CI = 1.58–38.77). In addition, using the absence of an APOE ɛ4 allele as a reference, after adjusting for age, individuals with the APOE ɛ4 allele had an odds ratio of 2.54 (95% CI = 1.49–4.31) for AD (Table 3).

Table 3

Risk for AD with respect to APOE genotypes in subjects with poor performance in screening tests¹

	AD	Non dementia²	p ^*	AOR^††
APOE genotype frequency (n, %)			0.011
APOEɛ3/ɛ3	92 (56.8)	99 (67.3)		Reference group
APOEɛ2/ɛ2	1 (0.6)	1 (0.7)		1.62 (0.10–26.52)
APOEɛ2/ɛ3	7 (4.3)	15 (10.2)		0.64 (0.24–1.75)
APOEɛ2/ɛ4	2 (1.2)	3 (2.0)		0.69 (0.11–4.37)
APOEɛ3/ɛ4	50 (30.9)	27 (18.4)		2.31 (1.30–4.12)
APOEɛ4/ɛ4	10 (6.2)	2 (1.4)		7.84 (1.58–38.77)
APOEɛ4 allele frequency (n, %)			0.002
APOEɛ4 allele –	100 (61.7)	115 (78.2)		Reference group
APOEɛ4 allele+	62 (38.3)	32 (21.8)		2.54 (1.49–4.31)

¹Z-score of MMSE-DS< –1.5; ²Normal cognition group and mild cognitive impairment group; APOE, Apolipoprotein E; AD, Alzheimer’s disease; Results are expressed as total numbers (%) for all variables; ^*Chi-squared test (level of significance: p < 0.05); ^†AOR, Adjusted odds ratio calculated using standard logistic regression, with 95% confidence intervals (adjusted by age).

In an examination of the combined effect of the APOE ɛ4 allele and FHx, age-adjusted ORs for AD conferred by the APOE ɛ4 allele were 15.81 (95% CI = 2.74–91.21) in the group with FHx and 1.82 (95% CI = 1.009–3.270) in the group without FHx. The OR for the association between the APOE ɛ4 allele and AD was significantly higher in the group with FHx than in the group without FHx (z = 2.293, p = 0.011) (Table 4).

Table 4

Odds ratio for AD conferred by the APOE ɛ4 allele in subjects with poor performance¹ with or without a family history of dementia

		APOEɛ4 allele+	APOEɛ4 allele–
FHx+	AD (n, %)	21 (91.3)	23 (53.5)
	Non dementia² (n, %)	2 (8.7)	20 (46.5)
	OR (95% CI)^†	15.81 (2.74–91.21)	Reference
FHx–	AD (n, %)	41 (57.7)	77 (44.8)
	Non dementia² (n, %)	30 (42.3)	95 (55.2)
	OR (95% CI)^†	1.82 (1.009–3.270)	Reference

¹Z-score of MMSE-DS < –1.5; ²Normal cognition group and mild cognitive impairment group; APOE, Apolipoprotein E; AD, Alzheimer’s disease; FHx+, positive family history of dementia; FHx–, negative family history of dementia; Results are expressed as percentages (%) for all variables; ^†OR, adjusted odds ratio (adjusted by age) using standard logistic regression, with 95% confidence intervals.

In the group with FHx, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of APOE genetic testing for the diagnosis of AD were 47.7%, 90.9%, 91.3%, and 46.5%, respectively. However, in the group without FHx, these values were 34.7%, 76.0%, 57.7%, and 55.2%, respectively (Table 5).

Table 5

Comparison of the sensitivity, specificity, positive predictive value, and negative predictive values of the APOE genetic test for the clinical diagnosis of AD in subjects with poor performance in screening tests¹

APOE genetic test	FHx+	FHx–	Total
Sensitivity (%)	47.7	34.7	38.3
Specificity (%)	90.9	76.0	77.5
Positive predictive value (%)	91.3	57.7	59.6
Negative predictive value (%)	46.5	55.2	59.2

¹Z-score of MMSE-DS < –1.5. APOE, Apolipoprotein E; AD, Alzheimer’s disease; FHx+, positive family history of dementia; FHx–, negative family history of dementia.

DISCUSSION

The joint ACMG and American Society of Human Genetics (ASHG) working group announced that APOE genetic testing is not recommended for routine clinical diagnosis nor should it be used for predictive testing. As the APOE genotype alone does not provide sufficient sensitivity or specificity [22] and the APOE ɛ4-attributable risk of AD is less than 50% [23, 24], it provides no diagnostic certainty in the community-dwelling elderly population. Another study has also emphasized that the potential for false-positive and false-negative results limits the use of the APOE genotype alone as a diagnostic tool [21]. Although an association between the APOE ɛ4 allele and an increased risk of AD has been established based on extensive clinical and basic studies, the diagnostic value of APOE genetic testing is still unclear in clinical settings [25, 26].

In this study, after adjusting for age, subjects with the APOE ɛ4 allele had a more than 2-fold higher risk of AD (OR = 2.54, 95% CI = 1.49–4.31) than that of subjects without the APOE ɛ4 allele. The contribution of the APOE ɛ4 allele to the development of AD varies among ethnic groups [27] and ethnic differences in APOE allelic frequencies have been reported, even among East Asians [28]. Accordingly, it is reasonable to compare our results with those of other studies of the Korean population, in particular. In previous studies of Koreans, the ORs for AD conferred by the APOE ɛ4 allele were 3.5 (95% CI = 1.9–5.4) [28] and 4.4 (95% CI = 3.2–5.9) [23]. The differences in reported ORs between this study and these two previous studies (z = –0.919, p = 0.179 [28]; z = –1.781, p = 0.037 [23]) may be explained by the differences in subject characteristics. In previous studies, subjects were selected without screening tests. As expected, the percentages of AD were higher in subjects with poor performance than in subjects without screening tests, regardless of the presence of the APOE ɛ4 allele. However, the ratio of the percentage of AD for subjects with poor performance to subjects without screening tests was higher in APOE ɛ4 allele non-carriers than in APOE ɛ4 allele carriers, resulting in a lower OR for the APOE ɛ4 allele in this study in previous studies.

FHx is an established risk factor for AD [12 , 30]. In this study, after adjusting for age, the odds ratio for AD by FHx was 2.62 (95% CI = 1.43–4.78, not presented in the Results), independent of the APOE ɛ4 allele. Similarly, a previous study of 420 patients with AD and 109 controls has shown that FHx is indeed associated with an increased risk of AD (OR = 2.71, 95% CI = 1.44–5.09), independent of the APOE ɛ4 allele [31]. These results are consistent with a number of previous studies [15 , 33]. However, few prospective studies, including pooled analyses, have found an association between FHx and the risk of AD [16 , 35]. These contradictory findings might reflect the misclassification of patients due to recall bias and/or the uncertainty in data collected from informants, suggesting that although individuals with FHx are generally considered to be at risk of developing AD, the diagnostic value of FHx may be insufficient.

The above findings, taken together, suggest that the APOE ɛ4 allele alone or FHx alone may lack diagnostic value in clinical settings. Therefore, we further investigated the combined effect of the APOE ɛ4 allele and FHx on the risk of AD [27 , 37]. The OR for the APOE ɛ4 was significantly higher in the group with FHx than in the group without FHx (OR = 15.81, 95% CI = 2.74–91.21 versus OR = 1.82, 95% CI = 1.009–3.270, z = 2.892, p = 0.011). The presence of the APOE ɛ4 allele significantly increased the probability of AD in the group with FHx compared to that in the group without FHx.

In a previous meta-analysis, there was no significant difference in ORs for APOE ɛ4 allele between groups with and without FHx based on subjects not selected in screening tests. The pooled OR for the APOE ɛ4 allele in the subjects with FHx was significantly lower than that in subjects with poor performance and FHx in this study (pooled OR = 3.09, 95% CI = 2.53–3.77 versus OR = 15.81, 95% CI = 2.74–91.21, z = 1.814, p = 0.035) [38], suggesting the combined effect of the APOE ɛ4 allele and FHx is high in subjects with poor performance in screening tests.

Additionally, we examined the diagnostic value of the APOE genetic testing for the clinical diagnosis of AD in subjects with poor performance with or without FHx. The usefulness of this diagnostic test (i.e., its ability to detect or exclude the disease) is usually described by the sensitivity, specificity, PPV, and NPV [39]. Generally, a high PPV is desirable for diagnostic tests, implying that false positive results are minimized under a variety of circumstances. In this study, in the group with FHx and the presence of at least one APOE ɛ4 allele, the sensitivity, specificity, PPV, and NPV were 47.7%, 90.9%, 91.3%, and 46.5%, respectively. These estimates, especially the PPV, were much higher than those in the group without FHx. Additionally, regardless of the FHx status, the presence of at least one APOE ɛ4 allele had sensitivity, specificity, PPV, and NPV values of 38.3%, 78.2%, 66.0%, and 53.5%, respectively. These are similar to the results obtained from an earlier study of 336 Korean subjects, in which the sensitivity, specificity, PPV, and NPV were 38.2%, 83.6%, 53.2%, and 73.5%, respectively [28]. Accordingly, although the APOE ɛ4 allele is related to the pathology of AD, APOE genetic testing provides uncertain diagnostic results owing to the high rate of false positive results in elderly subjects not subjected to screening tests. However, the PPV of 91.3% in this study supports the potential value of APOE genotyping for the diagnosis of AD in subjects with poor performance in MMSE-DS and FHx.

This study had some limitations. First, the contribution of the APOE ɛ4 allele to the development of AD is not equal in all ethnic groups, and ethnic differences in the APOE allelic frequencies and the association between APOE ɛ4 and the risk of AD are evident, even among East Asians [28]. It is necessary to compare the results of this study with those for other ethnic groups in a future study. Second, the MMSE-DS has limitations as a screening test owing to its variability and low sensitivity and specificity [6]. Therefore, it is necessary to use other screening tests in future studies. Third, errors in the assessment of FHx might have resulted from inaccurate reporting. However, information on FHx was collected from multiple informants, which is considered a reliable approach [15]. Fourth, our findings do not demonstrate a causal relationship, and a longitudinal study design is needed to assess the potential causal pathways between AD and various factors. Fifth, there may be a cohort effect on risk estimates, in which dementia is less likely to be reported in parents than in siblings owing to lack of awareness of the disease [16].

Conclusion

Although the APOE ɛ4 allele and positive FHx status each increased the risk of AD, the diagnostic value of each factor alone was insufficient in the elderly population. However, the diagnostic value of the APOE ɛ4 allele was significantly elevated in the subset of individuals with poor performance in screening tests (MMSE-DS) and positive FHx. It would be a wise choice to perform the APOE genetic testing for the diagnosis of AD in individuals with a Z-score of MMSE-DS below –1.5 and a positive family history of dementia in clinical settings.

Footnotes

ACKNOWLEDGMENTS

This study was supported by a grant from the Korean Health Industry Development Institute (KHIDI), funded by Ministry of Health and Welfare, Republic of Korea (Grant No. HC15C1509).

Authors’ disclosures available online ().

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