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Lower plasma β-amyloid (Aβ) 42 and 42/40 have been associated with incident dementia, but results are conflicting and few have investigated cognitive decline among non-demented elders.
To determine if plasma β-amyloid is associated with cognitive decline and if this association is modified by measures of cognitive reserve.
We studied 997 black and white community-dwelling older adults from Memphis, TN and Pittsburgh, PA enrolled in the Health ABC Study, a prospective observational study begun in 1997–98 with 10-year follow-up in 2006–07.
Association of near baseline plasma β-amyloid (42 and 42/40 measured in 2010) and repeatedly measured Modified Mini-Mental State Exam (3MS).
Participant mean age was 74.0 (3.0) years, 55.2% (N=550) were female, 54.0% (N=538) were black. Low β-amyloid 42/40 level was associated with greater 9-year 3MS cognitive decline (Low tertile [mean(95% CI)] −6.59 −(5.21–7.67) points, mid −6.16 −(4.92–7.32) and high −3.60 −(2.27–4.73), p<0.001). Results were similar after multivariate adjustment for age, race, education, diabetes, smoking and APOE e4 and after excluding the 72 participants with incident dementia. Measures of cognitive reserve modified this association whereby among those with high reserve (education ≥ high school (HS), literacy >6th grade, or no APOE e4), β-amyloid 42/40 was less associated with multivariate adjusted 9-year decline. For example, among participants with education <HS, 3MS decline was −8.94 −(6.94–10.94) for the low tertile compared with −4.45 −(2.31–6.59) for high tertile, but for education ≥HS, decline was −4.60 −(3.07–6.13) for low tertile and −2.88 −(1.41–4.35) for high tertile (p for interaction = 0.004). Interactions were also observed for literacy (p=0.005) and for APOE e4 (p=0.02).
Lower plasma β-amyloid 42/40 is associated with greater cognitive decline among non-demented elders over 9 years, and this association is stronger among those with low measures of cognitive reserve.
An estimated 36 million people currently have dementia, with the prevalence expected to double every 20 years.1 Thus, biomarkers to identify elders at risk for developing dementia could be useful for early prevention, if and when such interventions are available, and treatment. Plasma β-amyloid measurement has emerged as a promising biomarker, with lower β-amyloid 42 and 42/40 shown to be associated with increased risk of developing AD.2–4 However, both cross-sectional and prospective studies have reported conflicting results5–7 which may be due to variations in participant diversity, follow-up time, and choice of lab assays.2, 3, 5, 6 In addition, few studies have investigated the association of plasma β-amyloid level and rate of cognitive decline as opposed to dementia. Thus, one objective of our study was to prospectively investigate the association between plasma β-amyloid 42 and 42/40 and cognitive decline over 9 years in a large cohort of non-demented, biracial, community-dwelling older adults.
While evidence suggests that β-amyloid accumulation in the brain is one of the key aspects of AD clinico-pathology,8–10 there is tremendous variation in β-amyloid deposition, as measured by autopsy or neuroimaging, and the manifestation of clinical symptoms.11–13 One explanation for this difference has been termed the cognitive reserve hypothesis, which proposes that some older adults with AD pathology experience fewer clinical symptoms due to a variety of compensatory factors, such as higher occupational or educational achievement, greater efficiency or flexibility of neural networks, and larger brain size.14, 15 Indeed, several studies have demonstrated that among people with higher education, amyloid burden as measured by neuroimaging was less associated with cognitive function compared with those with less education.12, 13 Therefore, another goal of our study was to determine whether measures of cognitive reserve modified the effect of plasma β-amyloid level on cognitive decline.
Participants were enrolled in the ongoing Health Aging and Body Composition (Health ABC) study, a prospective cohort of 3,075 community-dwelling white and black older adults. The study enrollment period was 1997–98, and at baseline the adults ranged in age from 70 to 79 years, and lived in Memphis, TN or Pittsburgh, PA. Participants were recruited from a random sample of Medicare eligible adults living within the designated zip codes, and were eligible if they reported no difficulties performing activities of daily living, walking a quarter mile, or climbing 10 steps without resting. They also had to be free of life-threatening cancers, and plan to remain within the study area for at least three years.16 Of the 22,999 elders identified, 8,695 were unavailable for eligibility screening, 897 were institutionalized, dead, or had moved, 7,250 declined to participate, 3,082 were ineligible. The 3075 eligible elders were enrolled in Health ABC. Our analytic cohort comprised a subgroup of 997 participants with repeated cognitive testing who had β-amyloid 42 and β-amyloid 40 measurement (a random sample of sex and race-stratified participants with baseline and at least one other cognitive measure over time). Compared with the Health ABC participants who did not have β-amyloid measured, those in the subgroup were more likely to be female and black and to have lower mean education but did not differ on other basic characteristics. This study was approved by the institutional review boards of the University of Pittsburgh and the University of Tennessee, Memphis, and that of the coordinating center, the University of California, San Francisco. All participants signed a written informed consent.
β-amyloid 40 and β-amyloid 42 level were measured from stored plasma obtained at the first Health ABC follow-up visit (median time from baseline of 53.4 weeks; 25th–75th percentile 51.0–58.1 weeks). Plasma was stored at −70° C at Fisher BioServices, Inc. Laboratories and shipped directly to the analytical laboratory. Plasma β-amyloid was measured in 2010 by the laboratory of Dr. Steven Younkin at the Mayo Clinic using Innogenetics INNO-BIA assays. The detection limit for this assay is 12 pg/ml for β-amyloid 40 and 5 pg/ml for β-amyloid 42. Mean inter-assay coefficient of variation was 9.9% for β-amyloid 40 and 9.3% for β-amyloid 42 and mean coefficient of variation within assay was 3.5% for β-amyloid 40 and 2.3% for β-amyloid 42.
Cognitive function was measured with the Modified Mini-Mental Status Exam (3MS). The 3MS, an assessment of global cognitive function, is a brief, general cognitive battery with components for orientation, concentration, language, praxis, and immediate and delayed memory with a maximum or best score of 100.17 The 3MS was administered to participants during the baseline visit (Year 1) and repeated at the Year 3 (N=932), 5 (N=854), 8 (N=642), and 10 (N=568) follow-up visits ending in 2006–7. Incident dementia was recorded over follow-up and ascertained from use of dementia medications at each visit (cholinesterase inhibitors and memantine) and from review of hospitalization records.
Several studies have used measures of education and intelligence as markers or proxies of cognitive reserve.12, 13, 18 Based on this, we used years of education and literacy as two commonly used measures of reserve. Self-reported years of education were coded as <High School (HS) and ≥HS. Literacy was measured with the Rapid Estimate of Adult Literacy in Medicine (REALM).19, 20 The REALM instrument has been validated in adult populations, and scores are highly correlated with other tests of literacy.21 REALM scores were categorized as ≤6th grade (REALM score ≤44) and >6th grade (REALM ≥45), as has been suggested by the scale developers who have reported that this cutoff differentiates those who are functionally illiterate versus literate in a healthcare setting.22 As a measure of genetic vulnerability or reserve, we also assessed Apolipoprotein E (APOE) e4 allele status using standard SNP techniques and dichotomized into having one or more APOE e4 allele versus having no APOE e4 allele (NCBI Database, RS# 429358 and RS# 7412).
At baseline, participants reported their age, race and sex. Prevalent disease algorithms based on both self-report and physician diagnoses, recorded medications and laboratory data were used to create comorbidity variables indicating presence of diabetes mellitus (based on fasting blood glucose level, current medications or self-report), hypertension (based on clinic measure, current medications or self-report), stroke or transient ischemic attack (TIA) (based on self-report), and myocardial infarction (MI) (based on self-report). Body mass index (BMI) (kg/m2) was calculated from direct height and weight measurements at baseline. Participants self-reported current smoking, alcohol use, and physical activity (evaluated by a modified Paffenbarger Scale to calculate total kilocalories expended per week).23 The Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess depressive symptoms with a score ≥16 consistent with possible depression.24 High sensitivity C-reactive protein (CRP) and serum creatinine were also measured from baseline blood samples.
We first created tertiles (determined a priori) to categorize β-amyloid 40, 42 and 42/40 into “low” “medium” and “high”. We then determined the association between baseline participant characteristics and β-amyloid 42/40 tertile, using Pearson χ2 and ANOVA tests. The ANOVA model used was a fixed effects model of the means of each variable across the three tiers of β-amyloid level. To determine the association between β-amyloid 42, 40 and 42/40 tertile and longitudinal repeated measures of 3MS, unadjusted mixed effects models were used. We then created multivariate models controlling for the dependent nature of observations of the same individual through time as well as adjusting for characteristics that significantly differed across tertile at baseline (p<0.05, described in Table 1), or that have been previously shown to be associated with cognitive function (age, race, education, diabetes, and APOE e4). Literacy and education were tightly correlated, so only education was included in the adjusted model. As plasma β-amyloid 42 and β-amyloid 40 level may be sensitive to serum creatinine level,25 we also adjusted models for serum creatinine, but this did not significantly change any results, so our final model did not include this variable. Finally, we conducted a series of pre-planned adjusted mixed effects models to determine whether the β-amyloid associations with cognitive decline were modified by measures of cognitive reserve, either education, literacy, or APOE e4, and tested for an interaction. We also repeated all analyses excluding those participants with incident dementia and evaluating β-amyloid as a continuous predictor. All analyses were performed using SAS version 9.2 statistical software and were two-tailed with statistical significance level set at p<0.05.
At baseline, mean age was 74.0 (3.0) years, 550 (55.2%) were female, and 538 (54.0%) were black. The mean (SD) β-amyloid 42 level of the 997 participants was 33.9 (9.6) pg/ml, of β-amyloid 40 was 191.6 (50.6) pg/ml, and of β-amyloid 42/40 was 0.19 (0.17). Participants in the low β-amyloid 42/40 tertile were more likely to be black (p=0.008), have diabetes (p=0.04), have lower literacy (p=0.03), smoke currently (p=0.05), and have an APOE e4 allele (p<0.001) (Table 1). Those in the low tertile tended to be less educated (p=0.06) but did not differ on other baseline characteristics.
In unadjusted mixed effects repeated measures models, β-amyloid 42/40 was not associated with baseline 3MS score (Table 2). However, low β-amyloid 42/40 was associated with greater cognitive decline over nine years (low tertile −6.59 (95% confidence interval −5.21 to −7.67) points, mid −6.16 −(4.92–7.32) and high −3.60 −(2.27–4.73), p-value<0.001) (Table 2). After adjustment for age, race, education, diabetes, smoking and APOE e4, the results remained statistically significant (−6.38 −(5.15–7.61) for low, −6.09 −(4.89–7.29) for mid and −3.44 −(2.21–4.67) for high tertile, p=0.02). There was also a significant association between plasma β-amyloid 42 and cognitive decline (low tertile −6.96 −(5.53–8.03), mid −5.14 −(3.94–6.34) and high −4.30 −(3.03–5.47), p=0.007), and multivariate adjustment for age, race, education, diabetes, smoking, and APOE e4 did not appreciably change these results (low tertile −6.70 −(5.45–7.95), mid −5.03 −(3.81–6.25) and high −4.29 −(3.06–5.52)). There was no association between plasma β-amyloid 40 and baseline cognitive function or decline. When β-amyloid 42/40 was analyzed as a continuous predictor, the β coefficient for 9-year cognitive decline in multivariate adjusted models is 0.68 per standard deviation of β-amyloid 42/40, p=0.03.
In multivariate adjusted models, cognitive reserve measures modified the association between β-amyloid 42/40 level and cognitive decline. Older adults with low reserve (as measured by education <HS or literacy ≤ 6th grade) had an even greater association with β-amyloid 42/40 level, whereas those with high reserve had less association (p for interaction <0.05 for both measures on 3MS decline) (Figure). For example, among participants with education <HS, the 9-year decline on the 3MS was −8.94 −(6.94–10.94) for low β-amyloid 42/40 tertile compared with −4.45 −(2.31–6.59) for the high tertile, but among those with education ≥HS, the 9-year decline for low tertile was −4.60 −(3.07–6.13) and for high was −2.88 −(1.41–4.35) (p for interaction = 0.004).
APOE e4 status also modified the association between β-amyloid 42/40 level and cognitive decline, such that older adults with an e4 allele had an even greater association with β-amyloid 42/40 level. Among participants with an e4 allele, the 9-year decline on the 3MS was −7.75 −(5.75–9.75) for low tertile compared with −5.00 −(2.37–7.62) for high tertile but among those with no e4, decline was −5.50 −(3.95–7.05) for the low and −3.03 −(1.64–4.42) for the high tertile (p for interaction = 0.02).
Over the course of the follow-up, 72 participants had incident dementia and we repeated the analyses after excluding these elders. The association between plasma β-amyloid 42/40 tertile and 9-year cognitive decline remained statistically significant (low tertile −5.49 −(4.29–6.69), mid −5.26 −(4.10–6.42) and high −3.16 −(1.98–4.34), p=0.002). The interaction between education plasma β-amyloid 42/40 and cognitive decline remained statistically or borderline significant (p=0.03) whereas the interaction with literacy level was no longer significant (p=0.08) The interaction between APOE e4, β-amyloid 42/40, and cognitive decline also became non significant (p=0.43).
Our results suggest that older non-demented adults with lower β-amyloid 42/40 level have an increased rate of cognitive decline over nine years compared with those with higher levels, and this relationship is modified by measures of cognitive reserve. Specifically, our results indicate that the association between β-amyloid plasma level is greater among those with less education, lower literacy, and an APOE e4 allele. These results are important, as the prevalence of cognitive impairment is increasing exponentially, and prevention will be crucial.1 To identify those at risk for dementia, biomarkers like plasma β-amyloid level that are relatively easy to obtain and minimally invasive could be useful. In addition, our findings of an interaction of cognitive reserve with the association of plasma β-amyloid level and cognitive decline could have public health importance as it may suggest pathways for modifying β-amyloid effects on cognition.
Our results are supported by those from several prospective studies that reported an association between the β-amyloid 42/40 ratio and dementia.2, 26, 27 Notably, one of these studies also used the Innogenetics INNO-BIA assay, which is one of the newest methods of quantifying plasma β-amyloid.26, 28 However, our results differ from several other studies that found the opposite or no association between plasma β-amyloid 42 or the ratio and dementia.6, 7, 29 Difficulty in interpreting and comparing these results stems from heterogeneous study designs and differences in follow-up time, and methods in quantifying β-amyloid. It is also possible that studies that did not find an association between plasma β-amyloid and cognitive decline or dementia included of participants with high cognitive reserve.
The accumulation of β-amyloid 42 in the cortex is one of the hallmarks of the AD pathology.8–10 This has been documented not only post-mortem in autopsy studies but also with in vivo imaging of β-amyloid.10, 30, 31 However, some studies have indicated that clinically “normal” elders have β-amyloid deposition as well, suggesting a disconnect between clinical and pathologic findings at times. For example, some individuals with extensive β-amyloid deposition as measured by autopsy or neuroimaging demonstrate little to no clinical symptoms of AD.11–13 This has led to a hypothesis of cognitive reserve.13, 15 Cognitive reserve is a broad concept used to explain why some individuals have a measureable pathological burden of β-amyloid but do not experience clinical symptoms of cognitive decline.15 The concept is often explained by a wide variety of compensatory factors including more synapses, more flexible neural networks, larger brain size, and beneficial life factors such as higher achieved education and occupational achievement.14, 15 While difficult to quantify, studies have used education and literacy as measures of cognitive reserve.12, 13, 18
Our results extend the hypothesis that cognitive reserve modifies the association between β-amyloid and cognitive impairment.12, 13, 18 We found that participants with high cognitive reserve (high education, high literacy, and no APOE e4 allele) experienced less cognitive decline than those with low reserve, and most importantly, those with high cognitive reserve had less or no association with β-amyloid level and rate of decline. Our findings are supported by reports that the association between cognitive performance and amyloid burden on imaging or pathology was modified by reserve, as measured by education and intelligence.13, 18 A recent study reported that both baseline and decreasing level of plasma β-amyloid 42 are associated with cognitive decline in older adults.32 However, no prior study has demonstrated this pattern of an interaction with cognitive reserve and plasma or CSF β-amyloid level on rate of cognitive decline.
This study has several strengths, including the prospective design and cognitive function measured repeatedly throughout the course of the study and a relatively large sample size. We were able to adjust for numerous potential confounders including those that have previously been shown to be related to cognitive function. We used Innogenetics INNO-BIA assays to measure β-amyloid 42 and 40, which may provide more accurate measurements of β-amyloid 42 and β-amyloid 40 due to its high sensitivity, low variability, and high reproducibility.28 Finally, we were able to assess cognitive reserve in term of education, literacy, and ApoE4.
There are also several weaknesses that should be taken into consideration when interpreting these results. As we did not have CSF measurements of β-amyloid, we could not correlate plasma β-amyloid to measurements of CSF β-amyloid. We also did not have measures on all cognitive domains, so future studies should investigate if similar results are found when different measures of cognitive function are used. In addition, while we used variables that often are used to assess cognitive reserve, we did not have others such as occupation or intellectual activity. Finally, the relative differences in cognitive decline in our cohort are moderate; a decline of 5 points on the 3MS has been used to define clinically significant cognitive impairment,33 and the observed differences between the high and low β-amyloid tertile in our study are approximately 3 points., However, this difference may be clinically significant and was sufficient to demonstrate the interaction of cognitive reserve with β-amyloid and cognitive decline.
Our results suggest that the plasma β-amyloid 42/40 ratio appears to be a biomarker of cognitive decline. Furthermore, we found that the association between this measure and rate of decline is modified by cognitive reserve. This suggests possible pathways such as cognitive activity or ongoing education for mitigating or preventing β-amyloid effects on cognition. Future studies should further explore the use of plasma β-amyloid as a biomarker, assess the mechanisms by which cognitive reserve modifies this association, and determine whether increasing cognitive reserve through interventions can reduce the risk of AD.
Dr. Yaffe had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding Support: NIA contract #’s N01-AG62101, N01-AG62103, N01-AG62106. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Dr. Yaffe is supported in part by a National Institute of Aging Grant (K24AG031155) and by an anonymous foundation.
Role of the Sponsor: The Intramural Research Program of the NIA participated in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript