Benecial impact of education on cognition in amyloid-positive individuals with subjective cognitive decline: The SILCODE study

Background: Previous studies suggest that education is associated with a decreased risk of dementia in individuals with subjective cognitive decline (SCD). However, the inuence of education on cognition in amyloid-positive SCD subjects is not clear. Methods: We performed a cross-sectional study that involved 43 amyloid-negative and 29 amyloid-positive SCD subjects from the Sino Longitudinal Study on Cognitive Decline (SILCODE) project. Cognitive assessment included episodic memory, executive function, language, and general cognitive function. Multiple linear regression model was used to assess the association of education on cognitive performance. Results: Multiple linear regression analysis suggested that education has a protective effect on executive function, language for the amyloid-negative SCD group and language, global cognition for the amyloid-positive SCD group. Conclusions: The present study indicated that education has the potential to delay disease progression in amyloid-positive SCD subjects.


Introduction
Alzheimer's disease (AD) is the major cause of dementia in the elderly and its pathological hallmarks are the accumulation of β-amyloid (Aβ) plaques and neuro brillary tangles [1]. Patients with AD typically present with memory loss and di culties with thinking or language and that eventually leads to impairment for daily activities [2]. According to the latest data from the Global Burden of Diseases, Injuries, and Risk Factors Study, 43.8 million people suffer from dementia worldwide in 2016 [3]. For now, there is no approved disease-modifying treatments since 2003 though several medications can relieve the symptom [4]. Therefore, AD is a global public health priority. Nevertheless, accumulating evidence has proposed that people may have the potential to reduce their risk of cognitive decline, and dementia at an individual level [5]. Existing research reports that up to half of AD cases worldwide might be attributed to potentially modi able risk factors and may be preventable through addressing these factors [6].
Education has been considered as one of the modi able factor for AD. It was estimated that low educational attainment has the highest population-attributable risk (PAR) of AD worldwide (19.1%, 95% CI 12.3-25.6) [7]. Conversely, higher level of education has been shown to prevent or delay the onset of dementia [8,9].
Subjective cognitive decline (SCD) refers to a condition that an individual subjectively experienced decline in cognitive function in the absence of evidence for objective cognitive impairment [10]. Mounting evidence suggests that SCD is an early indicator of AD, which subjects with SCD are at high-risk for developing AD [11][12][13]. At the same time, it should be noted that the majority of individuals with SCD will not progress to AD [14]. In order to increase the likelihood of preclinical AD in individuals with SCD, a set of features (SCD-plus) was proposed in 2014 [10]. Aβ is a feature of the SCD-plus and Aβ positive (Aβ+) A paper case report form (CRF) was used to record demographic features (for example, name, age,  [27]. Details on neuropsychological tests published previously [19].

APOE genotyping
For each participant, a fasting blood sample was drawn in the department of laboratory, Xuanwu Hospital at baseline. A part of this blood sample was used for analysis of the level of blood glucose, blood lipids, anti-syphilis, homocysteine, folic acid, vitamin B12, thyroid hormone, hemoglobin, blood coagulation and the other part was used to determine the Apolipoprotein E (ApoE) gene polymorphism status. Details of APOE genotyping have been published elsewhere [19]. In this study, APOE genotype was dichotomized into SCD individuals with 1 or 2 copies of the ε4 allele (APOE ε4 carriers) and those without any copies of the ε4 allele (APOE ε4 non-carriers).

AV45-PET Analysis
PET images were preprocessed with statistical parametric mapping (SPM12, available at https://www. l.ion.ucl.ac.uk/spm/software/spm12/) software in MATLAB (version R2014a; MathWorks, Natick, MA, United States). For subjects with T1 scans, their PET images were registered to the corresponding structural MRI image. The structural MRI images were segmented into gray matter, white matter and cerebrospinal uid tissue probability maps, in which nonlinear transformation parameters were obtained. Then, the non-linear transformation parameters were used to normalize the registered PET images into the Montreal Neurological Institute (MNI) stereotactic template. For subjects without T1 scans, their PET images were spatially normalized into MNI brain space with the TPM atlas. Then all PET images were resampled into 3 × 3 × 3 mm 3 voxels. Finally, normalized PET images were smoothed by an isotropic Gaussian smoothing kernel with the full-width at half maximum (FWHM) of 8 × 8 × 8 mm 3 to improve the signal-to-noise ratio. PET images were subsequently scaled to the whole cerebellum to get the SUVR maps. Then, mean SUVR maps of each group were obtained for visualization by MRIcroN (available at https://www.nitrc.org/projects/mricron) to show the difference in Aβ level between the two groups.

Statistical analyses
First, continuous variables were tested for normality using the Shapiro-Wilk test. Normally distributed variables were reported as the mean ± standard deviation, while not normally distributed variables were described as median ± interquartile range. Categorical variables were expressed in absolute numbers and percentiles. Statistical differences between the two groups were analysed using t test, Mann Whitney U test or Chi-square test. Second, explorative analysis probed the association between education and score of neuropsychological tests including AVLT-H-N5, AVLT-H-N7, STT-A, STT-B, AFT, BNT and MoCA-B. Third, multiple linear regression analysis was used to quantify the in uence of education on cognitive function with the score of neuropsychological tests as the dependent variable and education as independent variables. Age, education, gender were entered as independent variables. Regression diagnostics were performed to ensure the assumptions for linear regression were met. Residuals were normally distributed. Durbin-Watson test statistics indicated independence of observations and heteroscedasticity was in conformance with test assumptions (results not shown). All statistical analyses were performed in R (R version 3.6.3). The signi cant level was set at p< 0.05 (2-sided).

Subject characteristics
Demographic and clinical characteristics of the total sample and according to Aβ load are summarized in table 1. Of the 72 SCD participants, 43 (59.7%) were Aβ-and 29 (40.3%) were Aβ+. The average age was 65 years. The sample consisted predominantly of women (66.7%). The mean years of education was 12.
The mean cortical SUVR of Aβ-PET values was 1.16. The proportion of APOE ε4 carriers was 30.6%. There was no statistically signi cant difference between two groups in demographic characteristics and neuropsychological test scores. However, the SUVR of Aβ+ SCD group was signi cantly higher than that of Aβ-SCD group. The SUVR maps of Aβ load were illustrated in gure 2 for each group. In addition, no subjects in the Aβ+ SCD group had diabetes.

Discussion
In the present study, we investigated the effects of education on multiple cognitive functions in Aβ+ SCD subjects. The main nding of our study is that education has a bene cial effect on cognition in Aβ+ SCD subjects.
Our recent study has shown that education exerted a protective effect on all neuropsychological tests among SCD subjects without explicit consideration of the Aβ status [17]. Thus, this study extends our previous ndings and provides direct con rmation that education could have a positive in uence on cognitive function in Aβ+ SCD individuals. Similarly to our results, a previous study demonstrated that education has a positive effect on attention, executive functioning, and global cognition in predementia participants (Aβ+ SCD/MCI) [28]. Recently, a systematic review and meta analysis based on 243 observational prospective studies and 153 randomised controlled trials including a total of 44 676 studies proposed that people should receive as much education as possible in early life for AD prevention (Class I, level A4) [29]. It is generally believed that years of education could be considered a proxy used to measure cognitive reserve (CR) [30]. The concept of CR refers to the ability to use alternate functional brain processes to cope with brain pathology or cognitive aging to sustain normal performance levels on cognitive function [31]. The theory of CR contributed to explain the disparity between an individual's level of AD pathology and the clinical manifestation of those brain damages [32,33]. According to the theory, individuals with high CR remain clinically normal in the early stage of AD, but the rate of decline in cognitive performance is more rapid than in those with low CR in the late stage of AD [34]. Indeed, there is a considerable amount of evidence supports that higher levels of CR protect against progression of from SCD to MCI [35,36], and diagnostic conversion for normal cognition [37,38]. In this sense, our ndings from this study are consistent with the theory of CR. However, the mechanism underlying the positive in uence of education on cognitive function in Aβ+ SCD subjects is not clear.
limitation Strength of this study was that we use biomarker to increase the likelihood of SCD due to AD. However, this study has several limitations. First, this study was the cross-sectional design, and future studies evaluating the impact of education on progression for Aβ+ SCD individuals longitudinally are desirable.
Second, the sample size was small with only 72 subjects due to insu cient access to the opportunities of Aβ-PET scans, which may have affected the stability and accuracy of these results. Third, we used SUVR of Aβ levels of 1.18 to de ne Aβ positive status, as referred from the Alzheimer's Disease Neuroimaging Initiative. However, this cutoff value, developed in western countries, has not been validated in a Chinese population. Therefore, direct application of that cutoff value may lead to misclassi cation of our Chinese samples.

Conclusions
In summary, the present study found that education has the potential to delay disease progression for Aβ+ SCD subjects. Therefore, improving the popularization of basic education may be a potentially promising approaches to preventing AD.

Declarations
Ethics approval and consent to participate The protocol of the study was approved by the medical ethics committee of Xuanwu Hospital of Capital Medical University. Beijing, China, and all participants gave their written informed consent before any study procedures began.

Consent for publication
Not applicable.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
This article was supported by the National Natural Science Foundation of China (Grant 61633018).
Authors' contributions GC collected, analyzed, interpreted the data and drafted this manuscript. CL analyzed the data. KY revised this manuscript. XJ and YH designed this study and revised this manuscript. All authors read and approved the nal manuscript.  Tables   Table 1 Demographic  The ow chart of this study. NC normal control, MCI mild cognitive decline, AD Alzheimer's disease, PET positron emission tomography, SCD subjective cognitive decline, Aβ-Aβ negative, Aβ+ Aβ positive.