Disease Mild Cognitive Impairment Research Articles

Resting state electroencephalographic alpha rhythms are sensitive to Alzheimer’s disease mild cognitive impairment progression at a 6-month follow-up

Are posterior resting-state electroencephalographic (rsEEG) alpha rhythms sensitive to the Alzheimer’s disease mild cognitive impairment (ADMCI) progression at a 6-month follow-up? Clinical, cerebrospinal, neuroimaging, and rsEEG datasets in 52 ADMCI and 60 Healthy old seniors (equivalent groups for demographic features) were available from an international archive (www.pdwaves.eu). The ADMCI patients were arbitrarily divided into two groups: REACTIVE and UNREACTIVE, based on the reduction (reactivity) in the posterior rsEEG alpha eLORETA source activities from the eyes-closed to eyes-open condition at ≥ −10% and −10%, respectively. 75% of the ADMCI patients were REACTIVE. Compared to the UNREACTIVE group, the REACTIVE group showed (1) less abnormal posterior rsEEG source activity during the eyes-closed condition and (2) a decrease in that activity at the 6-month follow-up. These effects could not be explained by neuroimaging and neuropsychological biomarkers of AD. Such a biomarker might reflect abnormalities in cortical arousal in quiet wakefulness to be used for clinical studies in ADMCI patients using 6-month follow-ups.

Characteristic patterns of functional connectivity-mediated cerebral small vessel disease-related cognitive impairment and depression.

Cerebral small vessel disease is common in most individuals aged 60years or older, and it is associated with cognitive dysfunction, depression, anxiety disorder, and mobility problems. Currently, many cerebral small vessel disease patients have both cognitive impairment and depressive symptoms, but the relationship between the 2 is unclear. The present research combined static and dynamic functional network connectivity methods to explore the patterns of functional networks in cerebral small vessel disease individuals with cognitive impairment and depression (cerebral small vessel disease-mild cognitive impairment with depression) and their relationship. We found specific functional network patterns in the cerebral small vessel disease-mild cognitive impairment with depression individuals (P < 0.05). The cerebral small vessel disease individuals with depression exhibited unstable dynamic functional network connectivity states (transitions likelihood: P = 0.040). In addition, we found that the connections within the lateral visual network between the sensorimotor network and ventral attention network could mediate white matter hyperintensity-related cognitive impairment (indirect effect: 0.064; 95% CI: 0.003, 0.170) and depression (indirect effect: -0.415; 95% CI: -1.080, -0.011). Cognitive function can negatively regulate white matter hyperintensity-related depression. These findings elucidate the association between cognitive impairment and depression and provide new insights into the underlying mechanism of cerebral small vessel disease-related cognitive dysfunction and depression.

Interactions between functional networks in Parkinson's disease mild cognitive impairment

The study of mild cognitive impairment (MCI) is critical to understand the underlying processes of cognitive decline in Parkinson’s disease (PD). Functional connectivity (FC) disruptions in PD-MCI patients have been observed in several networks. However, the functional and cognitive changes associated with the disruptions observed in these networks are still unclear. Using a data-driven methodology based on independent component analysis, we examined differences in FC RSNs among PD-MCI, PD cognitively normal patients (PD-CN) and healthy controls (HC) and studied their associations with cognitive and motor variables. A significant difference was found between PD-MCI vs PD-CN and HC in a FC-trait comprising sensorimotor (SMN), dorsal attention (DAN), ventral attention (VAN) and frontoparietal (FPN) networks. This FC-trait was associated with working memory, memory and the UPDRS motor scale. SMN involvement in verbal memory recall may be related with the FC-trait correlation with memory deficits. Meanwhile, working memory impairment may be reflected in the DAN, VAN and FPN interconnectivity disruptions with the SMN. Furthermore, interactions between the SMN and the DAN, VAN and FPN network reflect the intertwined decline of motor and cognitive abilities in PD-MCI. Our findings suggest that the memory impairments observed in PD-MCI are associated with reduced FC within the SMN and between SMN and attention networks.

SAGE-718 in Parkinson's disease mild cognitive impairment: results from the Phase 2 PARADIGM Study

SAGE-718 in Parkinson's disease mild cognitive impairment: results from the Phase 2 PARADIGM Study

Optimizing detection of Alzheimer’s disease in mild cognitive impairment: a 4-year biomarker study of mild behavioral impairment in ADNI and MEMENTO

BackgroundDisease-modifying drug use necessitates better Alzheimer disease (AD) detection. Mild cognitive impairment (MCI) leverages cognitive decline to identify the risk group; similarly, mild behavioral impairment (MBI) leverages behavioral change. Adding MBI to MCI improves dementia prognostication over conventional approaches of incorporating neuropsychiatric symptoms (NPS). Here, to determine if adding MBI would better identify AD, we interrogated associations between MBI in MCI, and cerebrospinal fluid biomarkers [β-amyloid (Aβ), phosphorylated-tau (p-tau), and total-tau (tau)-ATN], cross-sectionally and longitudinally.MethodsData were from two independent referral-based cohorts, ADNI (mean[SD] follow-up 3.14[1.07] years) and MEMENTO (4.25[1.40] years), collected 2003–2021. Exposure was based on three-group stratification: 1) NPS meeting MBI criteria; 2) conventionally measured NPS (NPSnotMBI); and 3) noNPS. Cohorts were analyzed separately for: 1) cross-sectional associations between NPS status and ATN biomarkers (linear regressions); 2) 4-year longitudinal repeated-measures associations of MBI and NPSnotMBI with ATN biomarkers (hierarchical linear mixed-effects models-LMEs); and 3) rates of incident dementia (Cox proportional hazards regressions).ResultsOf 510 MCI participants, 352 were from ADNI (43.5% females; mean [SD] age, 71.68 [7.40] years), and 158 from MEMENTO (46.2% females; 68.98 [8.18] years). In ADNI, MBI was associated with lower Aβ42 (standardized β [95%CI], -5.52% [-10.48-(-0.29)%]; p = 0.039), and Aβ42/40 (p = 0.01); higher p-tau (9.67% [3.96–15.70%]; p = 0.001), t-tau (7.71% [2.70–12.97%]; p = 0.002), p-tau/Aβ42 (p < 0.001), and t-tau/Aβ42 (p = 0.001). NPSnotMBI was associated only with lower Aβ42/40 (p = 0.045). LMEs revealed a similar 4-year AD-specific biomarker profile for MBI, with NPSnotMBI associated only with higher t-tau. MBI had a greater rate of incident dementia (HR [95%CI], 3.50 [1.99–6.17; p < 0.001). NPSnotMBI did not differ from noNPS (HR 0.96 [0.49–1.89]; p = 0.916). In MEMENTO, MBI demonstrated a similar magnitude and direction of effect for all biomarkers, but with a greater reduction in Aβ40. HR for incident dementia was 3.93 (p = 0.004) in MBI, and 1.83 (p = 0.266) in NPSnotMBI. Of MBI progressors to dementia, 81% developed AD dementia.ConclusionsThese findings support a biological basis for NPS that meet MBI criteria, the continued inclusion of MBI in NIA-AA ATN clinical staging, and the utility of MBI criteria to improve identification of patients for enrollment in disease-modifying drug trials or for clinical care.

Resting state electroencephalographic alpha rhythms predict and are sensitive to Alzheimer’s disease mild cognitive impairment progression at a 6-month follow-up

Resting state electroencephalographic alpha rhythms predict and are sensitive to Alzheimer’s disease mild cognitive impairment progression at a 6-month follow-up

Validation of the cross-cultural dementia screening test in Alzheimer's disease and Parkinson's disease.

The Cross-Cultural Dementia (CCD) is a new screening tool to evaluate cognitive impairment based on a cross-cultural perspective to reduce the bias of education, and language and cultural differences. We aimed to evaluate the diagnostic properties of the CCD in Spaniards for the assessment of patients with Alzheimer's disease in mild cognitive impairment (AD-MCI) and mild dementia stages (AD-D) and patients with mild cognitive impairment associated with Parkinson's disease (PD-MCI). Sixty participants with AD (50% MCI) and thirty with PD-MCI were enrolled. Each clinical group was compared against a healthy control group (HC) with the same number of participants and no significant differences in age, education, and sex. A comprehensive neuropsychological test battery and CCD were completed. Intergroup comparisons, ROC curves, and cut-off scores were calculated for the study of diagnostic properties. Intergroup differences were found in accordance with the cognitive profile of each clinical condition. Memory measures (Objects test) were especially relevant for the classification between AD and HC. Memory and executive function scores (Sun-Moon and Dots tests) were useful in the case of PD-MCI and HC. Furthermore, CCD described differences in executive functions and speed scores comparing AD-MCI and PD-MCI. Correlations between standardized neuropsychological tests and CCD measures supported the convergent validity of the test. CCD showed good discrimination properties and cut-off scores for dementia and extended its application to a sample of prodromal stages of AD and PD with mild cognitive impairment.

Early identification of subjective cognitive functional decline among patients with Parkinson’s disease: a longitudinal pilot study

Practical methods for early identification of Parkinson’s disease (PD) mild cognitive impairment (PD-MCI) through changes in real-life daily functioning are scarce. The aim of the study was to examine whether the cognitive functional (CF) feature, comprising of seven self-reported Movement Disorder Society’s (MDS) Unified Parkinson’s Disease Rating Scale (UPDRS) items, predicts PD patients’ cognitive functional status after a year. We conducted a 1-year follow-up of 34 PD patients (50–78 year; 70.6% men) suspected of MCI using the following measures: the MDS-UPDRS, UPDRS-CF feature, Beck Depression Inventory (BDI), Montreal Cognitive Assessment (MoCA), Trail Making Test (TMT), Parkinson’s Disease Cognitive Functional Rating Scale (PD-CFRS), and Daily Living Questionnaire (DLQ). The first and second UPDRS-CF feature scores, and additional measures at the 1-year follow-up significantly correlated. Hierarchical regression revealed that the initial MoCA, TMT, and BDI scores predicted the second UPDRS-CF, and the first UPDRS-CF predicted 31% of the second PD-CFRS score variance. Depression moderated the relationship between the first UPDRS-CF score and the DLQ Part A. These results suggest practical, self-reported, daily functional markers for identifying gradual decline in PD patients. They consider the patients’ heterogeneity, underlying cognitive pathology, and implications on daily functioning, health, and well-being.

Zoom-In Neural Network Deep-Learning Model for Alzheimer's Disease Assessments.

Deep neural networks have been successfully applied to generate predictive patterns from medical and diagnostic data. This paper presents an approach for assessing persons with Alzheimer's disease (AD) mild cognitive impairment (MCI), compared with normal control (NC) persons, using the zoom-in neural network (ZNN) deep-learning algorithm. ZNN stacks a set of zoom-in learning units (ZLUs) in a feedforward hierarchy without backpropagation. The resting-state fMRI (rs-fMRI) dataset for AD assessments was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The Automated Anatomical Labeling (AAL-90) atlas, which provides 90 neuroanatomical functional regions, was used to assess and detect the implicated regions in the course of AD. The features of the ZNN are extracted from the 140-time series rs-fMRI voxel values in a region of the brain. ZNN yields the three classification accuracies of AD versus MCI and NC, NC versus AD and MCI, and MCI versus AD and NC of 97.7%, 84.8%, and 72.7%, respectively, with the seven discriminative regions of interest (ROIs) in the AAL-90.

Can the prediction model using regression with optimal scale improve the power to predict the Parkinson's dementia?

BACKGROUNDEfficiently detecting Parkinson's disease (PD) with dementia (PDD) as soon as possible is an important issue in geriatric medicine.AIMTo develop a model for predicting PDD based on various neuropsychological tests using data from a nationwide survey conducted by the Korean Centers for Disease Control and Prevention and to present baseline data for the early detection of PDD.METHODSThis study comprised 289 patients who were 60 years or older with PD [110 with PDD and 179 Parkinson's Disease-Mild Cognitive Impairment (PD-MCI)]. Regre-ssion with optimal scaling (ROS) was used to identify independent relationships between the neuropsychological test results and PDD.RESULTSIn the ROS analysis, Korean version of mini mental state ex-amination (MMSE) (KOREAN version of MMSE) (b = -0.52, SE = 0.16) and Hoehn and Yahr staging (b = 0.44, SE = 0.19) were significantly effective models for distinguishing PDD from PD-MCI (P < 0.05), even after adjusting for all of the Parkinson's motor symptom and neuropsychological test results. The optimal number of categories (scaling factors) for KOREAN version of MMSE and Hoehn and Yahr Scale was 10 and 7, respectively.CONCLUSIONThe results of this study suggest that among the various neuropsychological tests conducted, the optimal classification scores for KOREAN version of MMSE and Hoehn and Yahr Scale could be utilized as an effective screening test for the early discrimination of PDD from PD-MCI.

Transcranial Current Stimulation as a Tool of Neuromodulation of Cognitive Functions in Parkinson's Disease.

Decrease in cognitive function is one of the most common causes of poor life quality and early disability in patients with Parkinson’s disease (PD). Existing methods of treatment are aimed at both correction of motor and non-motor symptoms. Methods of adjuvant therapy (or complementary therapy) for maintaining cognitive functions in patients with PD are of interest. A promising subject of research in this regard is the method of transcranial electric current stimulation (tES). Here we reviewed the current understanding of the pathogenesis of cognitive impairment in PD and of the effects of transcranial direct current stimulation and transcranial alternating current stimulation on the cognitive function of patients with PD-MCI (Parkinson’s Disease–Mild Cognitive Impairment).

Heterogeneity of PD-MCI in Candidates to Subthalamic Deep Brain Stimulation: Associated Cortical and Subcortical Modifications.

Parkinson's disease mild cognitive impairment (PD-MCI) is frequent and heterogenous. There is no consensus about its influence on subthalamic deep brain stimulation (STN-DBS) outcomes. To determine the prevalence of PD-MCI and its subtypes in candidates to STN-DBS. Secondarily, we sought to identify MRI structural markers associated with cognitive impairment in these subgroups. Baseline data from the French multicentric PREDISTIM cohort were used. Candidates to STN-DBS were classified according to their cognitive performance in normal cognition (PD-NC) or PD-MCI. The latter included frontostriatal (PD-FS) and posterior cortical (PD-PC) subtypes. Between-group comparisons were performed on demographical and clinical variables as well as on T1-weighted MRI sequences at the cortical and subcortical levels. 320 patients were included: 167 (52%) PD-NC and 153 (48%) PD-MCI patients. The latter group included 123 (80%) PD-FS and 30 (20%) PD-PC patients. There was no between-group difference regarding demographic and clinical variables. PD-PC patients had significantly lower global efficiency than PD-FS patients and significantly worse performance on visuospatial functions, episodic memory, and language. Compared to PD-NC, PD-MCI patients had cortical thinning and radiomic-based changes in the left caudate nucleus and hippocampus. There were no significant differences between the PD-MCI subtypes. Among the candidates to STN-DBS, a significant proportion has PD-MCI which is associated with cortical and subcortical alterations. Some PD-MCI patients have posterior cortical deficits, a subtype known to be at higher risk of dementia.

Physical inactivity is associated with Parkinson's disease mild cognitive impairment and dementia

Parkinson's disease (PD) is a neurodegenerative disorder marked by both motor symptoms and cognitive impairment. Individuals with PD are generally less physically active relative to healthy older adults. This study examined if physical activity predicted future PD mild cognitive impairment (PD-MCI) and PD dementia (PDD).Participants were part of the Parkinson's Progression Markers Initiative (PPMI), a longitudinal cohort study of individuals newly diagnosed with PD. 307 participants were followed for up to three years. Individuals were classified as cognitively normal (CN), PD mild cognitive impairment (PD-MCI), or PD dementia (PDD) at each year. A self-report measure of physical activity was completed annually. Ordinal multilevel models were computed to examine the longitudinal relationship between physical activity and cognitive status. Less self-reported engagement in physical activities predicted worse cognitive status. Specifically, we found evidence of a significant within-person effect. Individuals with PD who became less active were at greater risk of developing PD-MCI or PDD. This effect was driven by longitudinal decreases in leisure/recreational physical activities. Findings support the hypothesis that longitudinal changes in physical activity are associated with clinically meaningful diagnostic outcomes of cognitive status. Since individuals with PD are prone to sedentary behaviors, future studies are needed to determine the clinical utility of interventions promoting routine physical activity.

Does transcranial direct current stimulation enhance cognitive performance in Parkinson's disease mild cognitive impairment? An event-related potentials and neuropsychological assessment study.

Parkinson's disease-mild cognitive impairment (PD-MCI) is garnering attention as a key interventional period for cognitive impairment. Currently, there are no approved treatments for PD-MCI and encouraging results of transcranial direct current stimulation (tDCS) combined with other interventions have been proposed, though the efficacy and neural mechanisms of tDCS alone have not been studied in PD-MCI yet. The present double-blind, randomized, sham-controlled study assessed the effects of tDCS over the dorsolateral prefrontal cortex on cognitive functions via neuropsychological and electrophysiological evaluations in individuals with PD-MCI for the first time. Twenty-six individuals with PD-MCI were administered 10 sessions of active (n = 13) or sham (n = 13) prefrontal tDCS twice a day, for 5days. Changes were tested through a comprehensive neuropsychological battery and event-related potential recordings, which were performed before, immediately, and 1month after the administrations. Neuropsychological assessment showed an improvement in delayed recall and executive functions in the active group. N1 amplitudes in response to targets in the oddball test-likely indexing attention and discriminability and NoGo N2 amplitudes in the continuous performance test-likely indexing cognitive control and conflict monitoring increased in the active group. Active stimulation elicited higher benefits 1month after the administrations. The present findings substantiate the efficacy of tDCS on cognitive control and episodic memory, along with the neural underpinnings of cognitive control, highlighting its potential for therapeutic utility in PD-MCI. NCT 04,171,804. Date of registration: 21/11/2019.

Causal Evidence for the Multiple Demand Network in Change Detection: Auditory Mismatch Magnetoencephalography across Focal Neurodegenerative Diseases.

The multiple demand (MD) system is a network of fronto-parietal brain regions active during the organization and control of diverse cognitive operations. It has been argued that this activation may be a nonspecific signal of task difficulty. However, here we provide convergent evidence for a causal role for the MD network in the “simple task” of automatic auditory change detection, through the impairment of top-down control mechanisms. We employ independent structure-function mapping, dynamic causal modeling (DCM), and frequency-resolved functional connectivity analyses of MRI and magnetoencephalography (MEG) from 75 mixed-sex human patients across four neurodegenerative syndromes [behavioral variant fronto-temporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), posterior cortical atrophy (PCA), and Alzheimer's disease mild cognitive impairment with positive amyloid imaging (ADMCI)] and 48 age-matched controls. We show that atrophy of any MD node is sufficient to impair auditory neurophysiological response to change in frequency, location, intensity, continuity, or duration. There was no similar association with atrophy of the cingulo-opercular, salience or language networks, or with global atrophy. MD regions displayed increased functional but decreased effective connectivity as a function of neurodegeneration, suggesting partially effective compensation. Overall, we show that damage to any of the nodes of the MD network is sufficient to impair top-down control of sensation, providing a common mechanism for impaired change detection across dementia syndromes.SIGNIFICANCE STATEMENT Previous evidence for fronto-parietal networks controlling perception is largely associative and may be confounded by task difficulty. Here, we use a preattentive measure of automatic auditory change detection [mismatch negativity (MMN) magnetoencephalography (MEG)] to show that neurodegeneration in any frontal or parietal multiple demand (MD) node impairs primary auditory cortex (A1) neurophysiological response to change through top-down mechanisms. This explains why the impaired ability to respond to change is a core feature across dementias, and other conditions driven by brain network dysfunction, such as schizophrenia. It validates theoretical frameworks in which neurodegenerating networks upregulate connectivity as partially effective compensation. The significance extends beyond network science and dementia, in its construct validation of dynamic causal modeling (DCM), and human confirmation of frequency-resolved analyses of animal neurodegeneration models.

SAGE-718 in Parkinson's disease mild cognitive impairment: results from the phase 2 PARADIGM study

SAGE-718 in Parkinson's disease mild cognitive impairment: results from the phase 2 PARADIGM study

Resting State Electroencephalographic Alpha Rhythms Predict and are Sensitive to Alzheimer’S Disease Mild Cognitive Impairment Progression at a 6-Month Follow-Up

Resting State Electroencephalographic Alpha Rhythms Predict and are Sensitive to Alzheimer’S Disease Mild Cognitive Impairment Progression at a 6-Month Follow-Up

Resting-State Functional Connectivity in Frontostriatal and Posterior Cortical Subtypes in Parkinson's Disease-Mild Cognitive Impairment.

The "dual syndrome hypothesis" distinguished two subtypes in mild cognitive impairment (MCI) in Parkinson's disease: frontostriatal, characterized by attentional and executive deficits; and posterior cortical, characterized by visuospatial, memory, and language deficits. The aim was to identify resting-state functional modifications associated with these subtypes. Ninety-five nondemented patients categorized as having normal cognition (n=31), frontostriatal (n=14), posterior cortical (n=20), or mixed (n=30) cognitive subtype had a 3 T resting-state functional magnetic resonance imaging scan. Twenty-four age-matched healthy controls (HCs) were also included. A group-level independent component analysis was performed to identify resting-state networks, and the selected components were subdivided into 564 cortical regions in addition to 26 basal ganglia regions. Global intra- and inter-network connectivity along with global and local efficiencies was compared between groups. The network-based statistics approach was used to identify connections significantly different between groups. Patients with posterior cortical deficits had increased intra-network functional connectivity (FC) within the basal ganglia network compared with patients with frontostriatal deficits. Patients with frontostriatal deficits had reduced inter-network FC between several networks, including the visual, default-mode, sensorimotor, salience, dorsal attentional, basal ganglia, and frontoparietal networks, compared with HCs, patients with normal cognition, and patients with a posterior cortical subtype. Similar results were also found between patients with a mixed subtype and HCs. MCI subtypes are associated with specific changes in resting-state FC. Longitudinal studies are needed to determine the predictive potential of these markers regarding the risk of developing dementia. © 2021 International Parkinson and Movement Disorder Society.

Event‐Related Delta Oscillations are Diminished in Parkinson’s Disease with Different Cognitive Status: A Longitudinal EEG Study

AbstractBackgroundThe neurophysiological differences between Parkinson’s disease mild cognitive impairment (PD‐MCI) and cognitively normal Parkinson’s disease (PD‐CN) have been poorly understood, covering limited electrophysiological interpretation. Delta event‐related oscillations (ERO) are recognized as a useful electrophysiological indicator of cognitive decline (Güntekin et al., 2018; Yener et al., 2019). The aim of the present study was to investigate baseline and follow‐up delta EROs of individuals with PD‐CN and PD‐MCI in comparison with healthy controls (HC).MethodsThirty one PD‐CN, 23 PD‐MCI, and 30 demographically‐matched HC were included. All examinations were applied to participants in a time period of 12.50±0.80 months. A comprehensive neuropsychological test battery was used for the PD‐MCI classification (Litvan et al., 2012). EEGs were recorded during visual oddball paradigm. The maximum peak‐to‐peak event‐related delta (0.5‐3.5 Hz) responses of the groups to the target stimulus were measured. Repeated measures ANOVA included Group (3 levels: HC, PD‐CN, PD‐MCI) as a between‐subject factor, Time (2 levels: baseline, follow‐up), and Anterior‐Posterior Electrode Location [AP (6 levels: frontal, central, temporal, temporoparietal, parietal, occipital)] as a within‐subject factor.ResultsThere was an interaction effect for Group x Time on event‐related delta responses [F(2,81)=3.650, p=0.030], indicating follow‐up delta EROs were reduced only in PD‐CN group (Figure 1). Further analyses revealed that there was an interaction effect for AP x Group on baseline delta responses [F(10,405)=11.629, p&lt;0.001], and follow‐up delta [F(10,405)=9.569, p&lt;0.001] responses. At baseline, PD‐MCI had reduced delta EROs in all electrode locations except occipital than both PD‐CN and HC, while PD‐CN had reduced delta responses than HC over frontal and central areas (for all; p&lt;0.030) (Figure 2). At follow‐up, higher delta responses were detected in HC compared to both PD‐CN and PD‐MCI over all locations except occipital area (for all; p&lt;0.001) (Figure3).ConclusionsThe current study revealed that longitudinal delta ERO reduction was apparent only in PD‐CN group. Individuals with PD‐MCI demonstrated decline at both baseline and follow‐up assessments. These findings may be interpreted as diminished delta EROs can be a successful indicator of subtle cognitive alterations in PD‐CN before neuropsychological assessments.

The protective impact of education on brain structure and function in Alzheimer\u2019s disease

BackgroundThe Cognitive Reserve (CR) theory posits that brains with higher reserve can cope with more cerebral damage to minimize clinical manifestations. The aim of this study was to examine the effect of education (CR proxy) on brain structure and function in Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI) patients and in cognitively healthy elderly (HC) individuals.MethodsFifty-seven AD patients, 57 aMCI patients and 48 HCs were included to investigate the relationships between education years and gray matter volume (GMV), regional homogeneity (ReHo) and functional connectivity (FC) in brain regions to show associations with both structure and function. Taking the severity of the disease into account, we further assessed the relationships in AD stratified analyses.ResultsIn AD group, the GMV of the dorsal anterior cingulate cortex (dACC) and ReHo in the left inferior temporal cortex (ITC) were inversely associated with education years, after adjustment for age, sex, Mini-Mental State Examination (MMSE), and total intracranial volume or head motion parameters. Seed-based FC analyses revealed that education years were negatively correlated with the FC between the left anterior ITC and left mid frontal cortex as well as right superior frontal cortex and right angular gyrus. Stratified analyses results indicated that this negative relation between education and GMV, ReHo, FC was mainly present in mild AD, which was attenuated in moderate AD and aMCI groups.ConclusionsOur results support the CR theory, and suggest that CR may be protective against AD related brain pathology at the early stage of clinical dementia. These findings could provide the locus of CR-related functional brain mechanisms and a specific time-window for therapeutic interventions to help AD patients to cope better with the brain pathological damage by increasing CR.