Postmenopausal estrogen and estrogen-progestin use and 2-year rate of cognitive change in a cohort of older Japanese American women: The Kame Project.

BACKGROUND: The relation between estrogen and cognition among postmenopausal women remains controversial. Also uncertain is whether the proposed association varies between women taking unopposed estrogen and those taking estrogen combined with progestin. OBJECTIVE: To determine whether unopposed estrogen and combined estrogen-progestin use were associated with the rate of cognitive change in a cohort of older, Japanese American, postmenopausal women. METHODS: A prospective observational study in a population-based cohort of older Japanese Americans (aged > or =65 years) living in King County, Washington. Cognitive performance was measured in 837 women at baseline (1992-1994) and 2-year follow-up (1994-1997) examinations using the 100-point Cognitive Abilities Screening Instrument (CASI). Least squares means general linear models were used to estimate the 2-year rate of cognitive change according to categories of postmenopausal estrogen use. RESULTS: Approximately half of this cohort (n=455) had never used estrogen at any time since menopause, 186 were past users, 132 were current unopposed estrogen users, and 64 were current estrogen-progestin users. The majority of current estrogen users were taking conjugated estrogens, and all women receiving combined therapy were taking medroxyprogesterone acetate. After adjusting for age, education, language spoken at the interview, surgical menopause, and baseline CASI score, women who had never used postmenopausal estrogen improved slightly on the CASI scale (mean adjusted change, 0.79; SEM, 0.19). This change was significantly greater for current unopposed estrogen users (mean adjusted change, 1.68; SEM, 0.36; P=.04) and significantly worse for current estrogen-progestin users (mean adjusted change, -0.41; SEM, 0.50; P =.02) compared with never users. The improvement observed in past users (mean adjusted change, 1.12; SEM, 0.29) was intermediate between the changes for never users and current unopposed estrogen users and not significantly greater than that for never users (P=.35). CONCLUSIONS: Our findings support a modest beneficial association between current unopposed estrogen use and the rate of cognitive change. We also observed a modest detrimental association between current estrogen-progestin use and the rate of cognitive change. The clinical significance of these modest differences, however, is uncertain. Data from large, long-term randomized trials are required before applying this information to the clinical setting.

Is APOE--epsilon4 a risk factor for cognitive impairment in normal aging?

OBJECTIVES: To examine the relationship between APOE genotype and cognitive functioning in normal aging, and to determine whether this relationship was moderated by age or the presence of a number of disease conditions, including cardiovascular disease and diabetes. METHODS: The sample was drawn from the Charlotte County Healthy Aging Study, a community-based, cross-sectional study of randomly selected older adults in Charlotte County, FL. A total of 413 older adults (mean age = 72.90 years) were examined in the current study. Participants completed tasks that indexed a variety of dimensions of cognitive functioning, including episodic memory, implicit memory, psychomotor speed, and attention. In addition, participants provided self-reported and objective indices of health status and were genotyped for APOE. RESULTS: Mean-level results indicated that groups with and without the APOE-epsilon4 allele performed similarly on all domains of cognitive functioning. Significant age group differences were observed in episodic memory, psychomotor speed, and attention but not implicit memory. Significant gender differences were present for episodic memory and the Stroop test. Analyses also indicated that participants' age did not exert an impact on the relationship between APOE-epsilon4 and cognitive functioning. Further, the presence of cardiovascular disease or diabetes did little to moderate the relationship between APOE-epsilon4 and cognition. CONCLUSIONS: The authors found no evidence for a relationship between presence of the APOE-epsilon4 allele and cognitive functioning. Further, age or the presence of a number of chronic conditions did not significantly moderate the effect of APOE genotype on cognitive performance. These results indicate that the presence of the epsilon4 allele is not a risk factor for cognitive impairment in normal aging.

Impaired olfaction as a marker for cognitive decline: interaction with apolipoprotein E epsilon4 status.

OBJECTIVE: To determine whether olfactory status predicts cognitive decline (CD) over a 2-year follow-up period. METHODS: The authors enrolled individuals in a community-based longitudinal study of memory and aging in the Japanese-American community in King County, WA, between 1992 and 1994. At baseline they screened 1,985 persons using the Cognitive Abilities Screening Instrument (CASI) and the 12-item Cross-Cultural Smell Identification Test (CC-SIT). Of these 1,985 people, 1,836 were found not to be demented. Two years later the authors rescreened 1,604 participants with the CASI. They defined CD as a 2-year loss of > or =5.15 points/100 on the CASI. They genotyped 69% of the 1,604 people completing both examinations for apolipoprotein E (apoE). RESULTS: After adjusting for age, CASI score at baseline, education, smoking, sex, and follow-up time, the authors determined an odds ratio (OR) for CD of 0.90 (95% CI, 0.84 to 0.97) for an increase in each correct point on the CC-SIT (range, 0 to 12). Compared with normosmics, the OR for persons with impaired olfaction (microsmics) was 1.25 (95% CI, 0.83 to 1.89) and for anosmics the OR was 1.92 (95% CI, 1.06 to 3.47). Persons who were anosmic at baseline and who had at least one APOE-epsilon4 allele had 4.9 times the risk of CD (95% CI, 1.6 to 14.9) compared with normosmics without the epsilon4 allele. The estimated relative risk among women was 9.7 (95% CI, 1.3 to 70.4), and for men the risk was 3.2 (95% CI, 0.8 to 12.6). Receiver operating characteristic (ROC) curves showed that although the area under the curve (AUC) for baseline CASI was only 0.51, the AUC for CC-SIT alone was 0.62. Adding CC-SIT to the ROC model with CASI improved the AUC curve from 0.51 to 0.62. CONCLUSIONS: Unexplained olfactory dysfunction in the presence of one or more APOE-epsilon4 alleles is associated with a high risk of cognitive decline. Cross-Cultural Smell Identification Test classifies people with cognitive decline correctly to a greater degree than a global cognitive test.

Estrogen replacement therapy and cognitive function in postmenopausal women without dementia.

The epidemiologic evidence for an association between estrogen and cognitive function among healthy postmenopausal women remains controversial. Equivocal findings may be explained, in part, by differences in the methodologic approaches of these studies. Overall, the evidence for a positive relationship comes primarily from randomized clinical trials. These trials suggest an acute effect on specific tests of recent verbal memory and tasks incorporating concept formation and reasoning. The potential long-term effects of estrogen in slowing or delaying the age-related decline in cognitive function require further study. More data are needed to determine the effects of estrogen replacement therapy on cognitive function, independent of changes in mood and depressive symptoms. In addition, evidence suggests that progesterone may mitigate the beneficial effects of estrogen on mood. Research should be undertaken to determine the interactive effects of estrogen and progesterone on cognitive function. Lastly, there should be continued investigation by both epidemiologic and basic neuroscientific studies to further elucidate the specific cognitive domains that may respond to estrogen.

Estimation and sample design in prevalence surveys of dementia.

Population prevalence rates of dementia using stratified sampling have previously been estimated using two methods: standard weighted estimates and a logistic model-based approach. An earlier study described this application of the model-based approach and reported a small computer simulation comparing the performance of this estimator to the standard weighted estimator. In this article we use large-scale computer simulations based on data from the recently completed Kame survey of prevalent dementia in the Japanese-American residents of King County, Washington, to describe the performance of these estimators. We found that the standard weighted estimator was unbiased. This estimator performed well for a sample design with proportional allocation, but performed poorly for a sample design that included large strata that were lightly sampled. The logistic model-based estimator performed consistently well for all sample designs considered in terms of the extent of variability in estimation, although some modest bias was observed.

The association between aluminum-containing products and Alzheimer's disease.

The association between exposure to aluminum through the lifetime use of antiperspirants and antacids and Alzheimer's disease (AD) was explored in a case-control study of 130 matched pairs. Cases were clinically diagnosed between January 1980 and June 1985 at two geriatric psychiatric clinics in Seattle, Wash. Controls were friends or non-blood relatives of the case. Subjects were matched by age, sex, and the relationship between the case and his or her surrogate. For all antiperspirant/deodorant use, regardless of aluminum content, there was no association with AD (adjusted odds ratio (OR) = 1.2, 95% CI = 0.6-2.4). For aluminum-containing antiperspirants, the overall adjusted OR was 1.6 (95% CI = 1.04-2.4) with a trend toward a higher risk with increasing frequency of use (p for trend = 0.03), the adjusted OR in the highest tertile being 3.2. For antacids regardless of aluminum content, the overall adjusted OR was 3.1 (95% CI = 1.2-7.9). Here, a steep dose-response gradient was found (p for trend = 0.009), with an adjusted OR for the highest tertile of 11.7. However, when only aluminum-containing antacids were analyzed, the overall adjusted OR was only 0.7 (95% CI = 0.3-2.0) and there was no significant dose-response trend. These results are provocative but inconclusive due to methodologic problems relating to the necessary use of surrogate respondents and the long time period of potential exposure for this dementing disease.

Maternal age and Alzheimer's disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group.

To investigate the possible association between Alzheimer's disease and late maternal age at index birth, we conducted a collaborative re-analysis of existing case-control data sets. Of the 11 studies participating in the EURODEM project, four were included in the analyses regarding maternal age. In all four studies, cases were matched to controls by age and gender, and only population controls were considered. Analyses were conducted on the individual data sets, on the pooled sample, and on subgroups defined by gender, age at onset, and familial aggregation of dementia. Maternal age of 40 years and over was found to be suggestively associated with a higher risk of Alzheimer's disease (overall relative risk = 1.7; 95% confidence intervals: 1.0-2.9). In subgroup analyses, the association was statistically significant for women and for sporadic cases. Adjustments for education or analyses restricted to case-control pairs matched by type of respondent did not modify these results noticeably. The association was confirmed by a test of consistency with the Down's syndrome risk model; results of this test were again more definite for sporadic Alzheimer's disease. In addition, three of the four studies also suggested an increased risk for maternal age at index birth between 15 and 19 years (overall relative risk = 1.5; 95% confidence intervals: 0.8-3.0). Although consistency across studies was not always complete, only some of the increased relative risks reached statistical significance, and information regarding maternal age obtained through a next-of-kin interview may have limitations, our study suggests that both early and late maternal age should be further investigated as possible risk factors for Alzheimer's disease.

Head trauma as a risk factor for Alzheimer's disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group.

A re-analysis of the data from 11 case-control studies was performed to investigate the association between head trauma and Alzheimer's disease (AD). To increase comparability of studies, exposures were limited to head trauma with loss of consciousness (hereafter referred to as 'head trauma') and comparisons were restricted to community (versus hospital) controls. Test for heterogeneity across studies was negative; consequently, data were pooled in subsequent analyses. The pooled relative risk for head trauma was 1.82 (95% confidence interval: 1.26-2.67). Stratified analyses showed stronger associations in cases without a positive family history of dementia and in males (versus females). Adjustment of the pooled relative risk for family history of dementia, education and alcohol consumption did not alter significantly the association between head trauma and AD. There was no interaction effect between head trauma and family history of dementia, suggesting that these risk factors operate independently. Mean age of onset was not significantly different in cases with a history of head trauma compared to cases without such a history. The findings of the pooled analysis support an association between reported head trauma and AD.

Medical history and the risk of Alzheimer's disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group.

In a re-analysis of eight case-control studies on Alzheimer's disease we explored several medical conditions that had previously been suggested as possible risk factors for Alzheimer's disease. History of hypothyroidism was increased in cases as compared to controls (relative risk 2.3; 95% confidence interval 1.0-5.4). Severe headaches and migraine were inversely related to Alzheimer's disease (relative risk 0.7; 95% confidence interval 0.5-1.0). More cases than controls reported epilepsy before onset of Alzheimer's disease (relative risk 1.6; 95% confidence interval 0.7-3.5), especially for epilepsy with an onset within 10 years of onset of dementia. Neurotropic viruses, allergic conditions, general anaesthesia and blood transfusions were not associated with Alzheimer's disease.

Alcohol and tobacco consumption as risk factors for Alzheimer's disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group.

A meta-analysis, involving the secondary analysis of original data from 11 case-control studies of Alzheimer's disease, is presented for alcohol consumption and cigarette smoking. Five studies included in the meta-analysis of alcohol consumption. Alcohol consumption was computed in terms of average weekly intake, measured in ounces of 'pure alcohol'. This variable was categorized into tertiles to represent low, medium and high intake. Analyses showed no excess estimated risk of Alzheimer's disease for any level of alcohol intake. Smoking was analysed in three different manners: (1) lifetime prevalence of smoking (ever/never)--this included eight studies; (2) amount smoked (less than or equal to one pack per day versus more than one pack per day)--this included seven studies; and (3) pack-years--including four studies. A statistically significant inverse association between smoking and Alzheimer's disease was observed at all levels of analysis, with a trend towards decreasing risk with increasing consumption (p(trend) = 0.0003). A propensity towards a stronger inverse relation was observed among patients with a positive family history of dementia, but the difference between this group and the group with no such history was not statistically significant. Although the observed disturbance in nicotinic receptor function in Alzheimer's disease may provide an explanation for these findings, possible biases related to the selection or survival of study subjects cannot be fully ruled out at this time. Prospective, community-based studies of incident cases of Alzheimer's disease are needed to document in detail the smoking history, age of onset of disease and survival of patients and cognitively intact people by smoking status.

Occupational exposures to solvents and lead as risk factors for Alzheimer's disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group.

A meta-analysis, involving the secondary analysis of original data from 11 case-control studies of Alzheimer's disease, is presented for occupational exposures to solvents and lead. Three studies had data on occupational exposure to solvents. Among cases, 21.3% were reported to have been exposed; among controls, this figure was comparable (20.9%). This yielded a pooled matched relative risk of 0.76 (95% CI: 0.47-1.23). Four studies had data on exposure to lead. Exposure frequencies were 6.1% in cases and 8.3% in controls. This resulted in a pooled matched relative risk of 0.71 (95% CI: 0.36-1.41). The meta-analysis was particularly useful in validating negative results from individual studies and in increasing the statistical power for the analysis of lead exposure, where stratum-specific cell sizes were frequently smaller than five in individual studies. However, since exposure in the various studies was ascertained in a rather broad manner, prospective studies are recommended which focus on high-risk occupational populations and which determine the incidence of Alzheimer's disease in these and comparable unexposed populations.

Psychiatric history and related exposures as risk factors for Alzheimer's disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group.

Data from case-control studies of Alzheimer's disease (AD) were pooled to examine the possible roles of history of depression, anti-depressant treatment and adverse life events as risk factors. History of depression was found to be associated with AD, although the effect was confined to late onset cases. The association held for episodes of depression more than 10 years before AD onset, as well as for episodes occurring within a decade of onset. No association was found with anti-depressant treatment. However, data were only available from two studies, limiting the power of the analysis. Also, no association was found with the three major life events considered in the pooled analysis: death of spouse, death of a child and divorce.

Familial aggregation of Alzheimer's disease and related disorders: a collaborative re-analysis of case-control studies.

Case-control studies of Alzheimer's disease were re-analysed to examine the association of Alzheimer's disease with family history in first degree relatives of dementia, Down's syndrome and Parkinson's disease. Overall, the relative risk of Alzheimer's disease for those with at least one first degree relative with dementia was 3.5 (95% confidence interval 2.6-4.6). Stratification according to age of onset of Alzheimer's disease showed that the relative risk decreased with increasing onset age. However, among patients with an onset of disease after 80 years, there were still significantly more subjects with one or more first degree relatives with dementia as compared to controls (relative risk 2.6; 95% confidence interval 1.3-5.2). The relative risk of Alzheimer's disease was significantly lower in patients who had one first degree relative with dementia (relative risk 2.6; 95% confidence interval 2.0-3.5) as compared to those who had two or more affected relatives (relative risk 7.5; 95% confidence interval 3.3-16.7). Furthermore, the re-analysis showed a significant association between Alzheimer's disease and family history of Down's syndrome (relative risk 2.7; 95% confidence interval 1.2-5.7), which was strongest in those patients who had a positive family history of dementia. The relative risk of Alzheimer's disease for those with a positive family history of Parkinson's disease was 2.4 (95% confidence interval 1.0-5.8).

Ethnicity and cognitive performance among older African Americans, Japanese Americans, and Caucasians: the role of education.

This cross-sectional analysis evaluated the association between ethnicity and cognitive performance and determined whether education modifies this association for nondemented older people (103 African Americans, 1,388 Japanese Americans, 2,306 Caucasians) in a study of dementia incidence. African Americans scored lower (median 89 out of 100) than Japanese Americans (93) and Caucasians (94) on the Cognitive Abilities Screening Instrument (CASI). Education affected CA

Attitudes toward use of nursing homes and home care in older Japanese-Americans.

OBJECTIVE: A cohort of 1142 older Japanese Americans was identified to study preferences and attitudes regarding use of long-term care (nursing home or home care). DESIGN: Prospective cohort study. PARTICIPANTS AND SETTING: Older Japanese Americans in King County, Washington. RESULTS: Subjects were asked to consider hypothetical situations in which they were temporarily disabled by hip fracture or permanently disabled by dementing illness. If they fractured a hip, only 12% intended to use a nursing home; 29% intended to recover at home with the help of family or friends; another 54% intended to use paid home health care. If they became demented, the majority (53%) intended to use a nursing home; only 11% intended to rely on family or friends for care, and another 29% intended to use paid home health care. Similar responses were observed when subjects were asked what most members of their family or friends would wish them to do; however, they tended to value the perceived wishes of religious figures or the Japanese American community-at-large less than those of family or friends. Significant correlates with intention to enter nursing homes were lack of social support (unmarried, few or no close relatives or housemates), female gender, and high levels of acculturation into American society (never lived in Japan, English-speaking only). Other factors that were not significantly correlated were health perceptions, satisfaction and life control scales, and health care utilization (hospitalizations and MD visits). In multivariate logistic regression, marital status and level of acculturation were the most powerful independent predictors of intention to enter nursing homes. Age and female gender were predictors of intention to use home care. In the base population of subjects, the prevalence of nursing homes use (5%) was similar to that of the general US older population. CONCLUSIONS: We conclude that older Japanese Americans in the Pacific Northwest often intend to enter nursing homes if they became disabled by dementing illness. Actual use is similar to other older populations. This may be attributable largely to the existence of an ethically appropriate nursing home which is strongly supported by, and familiar to, this close-knit community. Intention to use long-term care services appears to be dependent primarily on the level of social supports and acculturation into American society.

Standardization of the clinical diagnosis of the dementia syndrome and its subtypes in a cross-national study: the Ni-Hon-Sea experience.

BACKGROUND: Clinical investigators from Seattle, Honolulu, Tokyo, and Hiroshima participated in two standardization exercises in which data were collected on independent assessments. Exercises were conducted to evaluate the interobserver agreement on clinical diagnoses of dementia and dementia subtypes in a cross-national study of dementia prevalence and incidence rates in the United States and Japan. METHOD: Fifteen clinicians from four participating sites assessed the diagnosis of 85 patients based on standardized summaries of clinical and diagnostic test data on each patient. Diagnostic guidelines and conventions were adopted on the basis of group consensus during standardization exercises. RESULTS: Using DSM-III-R criteria, generally good levels of agreement for all dementia diagnostic categories occurred in both years. For most measures of diagnostic agreement, improvements were observed between the 1995 and 1996 standardization sessions. Interrater agreement was highest for discrimination between dementia and nondementia (1996 overall kappa, K = .90). The kappa values for dementia subtypes in 1996 ranged from .5 to .85, and for all sites combined the value was .67. For dementia subtypes, percent agreement was highest for vascular dementia and Alzheimer's disease, but was less reliable for other types of dementia. CONCLUSIONS: Clinicians from different cultures and medical traditions can reliably use the DSM-III-R criteria to classify dementia cases in cross-national research. The interrater agreement on dementia and its subtypes improved after clear-cut guidelines for interpretation of diagnostic criteria were developed and followed.

Neuropsychological test performance in a cognitively intact sample of older Japanese American adults.

The purpose of this paper was to present population-based data showing the effects of age on cognitive test performance in a sample of older Japanese American adults. In addition, the relative effects of education, gender, and primary spoken language were compared to effects that have been reported in the literature for majority culture older adults. Subjects included 201 non-demented Japanese American adults age 70 and older currently enrolled in the Kame Project, a prospective study of aging and dementia in King County, WA. Cognitive tests included the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological assessment battery, WAIS-R Digit Span and Digit Symbol subtests, Trail Making Test, Purdue Pegboard, and Finger Tapping. Older age was associated with significantly (p<0.05) lower scores on all tests; less than high school education was associated with lower scores on all tests except Digit Span, Finger Tapping, and the Purdue Pegboard. Women and English-speaking participants scored higher than men and Japanese speakers on various tests of memory, attention, and visuomotor ability. These data reinforce the importance of using appropriately corrected norms when interpreting results of cognitive screening tests with minority culture older adults.

Cognitive decline and Japanese culture in a cohort of older Japanese Americans in King County, WA: the Kame Project.

OBJECTIVES: The prevalence of Alzheimer's disease in studies of Japanese show generally lower rates when compared with those of Caucasians. We hypothesized that among a cohort of Japanese Americans lifestyle differences would act to modify progression of the Alzheimer pathologic process over many years, resulting in a slower cognitive decline among persons whose lifestyle is more characteristically Japanese. METHODS: One thousand, eight hundred and thirty-six nondemented persons were screened with the Cognitive Abilities Screening Instrument (CASI) at baseline, and 1,604 were rescreened 2 years later. Baseline questions included migration status, exposure to Japanese culture in early life and maintenance of such culture in adulthood, and other risk factors. Cognitive decline was defined as a 2-year loss of > or = 5.15 points/100 on CASI. RESULTS: In multivariable logistic regression, variables relating to reading, writing, and speaking Japanese, being born or having lived in Japan in early life, and having friends who are only/mostly Japanese were inversely associated with cognitive decline (odds ratios ranged between 0.28 and 0.64, with p < .05). Two factors emerged in a factor analysis of these variables. The strongest explained 49% of the variance for acculturation and loaded heavily on knowledge of the Japanese language and having spent one's early years in Japan. When this factor was dichotomized into the top 20th percentile, it predicted cognitive decline with an odds ratio of 0.12 (95% CI 0.03-0.49). DISCUSSION: These results show that a Japanese lifestyle may decrease the risk of expressing cognitive decline over a 2-year follow-up period. Lower cardiovascular disease rates among Japanese may also predispose them to lower rates of cognitive decline. The greater social support characteristic of Japanese culture as well as the role that Japanese language and culture may play in neural connectivity during brain development and/or in mental stimulation in adult life may also explain our findings.

Opportunities and challenges in international collaborative epidemiologic research of dementia and its subtypes: studies between Japan and the U.S.

Estimates of the prevalence rates for dementia vary significantly among countries. Such variation may be explained, at least in part, by methodologic differences in studies. The disparities in prevalence rates of dementia subtypes, particularly Alzheimer's disease and multi-infarct dementia, are especially apparent in studies conducted in Eastern and Western countries. In Japan and China, the prevalence of multi-infarct dementia exceeds that of Alzheimer's disease, whereas in the West, Alzheimer's disease predominates in the vast majority of studies. Clearly, cross-cultural studies of incidence using standard methods are needed to investigate whether a true difference in risk exists, and which risk factors differentially contribute to this variation. Migrant studies of genetically homogeneous populations offer a unique opportunity to answer these questions. This article explores the value of migrant studies, their application to etiologic questions of dementia and its subtypes, and recommendations concerning how to conduct such studies.

Occupational exposure to electromagnetic fields and Alzheimer disease.

The association between occupational exposure to electromagnetic fields (EMF) and Alzheimer disease (AD) was examined. Subjects were identified from a large health maintenance organization in Seattle, Washington, and matched by age, sex, and proxy type. A complete occupational history was obtained from proxies and controls. Following the interview, two industrial hygienists (IHs) rated exposures to EMF for each job blinded to case-control status. Exposures to EMF were rated as probable intermittent exposure or probable exposure for extended periods to levels above threshold. Conditional logistic regression was used to calculate the risk of AD given EMF exposure stratified by IH. The odds ratios for ever having been exposed to EMF were 0.74 [95% confidence interval (CI) 0.29-1.92] and 0.95 (95% CI 0.27-2.43) for each IH, adjusting for age and education. No dose-response effect was noted. Agreement between the two IHs for ever having been exposed to EMF was good (kappa = 0.57, p < 0.0001). This study was unable to support an association between EMF and AD.