Health-related quality of life instrument with 8 items to measure health-related quality of life among family caregivers of people with dementia: A pilot validation study.

BACKGROUND: The health-related quality of life instrument with 8 items (HINT-8) was developed to measure health-related quality of life (HRQoL) in Korea. However, the HINT-8 has not yet been validated among the family caregivers of people with dementia (PwD). DESIGN: A cross-sectional pilot study. OBJECTIVE: The study aimed to examine the convergent and discriminant validity of the HINT-8 among family caregivers of individuals with dementia. SAMPLE: Forty-seven family caregivers of PwD. MEASUREMENTS: HINT-8 was compared with the 5-level EQ-5D (EQ-5D-5L) to assess its convergent and discriminant validity. Additionally, the association between the two instruments assessing HRQoL was examined using the short-form Bédard-Zarit Burden Interview (SZBI). RESULTS: The HINT-8 was a promising and valid HRQoL instrument for family caregivers of PwD. There was a significantly high correlation between the overall HINT-8 and EQ-5D-5L indices (r = 0.85, p < .001). The HINT-8 had acceptable psychometric properties compared to the commonly used EQ-5D-5L, as indicated by the subdomains associated with family caregivers' burden measured by the SZBI. CONCLUSION: Future studies should compare the HINT-8 with existing dementia carer-specific QoL instruments among a larger study sample to enhance its statistical power and confirm its reliability and structural validity.

Multi-Ethnic Norms for Volumes of Subcortical and Lobar Brain Structures Measured by Neuro I: Ethnicity May Improve the Diagnosis of Alzheimer's Disease1.

Background: We previously demonstrated the validity of a regression model that included ethnicity as a novel predictor for predicting normative brain volumes in old age. The model was optimized using brain volumes measured with a standard tool FreeSurfer. Objective: Here we further verified the prediction model using newly estimated brain volumes from Neuro I, a quantitative brain analysis system developed for Korean populations. Methods: Lobar and subcortical volumes were estimated from MRI images of 1,629 normal Korean and 786 Caucasian subjects (age range 59-89) and were predicted in linear regression from ethnicity, age, sex, intracranial volume, magnetic field strength, and scanner manufacturers. Results: In the regression model predicting the new volumes, ethnicity was again a substantial predictor in most regions. Additionally, the model-based z-scores of regions were calculated for 428 AD patients and the matched controls, and then employed for diagnostic classification. When the AD classifier adopted the z-scores adjusted for ethnicity, the diagnostic accuracy has noticeably improved (AUC = 0.85, ΔAUC = + 0.04, D = 4.10, p < 0.001). Conclusions: Our results suggest that the prediction model remains robust across different measurement tool, and ethnicity significantly contributes to the establishment of norms for brain volumes and the development of a diagnostic system for neurodegenerative diseases.

Association between the COVID-19 pandemic, caregiving burden, and quality of life of caregivers of people with dementia: A cross-sectional study.

This study aimed to examine the association of COVID-19-related stress, anxiety, access to public healthcare services, and the presence of secondary caregivers (CGs) on the burden of caregiving and health-related quality of life (HRQoL) for CGs of people with dementia (PwD). A cross-sectional survey with 218 family CGs for PwD was completed in various settings between August and September 2021. The CGs had moderate and severe stress (42.7%) and reported having difficulty accessing public healthcare services (51.8%) and receiving help from secondary CGs (42.7%). In the multivariable linear regression, the stress and anxiety levels related to COVID-19 had a positive association with caregiver burden (ß = 4.25, p < 0.001, and ß = 5.73, p = 0.032, respectively), with no statistically significant association to HRQoL. Unexpectedly, accessing public healthcare services and supporting the secondary CGs were unrelated to the caregiving burden and HRQoL. Therefore, interventions aiming to alleviate family CGs' stress and anxiety levels should be provided to ensure PwD live in their homes in terms of continuity of public health service delivery.

Caregiving burden and healthcare utilization in family caregivers of people with dementia: Long term impact of the public family caregiver intervention.

Despite community-based interventions to decrease the caregiving burden on family caregivers of people with dementia (PwD), long-term assessment of community-based public programs is lacking. Therefore, the study aims to identify the long-term effects of community-based dementia caregiver intervention on the caregiving burden and healthcare utilization among family caregivers for PwD. Additionally, we investigated the predictors of caregiving burden and healthcare utilization. Of the participants, 32 (76%) intervention and 15 (38%) control groups responded to the one-year follow-up. We assessed caregiver burden using the short-form Zarit Burden Interview (sZBI) and collected healthcare utilization data using questionnaire at baseline and 12 months. Compared with the control group, the intervention group did not experience a reduction in caregiving burden and healthcare utilization. Predictors of caregivers' perceived burden were spouses as the primary caregiver and having multiple comorbidities. The predictors identified in this study should be considered when implementing public family support programs.

Korean Medication Algorithm Project for Bipolar Disorder 2022: Comparisons with Other Treatment Guidelines.

The objective of this study was to compare recommendations of the Korean Medication Algorithm Project for Bipolar Disorder 2022 (KMAP-BP 2022) with other recently published guidelines for treating bipolar disorder. We reviewed a total of six recently published global treatment guidelines and compared treatment recommendation of the KMAP-BP 2022 with those of other guidelines. For initial treatment of mania, there were no significant differences across treatment guidelines. All guidelines recommended mood stabilizer (MS) or atypical antipsychotic (AAP) monotherapy or a combination of an MS with an AAP as a first-line treatment strategy in a same degree for mania. However, the KMAP-BP 2022 recommended MS + AAP combination therapy for psychotic mania, mixed mania and psychotic depression as treatment of choice. Aripiprazole, quetiapine and olanzapine were the first-line AAPs for nearly all phases of bipolar disorder across guidelines. Some guideline suggested olanzapine is a second-line options during maintenance treatment, related to concern about long-term tolerability. Most guidelines advocated newer AAPs (asenapine, cariprazine, long-acting injectable risperidone, and aripiprazole once monthly) as first-line treatment options for all phases while lamotrigine was recommended for depressive and maintenance phases. Lithium and valproic acid were commonly used as MSs in all phases of bipolar disorder. KMAP-BP 2022 guidelines were similar to other guidelines, reflecting current changes in prescription patterns for bipolar disorder based on accumulated research data. Strong preference for combination therapy was characteristic of KMAP-BP 2022, predominantly in the treatment of psychotic mania, mixed mania and psychotic depression.

Korean Medication Algorithm Project for Bipolar Disorder 2022, Fifth Revision: An Executive Summary.

Objective: We revised the Korean Medication Algorithm Project for Bipolar Disorder (KMAP-BP), first published in 2002 and revised in 2006, 2010, 2014, and 2018, to reflect recent progress in the treatment of bipolar disorder. Methods: The questionnaires consisted of 56 items for adult patients and 7 items for child/adolescent patients, and were used to obtain the consensus of experts regarding pharmacological treatment strategies for various phases of bipolar disorder. The review committee included 87 Korean psychiatrists and 40 child and adolescent psychiatry experts. Results: For treatment of manic episodes, a combination of a mood stabilizer (MS) and atypical antipsychotics (AAP), or monotherapy with MS or AAP were recommended as first-line treatments. Combinations of MS and AAP, or AAP and lamotrigine (LMT) were recommended as first-line treatments for depressive episodes regardless of the severity. Monotherapy with MS, AAP, or LMT were also first-line treatments for mild to moderate depressive episodes. For mixed features, a combination of MS and AAP, or monotherapy with AAP or MS were recommended as first-line treatments, and a combination of AAP and LMT, or MS and LMT were the first-line treatments for depressive mixed state. Conclusion: The recommendations of the KMAP-BP 2022 have changed from the previous version, to reflect the evolution of the social culture and healthcare system in Korea and recent evidence regarding pharmacotherapy of bipolar disorder. The KMAP-BP 2022 provides clinicians with a wealth of information regarding appropriate strategies to treat patients with bipolar disorder.

A Single Baseline Amyloid Positron Emission Tomography Could Be Sufficient for Predicting Alzheimer's Disease Conversion in Mild Cognitive Impairment.

OBJECTIVE: Baseline amyloid burden in mild cognitive impairment (MCI) has been linked to conversion to Alzheimer's disease (AD), but the comparison of baseline and longitudinal changes in amyloid burden for predicting AD remains unresolved. The objectives of this study aimed to compare the prognostic ability of baseline and longitudinal changes in amyloid burden in MCI patients. METHODS: Seventy-five individuals with MCI were recruited and examined annually by clinical interviews for a mean follow-up of 24 months (range, 11.6-42.0). [18F]Florbetaben positron emission tomography (PET) scans were performed. T1-weighted 3D volumes were acquired for co-registration, and to define regions of interest. We examined whether baseline and longitudinal amyloid burden changes can improve AD conversion by Cox proportional hazard model analysis and receiver operating characteristic (ROC) curve analysis. RESULTS: Cox proportional hazards model analysis showed that baseline amyloid burden was significantly associated with increased risk of conversion to AD (hazard ratio [HR]=10.0; 95% confidence interval [CI], 1.15-85.39; p=0.04), but longitudinal amyloid burden changes was not (HR=0.2; 95% CI, 0.02-1.18; p=0.07). When predicting AD, longitudinal amyloid burden changes had better ROC accuracy of 65.2% (95% CI, 48.4-82.0) than baseline amyloid burden of 59.6% (95% CI, 40.3-79.0), without statistical significance in pairwise comparison. CONCLUSION: A single baseline amyloid PET could be sufficient in the prediction of AD conversion in MCI.

The Korean Medication Algorithm Project for Depressive Disorder 2021: Comparisons with Other Treatment Guidelines.

The Korean Medication Algorithm Project for Depressive Disorder (KMAP-DD) first was published in 2002, and has been revised four times, in 2006, 2012, 2017, and 2021. In this review, we compared recommendations from the recently revised KMAP-DD 2021 to four global clinical practice guidelines (CPGs) for depression published after 2010. The recommendations from the KMAP-DD 2021 were similar to those from other CPGs, although there were some differences. The KMAP-DD 2021 reflected social culture and the healthcare system in Korea and recent evidence about pharmacotherapy for depression, as did other recently published evidence-based guidelines. Despite some intrinsic limitations as an expert consensus-based guideline, the KMAP-DD 2021 can be helpful for Korean psychiatrists making decisions in clinical settings by complementing previously published evidence-based guidelines, especially for some clinical situations lacking evidence from rigorously designed clinical trials.

Korean Medication Algorithm for Depressive Disorder 2021, Fourth Revision: An Executive Summary.

OBJECTIVE: In the 19 years since the Korean College of Neuropsychopharmacology and the Korean Society for Affective Disorders developed the Korean Medication Algorithm Project for Depressive Disorder (KMAP-DD) in 2002, four revisions have been conducted. METHODS: To increase survey efficiency in this revision, to cover the general clinical practice, and to compare the results with previous KMAP-DD series, the overall structure of the questionnaire was maintained. The six sections of the questionnaire were as follows: 1) pharmacological treatment strategies for major depressive disorder (MDD) with/without psychotic features; 2) pharmacological treatment strategies for persistent depressive disorder and other depressive disorder subtypes; 3) consensus for treatment-resistant depression; 4) the choice of an antidepressant in the context of safety, adverse effects, and comorbid physical illnesses; 5) treatment strategies for special populations (children/adolescents, elderly, and women); and 6) non-pharmacological biological therapies. Recommended first-, second-, and third-line strategies were derived statistically. RESULTS: There has been little change in the four years since KMAP-DD 2017 due to the lack of newly introduced drug or treatment strategies. However, shortened waiting time between the initial and subsequent treatments, increased preference for atypical antipsychotics (AAPs), especially aripiprazole, and combination strategies with AAPs yield an active and somewhat aggressive treatment trend in Korea. CONCLUSION: We expect KMAP-DD to provide clinicians with useful information about the specific strategies and medications appropriate for treating patients with MDD by bridging the gap between clinical real practice and the evidence-based world.

Multi-Racial Normative Data for Lobar and Subcortical Brain Volumes in Old Age: Korean and Caucasian Norms May Be Incompatible With Each Other†.

Brain aging is becoming an increasingly important topic, and the norms of brain structures are essential for diagnosing neurodegenerative diseases. However, previous studies of the aging brain have mostly focused on Caucasians, not East Asians. The aim of this paper was to examine ethnic differences in the aging process of brain structures or to determine to what extent ethnicity affects the normative values of lobar and subcortical volumes in clinically normal elderly and the diagnosis in multi-racial patients with Alzheimer's disease (AD). Lobar and subcortical volumes were measured using FreeSurfer from MRI data of 1,686 normal Koreans (age range 59-89) and 851 Caucasian, non-Hispanic subjects in the ADNI and OASIS datasets. The regression models were designed to predict brain volumes, including ethnicity, age, sex, intracranial volume (ICV), magnetic field strength (MFS), and MRI scanner manufacturers as independent variables. Ethnicity had a significant effect for all lobar (|ß| > 0.20, p < 0.001) and subcortical regions (|ß| > 0.08, p < 0.001) except left pallidus and bilateral ventricles. To demonstrate the validity of the z-score for AD diagnosis, 420 patients and 420 normal controls were selected evenly from the Korean and Caucasian datasets. The four validation groups divided by race and diagnosis were matched on age and sex using a propensity score matching. We analyzed whether and to what extent the ethnicity adjustment improved the diagnostic power of the logistic regression model that was built using the only z-scores of six regions: bilateral temporal cortices, hippocampi, and amygdalae. The performance of the classifier after ethnicity adjustment was significantly improved compared with the classifier before ethnicity adjustment (ΔAUC = 0.10, D = 7.80, p < 0.001; AUC comparison test using bootstrap). Korean AD dementia patients may not be classified by Caucasian norms of brain volumes because the brain regions vulnerable to AD dementia are bigger in normal Korean elderly peoples. Therefore, ethnicity is an essential factor in establishing normative data for regional volumes in brain aging and applying it to the diagnosis of neurodegenerative diseases.

Corrigendum: The Aging Slopes of Brain Structures Vary by Ethnicity and Sex: Evidence From a Large Magnetic Resonance Imaging Dataset From a Single Scanner of Cognitively Healthy Elderly People in Korea.

[This corrects the article DOI: 10.3389/fnagi.2020.00233.].

The Aging Slopes of Brain Structures Vary by Ethnicity and Sex: Evidence From a Large Magnetic Resonance Imaging Dataset From a Single Scanner of Cognitively Healthy Elderly People in Korea.

The aging of the brain is a well-investigated topic, but existing analyses have mainly focused on Caucasian samples. To investigate brain aging in East Asians, we measured cortical and subcortical volumes from magnetic resonance imaging (MRI) scans of 1,008 cognitively normal elderly Koreans from the Gwangju Alzheimer's and Related Dementia cohort and 342 Caucasians from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. To determine whether the aging effect varies with ethnicity and sex, beta coefficients of age and confidence intervals (CIs) were estimated in each ethnicity-sex group using a bootstrap method and a regression analysis using the relative volume to intracranial volume as predicted. The betas or aging slopes largely were not significantly different between ethnicity and sex groups in most types of brain structures. However, ethnic differences between the two female groups were found in the brain, most cortical regions, and a few subcortical regions. Ethnic differences in brain aging are likely due in large part to genetic factors; thus, we compared carriers and non-carriers of a gene relevant to longevity and neurodegenerative diseases, such as apolipoprotein E (APOE) ε4. The regions with ethnic differences in women also showed significant differences between Korean APOE ε4 non-carriers and Caucasian APOE ε4 carriers. Furthermore, Caucasian women showed significant APOE ε4 effects in the largest number of regions. These results illustrate that much of the ethnic differences in females may be explained by synergistic effects of ethnic background and APOE ε4 carrier status. Our results suggest that sex-dependent differences of aging between ethnic backgrounds may be due to ethnicity-dependent effects of genetic risk factors, such as APOE ε4. We also presented the normative information on volume estimates of the brain structures of the elderly Korean people in the subdivided age groups. This normative information of the aging brain stratified by ethnicity provides the age-related reference ranges quantified to replace visual judgment and facilitate precise clinical decision-making.

Association of Subjective Memory Complaints with the Left Parahippocampal Amyloid Burden in Mild Cognitive Impairment.

BACKGROUND: Subjective memory complaints (SMC) are a risk factor for Alzheimer's disease. OBJECTIVE: We aimed to explore the association between SMC and regional amyloid-ß (Aß) deposition in mild cognitive impairment (MCI). METHODS: Sixty-eight individuals with MCI were recruited. [18F]Florbetaben PET scans were performed. T1-weighted 3D volumes were also acquired for co-registration with PET and for defining the regions of interest (ROI). Two step exploratory partial correlation analyses between SMC and Aß deposition were performed with covariates of age, sex, education, and depression. Furthermore, for the priori ROI that had the most significant partial correlation, we investigated the correlation between the SMC and regional Aß burden using a multiple linear regression model controlling for depression, age, sex, and education. RESULTS: Significant positive correlations between the SMC and Aß burden was found in the medial temporal ROI (first step) and in the left parahippocampus ROI (second step). In the priori left parahippocampus, we found significant correlation between the SMC and Aß burden (R2 = 0.473, p = 0.014). CONCLUSIONS: Our study suggested that the SMC was associated with amyloid accumulation, especially in the left parahippocampus, in individuals with MCI.

Neural Correlates of Self-referential Processing and Their Clinical Implications in Social Anxiety Disorder.

Social anxiety disorder (SAD) is associated with aberrant self-referential processing (SRP) such as increased self-focused attention. Aberrant SRP is one of the core features of SAD and is also related to therapeutic interventions. Understanding of the underlying neural correlates of SRP in SAD is important for identifying specific brain regions as treatment targets. We reviewed functional magnetic resonance imaging (fMRI) studies to clarify the neural correlates of SRP and their clinical implications for SAD. Task-based and resting fMRI studies have reported the cortical midline structures including the default mode network, theory of mind-related regions of the temporo-parietal junction and temporal pole, and the insula as significant neural correlates of aberrant SRP in SAD patients. Also, these neural correlates are related to clinical improvement on pharmacological and cognitive-behavioral treatments. Furthermore, these could be candidates for the development of novel SAD treatments. This review supports that neural correlates of SAD may be significant biomarkers for future pathophysiology based treatment.

Pre-Mild Cognitive Impairment: Can Visual Memory Predict Who Rapidly Convert to Mild Cognitive Impairment?

OBJECTIVE: Little is known about the natural course of pre-mild cognitive impairment (pre-MCI) and predictors to MCI. We followedup individuals with pre-MCI and cognitively normal (CN) elders to identify neuropsychological predictors for rapid conversion to MCI. METHODS: Seventy-seven individuals with pre-MCI and 180 CN elders were recruited from the pool of individuals registered at the National Research Center for Dementia in Gwangju, Korea. We followed-up with them after a mean of 14±2.29 months. All participants underwent comprehensive clinical and neuropsychological assessment. Logistic regression analysis examined the ability of neuropsychological tests to predict conversions to MCI. RESULTS: Of 257 participants, 142 (55.3%) were eligible for the follow-up study (102 CN, 40 pre-MCI). Logistic regression revealed that spatial delayed recall significantly predicted the conversion from pre-MCI to MCI. In CN, copy for a complex figure significantly predicted the conversion to pre-MCI or MCI. CONCLUSION: Our findings indicated that spatial delayed recall was associated with rapid conversion from pre-MCI to MCI. Spatial organization and planning, measured by complex figure reproduction, were associated with rapid conversion from CN to pre-MCI or MCI. Our study suggests that inclusion of visuospatial reproduction and memory using a complex figure further facilitates early detection of MCI.

Association of subjective memory complaint and depressive symptoms with objective cognitive functions in prodromal Alzheimer's disease including pre-mild cognitive impairment.

BACKGROUND: Subjective memory complaints (SMC) and depressive symptoms (SDS) are common in the elderly population. However, the relationship among SMC, SDS, and cognitive function remains unclear. We investigated these associations in the elderly from cognitively normal (CN), pre-mild cognitive impairment (MCI), and amnestic MCI (aMCI) groups. METHODS: Participants (CN, 299; pre-MCI, 106; aMCI, 267) underwent comprehensive clinical and neuropsychological assessment. and self-report SMC and SDS questionnaires. SMC and SDS were administered in a self-report format. For each neuropsychological test z-score, stepwise multiple linear regressions were performed to assess the relative contribution of SMC, SDS, and their interactions. RESULTS: SMC are associated with lower objective memory, while SDS are associated with lower psychomotor speed. Interactions between SMC and SDS were significant for tests of memory, executive function, psychomotor speed, and global cognition. Additional analyses revealed that SDS moderated the SMC-cognition relationship such that only individuals with higher SDS showed significant SMC-cognition associations. LIMITATIONS: Due to the cross-sectional design, associations among SMC, SDS, and cognitive function was rather weak, albeit significant. Additionally, future biomarker studies, such as those assessing amyloid burden, are needed to explore the mechanisms underlying the relationship among SMC, SDS, and cognitive function. CONCLUSION: Early identification of individuals at risk for developing abnormal cognitive changes is critical. Our findings from the study involving a large sample of carefully selected participants suggest that SMC and SDS could be used as early detection markers of Alzheimer's disease.

Structural MRI and Amyloid PET Imaging for Prediction of Conversion to Alzheimer's Disease in Patients with Mild Cognitive Impairment: A Meta-Analysis.

OBJECTIVE: The aim of this study was to explore the prognostic values of biomarkers of neurodegeneration as measured by magnetic resonance imaging (MRI) and amyloid burden as measured by amyloid positron emission tomography (PET) in predicting conversion to Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI). METHODS: PubMed and EMBASE databases were searched for structural MRI or amyloid PET imaging studies published between January 2000 and July 2014 that reported conversion to AD in patients with MCI. Means and standard deviations or individual numbers of biomarkers with positive or negative status at baseline and corresponding numbers of patients who had progressed to AD at follow-up were retrieved from each study. The effect size of each biomarker was expressed as Hedges's g. RESULTS: Twenty-four MRI studies and 8 amyloid PET imaging studies were retrieved. 674 of the 1741 participants (39%) developed AD. The effect size for predicting conversion to AD was 0.770 [95% confidence interval (CI) 0.607-0.934] for across MRI and 1.316 (95% CI 0.920-1.412) for amyloid PET imaging (p<0.001). The effect size was 1.256 (95% CI 0.902-1.609) for entorhinal cortex volume from MRI. CONCLUSION: Our study suggests that volumetric MRI measurement may be useful for the early detection of AD.

Altered Executive Function in Pre-Mild Cognitive Impairment.

BACKGROUND: For the early detection of Alzheimer's disease (AD), there is increasing interest in pre-mild cognitive impairment (pre-MCI). OBJECTIVE: We explored the neuropsychological characteristics in a group of pre-MCI and cognitively normal (CN) elderly individuals, with the aim of providing measures sensitive to cognitive change in pre-MCI. METHODS: We included 188 CN elderly and 77 individuals with pre-MCI. All participants underwent comprehensive clinical and neuropsychological assessment. We compared 17 cognitive tests between the CN and pre-MCI groups by using one-way ANOVAs with false discovery rate correction for multiple comparisons. Pearson's correlations were also obtained between episodic memory and executive function tests in the pre-MCI group. RESULTS: The pre-MCI group showed significantly lower scores for visual immediate recall, fluency tests, and Stroop color naming in the color-word incongruent condition than the CN group (p < 0.05). Most of these executive function measures were significantly correlated with episodic memory (p < 0.05). There were no significant group-differences in other tests assessing attention, verbal memory, visuospatial ability, and language. CONCLUSION: Our findings indicate that poor executive function especially demanding inhibition and goal-directed behaviors within time limit could be the characteristics of the very early cognitive sign in the course of AD.

Topographical APOE ɛ4 Genotype Influence on Cerebral Metabolism in the Continuum of Alzheimer's Disease: Amyloid Burden Adjusted Analysis.

BACKGROUND: APOE ɛ4 contributes to Alzheimer's disease (AD) pathogenesis by amyloid-beta (Aß)-dependent and Aß-independent processes. OBJECTIVE: We investigated the APOE ɛ4 influence on regional cerebral glucose metabolism (rCMglc) in the continuum of AD after Aß adjustment. METHODS: We included 318 cognitively normal (CN) elderly, 498 mild cognitive impairment (MCI), and 178 AD from the Alzheimer's Disease Neuroimaging Initiative database. They had [18F] florbetapir positron emission tomography (PET) and [18F] fluorodeoxyglucose (FDG)-PET conducted within 3 months of a clinical and cognitive assessment visit and APOE genotype. At first, the rCMglc differences between APOE ɛ4 carriers (ɛ4+) and non-carriers (ɛ4-) were estimated on a voxel-based analysis using a 'two-sample t-test' design. In the second analysis, Aß was added as covariate. RESULTS: In CN, ɛ4+ showed reduced rCMglc compared to ɛ4-in the bilateral frontal, temporal, and the left parietal regions. In MCI, ɛ4+ showed reduced rCMglc compared to ɛ4- in the bilateral posterior parietal, temporal, and left frontal regions. In AD, ɛ4+ showed reduced rCMglc in the left hippocampus, right insular, and right temporal gyrus. However, after Aß adjustment, the significant differences in the temporal regions were absent in CN and MCI, and none of the areas detected as significant in the first analysis were statistically significant in AD. CONCLUSIONS: Our study demonstrated that Aß-independent APOE ɛ4 influence on rCMglc is limited to the parietal and frontal, but not temporal lobes. These results suggest that APOE ɛ4 may predispose for regional vulnerability according to Aß-independent and Aß-dependent processes.