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Und: Alzheimer's disease (AD) is characterized by cognitive dysfunction likely secondary to progressive neurodegeneration in the brain. However, to what extent regional cortical thickness (CT) changes are related to cognitive decline in the Asian population remains unclear. Method: We measured CT using Freesurfer v6 from T1‐weighted magnetic resonance imaging (MRI) data in 603 Korean participants, including 71 young and 288 old cognitively unimpaired (CU young and CU old), 149 with mild cognitive impairment (MCI), and 92 AD from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (KBASE). Cognitive function of each participant was quantified by the MMSE. MRI and cognitive data were acquired at baseline (n = 603) and a 2‐year follow‐up visit (n = 380). Linear mixed‐effect models were used to estimate diagnosis group, time, and group‐by‐time interaction effects on CT measurements, with age, sex, and education as covariates. Pearson's correlations between CT measurements and MMSE total score were computed, corrected for multiple comparisons by false discovery rate (FDR). Result: At baseline, CU old participants had lower CT values than CU young participants in the inferior parietal cortex and frontal and parietal regions. In comparison with CU old participants, MCI and AD showed widespread lower CT values, more pronounced in the medial temporal lobe (i.e., the entorhinal cortex and parahippocampal gyrus), inferior temporal cortex, medial prefrontal cortex, and medial parietal cortex (i.e., the posterior cingulate cortex and precuneus), with AD lower than MCI in these regions. These regions also showed the most longitudinal atrophy in both AD and MCI over 2 years. AD patients showed faster and more widespread atrophy patterns than MCI and CU old participants. We identified significant (PFDR<0.05) positive linear correlations between cognitive decline and regional CT measurements, particularly in regions showing significant cortical thinning across time. Conclusion: In this study, we replicated the typical cross‐sectional and longitudinal brain atrophy patterns, and relationships with cognitive decline in an Asian cohort. Our findings support the generalizability of atrophy patterns in MCI and AD, suggesting common neurobiological mechanisms underlying AD symptoms across different ethnoracial populations. [ABSTRACT FROM AUTHOR]

Background: Diffusion tensor imaging (DTI) measures water diffusion within brain tissue and can provide information regarding white matter, myelin, and axonal degeneration. We analyzed the cingulum bundle of the hippocampus (CBH), chosen for relevance to Alzheimer's Disease (AD) and memory (Wen et al, 2019; Dalboni da Rocha et al, 2020), using fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AxD), and mean diffusivity (MD), as well as their relationship to cognition, measured by DTI data from the initial phase of the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE). Methods: Participants from KBASE included cognitively normal older adults (CN, n = 276), mild cognitive impairment (MCI, n = 142), and AD dementia (AD, n = 87) studied with baseline neuroimaging and cognitive testing at Seoul National University and processed at Indiana University School of Medicine. Affine and non‐linear transformations were used to align individual FA maps to the FMRIB58FA template (FSL). Voxel values were extracted from unilateral CBH regions (determined using JHU ICBM‐DTI‐81‐white‐matter‐labels atlas) and averaged. Univariate‐GLM and Bonferroni‐corrected post‐hoc T‐tests controlling for age and sex were used to analyze diagnostic group differences, with lower FA and higher RD, AxD, and MD values expected in MCI and AD groups compared to CN. Bonferroni‐adjusted partial correlations controlling for age, sex, and education were used to test the hypothesis that DTI values would be associated with worsening cognitive scores. Results: As hypothesized, bilateral CBH DTI values in AD and MCI were significantly worse than those in CN (p<0.001) (Fig 1) with moderate effect sizes (η2 = 0.111 – 0.307). Worsening DTI values were significantly associated with worsening Digit Span Backward, Trailmaking A and B, GDS, MMSE‐KC, CDR‐SB, Word List Recall, and Logical Memory scores at the Bonferroni‐adjusted p‐value of 0.003. Bilaterally, higher Digit Span Forward scores were significantly associated with AxD values and lower Total SMCQ scores were associated with RD, AxD, and MD values. Conclusion: Within the KBASE cohort, MCI and AD demonstrated significantly worse DTI, memory, and cognition consistent with the pattern of white matter microstructural damage previously reported in MCI and AD (Wen et al, 2019; LoBuono et al., 2019). [ABSTRACT FROM AUTHOR]

INTRODUCTION: Using nationwide cohort data, we aimed to elucidate whether baseline obesity altered the relationship between loss in body mass index (BMI) or waist circumference (WC) and risk of dementia. METHODS: Among 9689 participants whose BMIs and WCs were repeatedly measured over 1 year, 1:1 propensity score matching was conducted between participants with and without obesity (n = 2976 per group, mean age 70.9). For each group, we explored the association between loss in BMI, or WC, and incidence of dementia during an approximately 4‐year follow‐up period. RESULTS: BMI loss was associated with an increased risk of all‐cause dementia and Alzheimer's disease in participants without obesity; however, this association was absent in participants with obesity. WC loss was associated with decreased Alzheimer's disease risk only in participants with obesity. DISCUSSION: Only unfavorable loss (loss from non‐obese state) in BMI, not WC, can be a metabolic biomarker of prodromal dementia. [ABSTRACT FROM AUTHOR]

Background: White matter injury had been mostly considered a result of chronic ischemia caused by cerebral small vessel disease. However, recent studies reported that white matter degeneration could also be an important pathophysiological feature in Alzheimer's disease (AD). This study aimed to identify the relationship between AD biomarkers, particularly amyloid‐beta (Aβ) and tau deposition, with white matter hyperintensities (WMHs) representing cerebral white matter injury. Method: A total 456 older adults aging from 55 to 90 years including cognitively normal and cognitively impaired individuals were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) cohort. The participants underwent comprehensive clinical and neuropsychological assessment, [11C] Pittsburgh Compound B PET for measuring Aβ deposition, [18F] AV‐1451 PET for measuring tau deposition, and MRI scans with fluid‐attenuated inversion recovery image for measuring WMH volume. For PET scans, standard uptake value ratio (SUVR) was used for the analyses; combined regions of hemispheric white matter, inferior cerebellum and pons were used as the reference region when obtaining SUVRs. The relationships between Aβ or tau deposition and WMH volume were examined using multiple regression analysis. In this analysis, baseline Aβ or tau were used as independent variables, and baseline as well as change of WMH volume over 2 years were used as dependent variables. Result: Baseline Aβ deposition levels had significant positive association with longitudinal change of WMH volume over 2 years (β = 0.238, p = 0.009), but not with WMH volume at baseline. Baseline tau was not related with any of WMH volume at baseline and longitudinal change of WMH volume over 2 years. We also found significant interaction effect between baseline Aβ deposition level and sex on longitudinal change of WMH volume. Subsequent subgroup analyses showed that high baseline Aβ deposition was associated with increase of WMH volume over 2 years in female (β = 0.427, p = 0.001), but not in male. Conclusion: Our findings suggest that Aβ deposition, but not tau, accelerates cerebral white matter injury, particularly in female. [ABSTRACT FROM AUTHOR]

Background: Circadian rest‐activity rhythm (RAR) alterations are common in the early stage of Alzheimer's disease (AD) disease. Given that the brainstem nuclei, the locus coeruleus (LC) and dorsal raphe nucleus (DRN) in particular, play key roles in modulating arousal and the sleep‐wake cycle, tau pathology in the brain stem nuclei, which occurs even before cortical tau progression, may relate to circadian RAR alteration in older individuals. Therefore, we aimed to test the hypothesis that in vivo tau deposition in the LC and DRN correlates with circadian RAR in non‐demented older adults. Method: A total of 63 non‐demented older adults from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) were included. All participants underwent [11C] PiB PET and [18F] AV1451‐PET. Circadian RAR variables were measured using actigraphy for 8 consecutive days. Tau deposition of the LC and DRN (LC‐tau and DRN‐tau, respectively) was measured in the regions of interest (ROI) masks for each participant prepared in native space using the Harvard arousal network atlas for the LC and DRN. For the purpose of comparison, tau deposition in the substantia nigra (SN‐tau) was also measured in the neuromelanin sensitive MRI‐based ROI for the SN. Result: Increased LC‐tau and DRN‐tau were significantly correlated with delayed acrophase (β = 0.303, p = 0.024 for LC‐tau and β = 0.398, p = 0.003 for DRN‐tau; Table 1 & Figure 1). In contrast, SN‐tau did not related with any RAR variables. Even after controlling for global tau deposition, the significance did not changed (β = 0.321, p = 0.021 for LC‐tau and β = 0.367, p = 0.008 for DRN‐tau, Table 1). In addition, Aβ positivity showed a significant moderation effect on the relationship between LC‐tau with acrophase. Subgroup analyses showed that increased LC‐tau significantly related with delayed acrophase in Aβ‐positivegroup (β = 0.427, p = 0.004), but did not in Aβ‐negative group (β = 0.099, p = 0.615)(Figure 2) Conclusion: Our findings support the possibility that the tau pathology in the LC and DRN underlie circadian RAR alteration, more specifically delayed phase, in non‐demented older adults. In addition, such relationship appears to be more prominent in individuals with brain Aβ pathology. [ABSTRACT FROM AUTHOR]

Background: Most genome‐wide association studies (GWAS) of Alzheimer's disease (AD) have been conducted in populations of European ancestry. It is important to determine if known AD‐related variants from these studies are associated with AD biomarkers. Therefore, we investigated the association between known AD risk loci and in vivo brain Aβ deposition in older Korean adults. Method: Participants (n = 503) from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (KBASE) were analyzed. Older adults who were cognitively normal (CN), had mild cognitive impairment (MCI) or AD dementia (264 CN, 148 MCI, 91 AD) underwent comprehensive assessments including 11C‐PiB‐PET/MRI and blood sampling. Among 76 AD‐related target single nucleotide polymorphisms (SNPs) with genetic evidence compiled by the AD Sequencing Project (ADSP), 38 SNPs with minor allele frequency (MAF)>1% were extracted from TOPMed‐based imputed GWAS genotyping data in KBASE. We employed exploratory univariable logistic regression analysis with Aβ positivity as the dependent variable for each SNP. Then, SNPs with a significance level of p<0.05 were subjected to confirmatory multivariable logistic regression analysis, adjusting for age and sex, with Bonferroni correction. Result: In the first step of exploratory analyses, we discovered significant differences in Aβ positivity rates between carriers and noncarriers of minor allele of several loci, including rs16824536 in MME, rs11218343 in SORL1, rs4985556 in IL34, rs4277405 in ACE and rs3851179, located in the intergenic region between EED and PICALM. The subsequent confirmatory analysis found an association between these variants and Aβ positivity after adjusting age and sex (Table 1). Notably, the negative association of rs3851179 with Aβ positivity remained significant after correcting for multiple comparisons and after controlling for APOE4 carrier status, age, and sex (OR 0.529, 95% CI 0.345–0.813). Conclusion: We identified associations between several known AD risk loci and Aβ positivity on PET. rs3851179, demonstrated a robust association with in vivo brain Aβ positivity that was independent of APOE4 status. Our findings suggest that rs3851179 may be protective for in vivo Aβ accumulation. Additionally, the findings are needed to be replicated in other populations with different ancestries. [ABSTRACT FROM AUTHOR]

Background: Polygenic risk scores (PRS) quantify the combined effects of genetic variants to enable the prediction of an individual's risk of developing the disease. Alzheimer's disease (AD) is a complex disorder in which the relationship among PRS, neuropathological substrates, and related cognitive decline remain especially understudied in Asian populations. We investigated the associations of PRS with AD neuroimaging biomarkers and cognitive phenotypes in a Korean Cohort. Method: The study included 501 older adults (264 cognitively normal [CN], 146 mild cognitive impairment [MCI], and 91 AD dementia) from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE). Comprehensive clinical and neuropsychological evaluations, as well as multi‐modal neuroimaging including 3T MRI and 11C‐PiB‐PET were administered. A subset of participants underwent 18F‐AV‐1451 PET (n = 167). Imaging phenotypes including beta‐amyloid (Aβ) positivity, global tau deposition, and adjusted hippocampal volume (HVa) were used for amyloid (A), tau (T), and neurodegeneration (N) biomarkers, respectively., which was imputed using the TOPMed reference panel. PRS was calculated using the summary statistics of a recent large‐scale GWAS study for AD by PRS‐CS. The Apolipoprotein E (APOE) region was excluded in the calculation. The associations between standardized PRS and imaging/cognitive phenotypes were examined using either multiple linear or logistic regression analysis with covariates (age and sex for neuroimaging biomarker phenotypes; age, sex and education for cognitive phenotypes). Result: PRS was significantly higher in the AD dementia group compared to the CN group. Higher PRS was associated with greater CDR‐sum‐of‐boxes (β[SE] = 0.233[0.083], t = 2.818, p = 0.005) and lower MMSE scores (β[SE] = ‐0.648[0.198], t = ‐3.271, p = 0.001). In terms of AD neuroimaging biomarkers (Figure 1), higher PRS was significantly associated with an increased likelihood of Aβ positivity (OR = 1.233, 95%CI = 1.024‐1.491), and lower HVa (β[SE] = ‐132.79[49.624], t = ‐2.676, p = 0.008), but not with global tau deposition (β[SE] = 0.075[0.048], t = 1.573, p = 0.118). Conclusion: These findings suggest that higher PRS predicts increased pathological Aβ deposition and accelerated neurodegeneration, as well as greater cognitive decline. Further investigation in larger and multiethnic samples are needed to determine generalizability to other ethnoracial populations. [ABSTRACT FROM AUTHOR]

Background: Physical activity (PA) has been reported to reduce the risk of Alzheimer's disease (AD) dementia and related cognitive decline. We aimed to investigate the influence of PA on the progression from cognitively normal (CN) status to mild cognitive impairment (MCI) or from MCI to AD dementia in non‐demented older adults. Method: This study included 194 non‐demented (148 CN and 46 MCI) participants from the Korean Brain Aging Study for Early diagnosis and prediction of Alzheimer's disease (KBASE), who completed both baseline and 2‐year follow‐up clinical evaluation. At baseline, the participants underwent comprehensive clinical and neuropsychological assessment, multimodal brain imaging including [11C] Pittsburgh Compound B positron emission tomography (PET), [18F] fluorodeoxyglucose PET and MRI, and current PA measured using the Lifetime Total Physical Activity Questionnaire. Result: After 2 years, five CN and 22 MCI participants progressed to MCI and AD dementia, respectively. Logistic regression analyses showed that high current PA (above the median value) reduced the risk of the progression from MCI to AD dementia even after controlling age, sex, education, apolipoprotein E e4 positivity, baseline brain amyloid deposition, AD‐signature region glucose metabolism, and AD‐signature region cortical thickness (Bonferroni corrected p‐value = 0.028). In contrast, PA had no effect on the progression from CN to MCI. Conclusion: The findings suggest that a physically active lifestyle in late‐life reduces the risk of conversion to AD dementia in MCI independently of AD‐related brain pathologies. [ABSTRACT FROM AUTHOR]

Background: Our previous work reported that mild cognitive impairment (MCI) patients with multiple mild behavioral impairment (MBI) domain symptoms (complex group) revealed a higher risk of developing Alzheimer's disease (AD) compared with those with no MBI symptoms (asymptomatic group) and cortical thinning in the parietal and frontal areas. However, MCI patients with only affective dysregulation (affective dysregulation group) were not associated with the risk of AD and revealed relative cortical thickening (Yoon EJ, Front Aging Neurosci 2023). To clarify relationships of cortical thickness changes and risk of progression to AD in MCI patients, we compared structural covariance patterns between hippocampal volume and cortical thickness among the MBI subgroups. Method: A total 201 older adults with amnestic MCI were classified based on profiles of MBI domain symptoms into asymptomatic, affective dysregulation, and complex groups. The FreeSurfer was used to estimate cortical thickness and volumes of hippocampal subfields (Fig 1). A vertex‐wise general linear interaction model was used to compare group map of covariance between volumes of hippocampus subfields and thickness at each of vertices. Correlations between the thickness in regions showing significant group differences and mini‐mental state examination (MMSE) scores were also assessed. Result: In the affective dysregulation group, the structural covariance of left CA1, CA4/DG and molecular layer were increased in the left superior and inferior parietal cortex (Fig 2a), and the thickness of this region showed positive correlation with MMSE (spearman's rho = 0.302, p‐value = 0.046). The structural covariance of left hippocampal tail for the affective dysregulation group was increased in left lateral occipital cortex, and those for the complex group was increased in left inferior parietal and lateral occipital cortex compared with the asymptomatic group (Fig 2b). Also, the complex group revealed decreased structural covariance of right subiculum with left rostral middle frontal cortex (Fig 2c). Conclusion: Our findings suggest that the lateral parietal area might have an important role in compensatory mechanisms in the affective dysregulation group. On the other hand, the complex group may be associated with more advanced stages of disease in which the patterns of increased covariance of hippocampal subfields were disappeared or inversed. [ABSTRACT FROM AUTHOR]

Background: Primary age‐related tauopathy (PART) is a neuropathological entity with neurofibrillary tangles in the absence of beta‐amyloid plaques in the brain. Recent advances in neuroimaging made it possible to identify amyloid PET‐negative (A‐) tau PET‐positive (T+) condition as a possible candidate for PART in living human brains. We tried to investigate neurodegenerative biomarkers of A‐T+ older adults compared to those of A+T+ and A‐T‐ [corresponding to Alzheimer's disease (AD) and no AD pathology, respectively] individuals. Method: A total of 156 older participants (64 cognitively normal, 43 mild cognitive impairment (MCI), and 49 dementia), were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE). All participants underwent comprehensive clinical evaluation and multimodal brain imaging including amyloid and tau PET, and MRI. Global PiB retention measured by 11C‐PiB‐PET and tau deposition in the regions corresponding to Braak stages measured by 18F‐AV‐1451 PET were used in this study. A+ was defined as global mean Aβ deposition standardized uptake value ratio (SUVR) > 1.4 and T+ was defined as tau burden corresponding to Braak stages I/II, III/IV, or V/VI. Hippocampal volume, AD‐signature cortical thickness (AD‐CT), AD‐signature cerebral glucose metabolism (AD‐CM) and white matter hyperintensity (WMH) volume were also measured as neurodegenerative biomarkers. Multiple linear regression analysis controlling for age, gender, and APOE ε4 positivity was used to investigate the group differences of neurodegenerative biomarkers. Result: Of the 156 participants, 31 were defined as A‐T‐, 53 as A+T‐, and 72 as A+T+. A‐T+ group had higher levels of hippocampal volume (B = 683.448, p<0.001), AD‐CT (B = 0.267, p<0.001) and AD‐CM (B = 0.174, p<0.001), but not WMH volume (B = ‐1.188, p = 0.651), compared to A+T+ group. When compared to A‐T‐ group, A‐T+ group did not show significant difference in any of the neurodegenerative biomarkers. Conclusion: Our findings suggest that, in regard of neurodegeneration, older adults with A‐T+ condition, close to pathological PART, are less severe than those with A+T+, while they appear similar to those with A‐T‐. [ABSTRACT FROM AUTHOR]

Background: Growing evidences suggest that degeneration of cerebral white matter (WM) occurs in Alzheimer's disease (AD) independently of cerebrovascular risks or injury. Previous studies using diffusion tensor imaging (DTI) have reported a loss of WM microstructural integrity in the corpus callosum (CC) and cingulum (CG) in AD dementia and mild cognitive impairment (MCI). However, only limited information is available for the relationship of in vivo AD‐specific pathologies including beta‐amyloid (Aβ) and tau accumulation with WM microstructal alterations. Thus, we aimed to examine the association between in vivo AD pathologies and microstructural integrity of the CC and CG through cross‐sectional and longitudinal approaches. Method: A total of 170 (74 cognitively normal, 58 MCI, and 38 AD dementia) older adults from the Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer's disease cohort were included. All participants underwent comprehensive clinical assessment and multi‐modal brain imaging including [11C]‐Pittsburgh‐Compound‐B‐positron emission tomography (PET), 18F‐AV‐1451 PET, and DTI. The mean fractional anisotropy (FA) values were obtained for 2 regions of interests, the CC and CG on DTI. The data was analyzed using linear regression model adjusted for age, sex, APOE4 positivity, and vascular risk factor score. Regression‐based mediation analysis was also conducted to assess the mediation of tau for the relationship between Aβ and FA. Result: In cross‐sectional analyses for baseline data, global tau deposition had a significant negative association with both CC and CG FA (β = ‐0.013, p = 0.004 and β = ‐0.011, p = 0.002), while global Aβ retention showed a negative association with only CG FA (β = ‐0.015, p = 0.004). Longitudinal analyses revealed that higher tau deposition at baseline was associated with both greater reduction of both CC and CG FA over 2 years (β = ‐0.010, p = 0.001 and β = ‐0.005, p = 0.046), whereas Aβ was associated with neither CC nor CG FA change over the period. Additional mediation analysis demonstrated that the cross‐sectional association between Aβ and CG FA was mediated by tau deposition, while there was no direct relationship between the two. Conclusion: Our findings suggest that regional alterations of WM microstructural integrity in MCI and AD dementia, which occurs independently of vascular risks, are mainly related with tau pathology rather than amyloid pathology. [ABSTRACT FROM AUTHOR]

Background: Interest in the role of Herpes Simplex Virus (HSV) infection in the pathogenesis of Alzheimer's disease (AD) has increased in recent years. However, previous studies yielded inconsistent findings and no studies have yet investigated the relationship between HSV infection and in vivo AD pathologies such as beta‐amyloid (Aβ) and tau deposition in brain. We examined whether the level of serum anti‐HSV immunoglobulin G (IgG) antibodies (HSV‐IgG), an index of past infection of HSV, is associated with in vivo Aβ and tau deposition in nondemented individuals. We also investigated the modulating effect of HSV‐IgG titer on the relationship between Aβ and tau deposition. Method: A total of 426 nondemented older individuals (55‐90 years old) were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) cohort. All participants underwent comprehensive clinical assessment, [11C]‐Pittsburgh Compound B positron emission tomography (PET), and blood sampling for measurement of serum HSV antibodies. A subset of participants (N = 129) underwent [18F] AV‐1451 PET. Individuals whose HSV‐IgG titer was lower than 25 percentile of the whole group was classified as the HSVlow group, while those with HSV‐IgG titer higher than 25 percentile were classified as the HSVhigh group. Result: There was no significant difference in age, sex, clinical diagnosis (cognitive normal vs. mild cognitive impairment), and apolipoprotein E e4 positivity (APOE4) between the HSVlow (N = 106) and HSVhigh (N = 320) groups. In terms of AD biomarkers, neither global Aβ nor tau deposition was different between the HSVhigh and HSVlow groups, even after controlling the effect of age, sex, and APOE4. However, there was a significant HSV group x Aβ deposition interaction effect on tau deposition (p = 0.037), suggesting the level of HSV‐IgG modulates the relationship between Aβ and tau deposition. Subsequent subgroup analyses showed a significant positive association between Aβ and tau deposition only in the HSVhigh group (p < 0.001), but not in the HSVlow group. Conclusion: Our finding suggests that past HSV infection may aggravate the influence of Aβ on tau deposition. In regard of AD prevention, the result also supports that more attention needed to be paid to controlling HSV infection. [ABSTRACT FROM AUTHOR]

Background: Previous studies reported the associations between vitamin D deficiency and increased risk of Alzheimer's disease (AD) dementia in older adults, but little is known how vitamin D is involved in the pathophysiology of AD. Thus, we aimed to examine the association and interaction of serum vitamin D level with in vivo AD pathologies including beta‐amyloid (Aβ) and neurodegeneration in nondemented older adults. Method: Nondemented older adults consisting of cognitively normal and mild cognitive impairment groups were recruited from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease, an ongoing prospective cohort that began in 2014. All participants underwent comprehensive clinical assessments, measurement of serum 25(OH)D, and multimodal brain imaging including Pittsburgh compound‐B (PiB) positron emission tomography and magnetic resonance imaging at baseline. Global PiB retention was measured for Aβ biomarker, and hippocampal volume adjusted for intracranial volume (HVa) was used for neurodegeneration biomarker. Age, sex, apolipoprotein E (APOE) e4 positivity was controlled as covariates in all analyses. Result: A total 428 participants (mean age [SD]: 70.54 [7.97], female [N, %]: 182 [43%]) were included for analysis. Serum 25(OH)D levels were directly associated neither Aβ deposition nor HVa. However, serum 25(OH)D level had significant moderation effect on the association between Aβ and hippocampal neurodegeneration, in that lower serum 25(OH)D level significantly exacerbate the negative association between global Aβ retention and HVa (β = 34.612, p = 0.008) (Figure). Conclusion: The present findings suggest that lower serum vitamin D level may increase AD dementia risk by aggravating Aβ‐related neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Recent evidences suggest that the use of antihypertensive medications (HTNmed) may decrease the incidence of Alzheimer's disease (AD) dementia. We investigated whether the use of HTNmed is associated with in vivo AD pathologies, particularly cerebral beta‐amyloid (Aβ) deposition, and whether the relationship between HTNmed and cerebral Aβ deposition differs according to the characteristics of HTNmed in older adults. Method: Participants were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) cohort. Both cognitively normal and cognitively impaired older adults (age range: 55‐90 years) who met the following criteria of hypertension (HTN) were included for this study: i) clinical diagnosis of hypertension or ii) systolic blood pressure higher than 130mmHg or diastolic blood pressure higher than 80mmHg measured at baseline. All participants underwent comprehensive clinical assessment and [11C] Pittsburgh Compound B positron emission tomography PET for measuring Aβ deposition. Result: Among total 413 older adults with hypertension, 227(54.8%) were taking HTNmed. Overall, individuals taking HTNmed showed significantly lower Aβ deposition compared to those without HTNmed (B = ‐0.104, p = 0.007), even after controlling age, sex, apolipoprotein E e4 positivity, and mean arterial blood pressure(MAP). Drug‐class specific analyses showed that the use of renin angiotensin system (RAS) inhibitor (i.e., angiotensin converting enzyme inhibitor and angiotensin receptor blocker) was associated with less cerebral Aβ deposition among older adults with HTNmed (B = ‐0.142, p = 0.006), but the use of other HTNmeds was not. In addition, the blood‐brain barrier permeability of HTNmed also did not have any relationship with Aβ deposition. Conclusion: The present finding suggests that the use of HTNmed, particularly RAS inhibitor, is associated with less Aβ deposition in older adults with hypertension. Further studies to explore the mechanism underlying the effect of RAS inhibitor on Aβ accumulation may provide clues for new therapeutic targets of AD. [ABSTRACT FROM AUTHOR]

Background: In the present study, we aimed to confirm the association between speech characteristics of individuals with Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI) and brain regions, and to investigate the neurobiological basis of speech‐based AD detection. Method: Individuals with MCI (n = 13, age = 78.3), mild‐to‐moderate AD (n = 12, age = 77.8) underwent a structural MRI scan and engaged in three speech tasks: an interview, sentence repetition, and paragraph recall. From the speech samples, we extracted frequency‐related, intensity‐related, and temporal features which were found to be altered in the course of AD and MCI pathology. We selected nine regions of interest (ROI) which were found to be involved in speech production and reduced in MCI and AD pathology; the Inferior Frontal Gyrus (IFG), the Medial Frontal Gyrus (MFG), the Precuneus, the Inferior Parietal Lobe (IPL), Inferior Temporal Gyrus (ITG), Medial Temporal Gyrus (MTG), the Superior Temporal Gyrus (STG), the Fusiform Gyrus (FFG), and the Cerebellum. The linear mixed‐effect analysis was used to identify the associations between speech features and regional brain volumes. Result: The Left IPL (χ2 (1) = 7.69, corrected P = 0.033), the Right ITG (χ2 (1) = 11.5, corrected P = 0.0128) the Right FFG (χ2 (1) = 9.35, corrected P = 0.0198) reduced the pitch of voice by about 0.887 ± 0.292, 1.368 ± 0.329, and 1.69 ± 0.429 respectively. The associations between the Right FFG (χ2 (1) = 4.58, corrected P = 0.0900), Left FFG (χ2 (1) = 5.87, corrected P = 0.0675) and loudness were marginally significant, with the reduction of volumes in the Right FFG and Left FFG decreasing the loudness by 0.096 ± 0.041, and 0.1165 ± 0.0454. The marginally significant associations were observed between the Right IPL (χ2 (1) = 4.75, corrected P = 0.0900), the Left FFG (χ2 (1) = 0.39, corrected P = 0.53) and the speech rate, and the atrophy of brain regions decreased the speech rate by 0.0824 ± 0.0363, 0.0535 ± 0.0079. Conclusion: The present study identified the associations between speech biomarkers and regional brain volumes providing clinical validity for the speech‐based Alzheimer's disease detection. [ABSTRACT FROM AUTHOR]

Background: Mild Behavioral Impairment (MBI) is a neurobehavioral syndrome characterized by later life emergence of sustained neuropsychiatric symptoms, as an at‐risk state for dementia (Ismail Z, Alzheimers Dement, 2016). However, the associations between MBI and a risk of phenocoversion to dementia and its neuroanatomical correlates in MCI are still unclear. Method: A total 1326 older adults with MCI was followed for a mean of 3.0 ± 2.0 years. MBI was approximated using a transformation algorithm for the neuropsychiatric inventory at baseline. Two‐step cluster analysis was used to explore classes of 5 MBI domains (decreased motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, abnormal perception/thought content). A Cox regression analysis was applied to investigate the association between the clusters and phenoconversion to AD. A subset of participants (n = 225) underwent 3D T1‐weighted MRI scans and cortical thickness was compared among the clusters of MBI domains. Result: The cluster analysis identified 3 groups of participants: (1) people without MBI (47.8%, asymptomatic); (2) people with only affective dysregulation (29.3%, affective dysregulation); (3) people with relatively high probability of affective dysregulation, followed by impulse dyscontrol and affective dysregulation (22.9%, multiple domains). Compared to the asymptomatic, multiple domains was associated with a higher risk of phenoconversion to AD (hazard ratio = 2.589 [1.981 – 3.385], p = < 0.001), but affective dysregulation did not predict phenoconversion (1.204 [0.896 – 1.620], p = 0.219) (Fig 1). MCI individuals with symptoms in multiple domains revealed thinning in the bilateral superior and inferior parietal, superior temporal, and prefrontal cortex, and the right precuneus compared to those with only affective dysregulation (Fig 2). We did not find differences in cortical thickness between phenocoverter and non‐phenoconverter, and interaction of clusters of MBI domains and phenoconversion. Conclusion: The multiple co‐occuring MBI domains in individuals with MCI are associated with a higher risk of phenoconversion to AD. Moreover, MCI individuals with symptoms in multiple domains revealed cortical thinning in the superior parietal and precuneus, which have suggested as AD signatures (Dickerson BC, Cereb Cortex, 2009). These results suggest that evaluation of MBI and neuroimaging characteristics could be useful for risk stratification in MCI individuals. [ABSTRACT FROM AUTHOR]

Background: While previous studies consistently reported regional microstructural changes of the cerebral white matter (WM) in Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI), little information is available for such changes in the preclinical stage of AD. We first aimed to investigate regional microstructural alteration of the WM in cognitively normal (CN) older adults with amyloid‐beta (Aβ) deposition. We also tried to develop a prediction model for Aβ positivity in CN using information on WM microstructural alteration and clinical variables that can be easily obtained in memory clinics. Method: Seventy‐five CN older adults from the Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer's disease (KBASE) cohort were included in the analyses. All Participants underwent comprehensive clinical and neuropsychological assessment, T1 MRI, diffusion tensor imaging (DTI), and [11C]PiB‐PET. All CN subjects were divided into Aβ positive (CN+) and negative (CN‐) based on the level of cerebral Aβ retention on [11C]PiB‐PET. Multivariate stepwise logistic regression analyses were conducted to develop Aβ positivity prediction models. Result: When compared to CN‐, CN+ showed high mean diffusivity (MD) value of the genu of the corpus callosum (CC_genu) (F(1,73) = 6.357, p = 0.014, Figure 1). The area under the curve (AUC) of the receiver operating characteristics curve for the Aβ positivity prediction model only using MD of the CC_genu was 0.653 [confidence interval (CI) = 0.511‐0.794]. Model with MD of the CC_genu, age, and word list recall and constructional recall test scores were finally selected. The AUC of the final model was 0.851 [CI = 0.765‐0.937] (Figure 2). Conclusion: The findings indicate that microstructural alteration of the CC_genu occurs even in the stage of preclinical AD. When taken together with episodic memory scores commonly available in clinical practice, information about such regional WM microstructural alteration can be used to screen preclinical AD. [ABSTRACT FROM AUTHOR]

Background: Depression is a common manifestation of Alzheimer's disease (AD) and frequently observed at the early phase of the disease. Several postmortem studies demonstrated that tau deposition was found at the brainstem nuclei including the locus coeruleus (LC) and dossal raphe nucleus (DRN) (3, 4), even before early Braak stages of neurofibrillary tangle pathology. Given the disturbance of monoaminergic system is related to depression in general, tau deposition in the LC or DRN may underlie depression in late‐life, as suggested in a couple of postmortem studies. In this context, we tried to examine the hypothetical association between in vivo tau depostion at the brain stem monoaminergic nuclei and depression in cognitively unimpaired older adults. Method: A total of 69 cognitively unimpaired older adults from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) were included. All participants underwent comprehensive clinical assessment including the Hamilton Rating Scale for Depression (HRSD) and [18F] AV‐1451 positron emission tomography. Tau deposition in the LC and DRN was measured using the Harvard Ascending Arousal Network Atlas (AAN). Tau deposition in the pons was also assessed as a non‐monoaminergic control for comparison. Age, education, sex, and apolipoprotein E ε4 positivity were controlled as covariates in the analyses for the association between brain stem tau and HRSD score. Result: Tau deposition in the LC was significantly associated with HRSD total score (β = 3.861, P =.009). In contrast, there was no significant association between tau deposition in the DRN and HRSD score (β = 2.229, P =.090). Tau deposition in the pons was also not related to HRSD score (β = 1.632, P =.207). Conclusion: The findings support the possibility that alteration of the noradrenergic neurons in the LC by tau pathology may underlie depressive manifestation in cognitively unimpaired older individuals. [ABSTRACT FROM AUTHOR]

Background: Previous studies reported the link between apolipoprotein E (apoE) in peripheral blood and risk of Alzheimer's disease (AD) dementia. However, underlying mechanism for this link remains unclear. We investigated whether serum apoE concentration is associated with in vivo AD pathologies in nondemented older adults. Method: A total 437 nondemented older adults were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) cohort. All participants underwent comprehensive evaluation including clinical assessment, blood sampling, as well as 11C‐PiB PET and MRI. A subset of participants (N=130) also underwent 18F‐AV1451 PET for measurement of brain tau pathologies. All participants were divided into low, middle, and high apoE concentration tertile groups (i.e., T1, T2, and T3). Result: There were no significant differences in demographic and clinical variables except the frequency of female and rate of apoE ε4 allele (APOE4) positivity; the lower serum apoE was associated with fewer female (40.1%, 61.6%, and 67.8% for T1, T2, and T3, respectively) and higher APOE4 positivity rate (34.3%, 25.2%, and 16.8%). In terms of AD biomarker, Aβ positivity rate showed significant negative association with serum apoE (40.1%, 31.8%, and 24.8%), which remained significant after adjustment of covariates including age, sex, and diagnosis. In addition, reduced AD‐signature region volume, a neurodegeneration biomarker of AD, was significantly associated with lower serum apoE after controlling the same covariates. With regard to tau biomarker, positivity rate of global tau deposition showed significant negative association with serum apoE level (56.8%, 50%, and 20%) after adjustment of covariates. When we additively controlled the effect of APOE4 positivity, the associations between low serum apoE and greater neurodegeneration and tau positivity remained significant, whereas the association between apoE and Aβ positivity did not reach statistical significance. Conclusion: In the present study, low serum apoE was associated with greater burden of in vivo AD pathologies and such association appears even independent of APOE4 carrier status in regard of tau deposition and neurodegeneration. The finding suggests a potential role of serum apoE as a surrogate marker for in vivo AD pathologies in nondemented older adults. [ABSTRACT FROM AUTHOR]

Background: Both physical activity (PA) and cognitive activity (CA) are known to reduce the risk of Alzheimer's disease (AD) and related cognitive decline. However, pathophysiological mechanism underlying their protective effects for AD is still poorly understood. We aimed to investigate the moderation effects of current PA and CA on the relationship between amyloid‐beta (Aβ) and AD‐signature neurodegeneration in non‐demented older adults. Both physical activity (PA) and cognitive activity (CA) are known to reduce the risk of Alzheimer's disease (AD) and related cognitive decline. However, pathophysiological mechanism underlying their protective effects for AD is still poorly understood. We aimed to investigate the moderation effects of current PA and CA on the relationship between amyloid‐beta (Aβ) and AD‐signature neurodegeneration in non‐demented older adults. Method: Two‐hundred sixty non‐demented (195 cognitively normal and 65 mild cognitive impairment) participants from the Korean Brain Aging Study for Early diagnosis and prediction of Alzheimer's disease (KBASE) were included in this analysis. All participants underwent comprehensive clinical and neuropsychological assessment, [11C]Pittsburgh Compound B (PiB) positron emission tomography (PET), [18F]fluorodeoxyglucose (FDG) PET, and magnetic resonance imaging. Using the multi‐modal brain imaging data, in vivo AD pathologies including Aβ deposition, AD‐signature region cerebral glucose metabolism (AD‐CM), and AD‐signature region cortical thickness (AD‐CT) were quantified. Current PA and CA were assessed using well‐validated questionnaires. General linear model analysis was conducted including AD‐CM (or AD‐CT) as a dependent variable and Aβ deposition, PA, CA, Aβ x PA interaction term, and Aβ x CA interaction term as independent variables. Result: We found significant Aβ x PA interaction effect on both AD‐CM and AD‐CT. Subgroup analyses showed that the inverse association between Aβ and AD‐CM (or AD‐CT) was weaker (i.e., smaller effect size) in higher PA group compared to that in lower PA group. In contrast, Aβ x CA interaction effect was not observed on neither AD‐CM nor AD‐CT. Conclusion: The findings suggest that current PA reduce AD‐type regional neurodegeneration induced by Aβ deposition, regardless of CA, in non‐demented older adults. When considered with PA, however, current CA appear not have any moderation effect on the relationship of Aβ deposition with the neurodegenerative change. [ABSTRACT FROM AUTHOR]

Background: Although depression is very common in the preclinical stage of Alzheimer's disease (AD), it is still unclear whether depression moderates the progression of AD or not. In the present study, we aimed to investigate the moderation of depression on the relationship between β‐amyloid (Aβ) deposition and progression of hippocampal atrophy and cognitive decline in cognitively normal (CN) older adults. Method: Two‐hundred eighty nine CN older adults (55–90 years; 48.4% female; 14.2% Aβ+) from an ongoing prospective cohort study, the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE), were followed up for 24 months. All participants underwent annual clinical assessments on depressive symptoms and cognitive function, and biennial [11C] Pittsburgh compound B‐PET and three‐dimensional MRI scans. Depression was defined based on the following: 1) depression diagnosed by a psychiatrist, 2) Geriatric Depression Scale score ≥ 11, or 3) the presence of any depressive symptom on Neuropsychiatric Inventory. Result: Among the subjects, 73.4% (n = 212) were followed up for two years and twelve converted to mild cognitive impairment. Association between Aβ and depression was not observed at baseline. There was a significant Aβ positivity x Depression x Time interaction effect on hippocampal volume (F = 4.252, p = 0.042) and verbal memory (F = 7.488, p = 0.007) even after controlling for age, sex, educational level, APOE genotype, subjective memory complaint, and baseline white matter hyper intensity volume. Aβ positive individuals with depression showed faster decline of hippocampal atrophy and verbal memory decline than those in other subgroups for two years. Conclusion: The findings indicate that the presence of depression may accelerate hippocampal atrophy and episodic memory loss in older adults with preclinical AD. [ABSTRACT FROM AUTHOR]

Background: Although previous studies have reported associations of diabetes mellitus (DM) with cognitive impairment or dementia, the exact pathophysiological links underlying the associations remain incompletely understood. In this context, we aimed to investigate the associations of DM or glycated hemoglobin (HbA1c) with in vivo Alzheimer's disease (AD) pathologies such as cerebral beta‐amyloid protein (Aβ) deposition and tau deposition. Method: Total 136 participants (71 cognitively normal, 31 mild cognitive impairment, and 34 AD dementia) from the Korean Brain Aging Study for Early Diagnosis & Prediction of Alzheimer's Disease (KBASE), an ongoing prospective cohort study, were included for this analysis. All participants underwent comprehensive clinical and neuropsychological assessment, 11C labelled Pittsburgh Compound B (PiB) positron emission tomography (PET), 11F AV‐1451 PET, magnetic resonance imaging, apolipoprotein E genotyping, and HbA1c measurement. Result: Neither the presence of DM nor HbA1c level was associated with global Aβ deposition after controlling for age, sex, education, vascular risk score (except DM), apolipoprotein e4 positivity, and clinical diagnosis. In contrast, higher HbA1c was significantly associated with lower AD‐signature region tau deposition and the presence of DM showed a trend level association with decreased tau deposition. Additionally, we found significant Aβ deposition x HbA1c (or the presence of DM) interaction effect on tau deposition. While higher Aβ deposition was significantly related to increased tau deposition in lower HbA1c (or DM negative) subgroup, there was no such relationship between Aβ and tau deposition in higher HbA1c (or DM positive) one. Sensitivity analyses including only cognitively normal individuals also showed similar results. Conclusion: Our results indicate that DM or higher blood glucose may not contribute to cognitive impairment or dementia via AD‐specific pathologies, especially amyloid deposition. Therefore, other non‐AD pathophysiological contributions including vascular pathologies should be considered. Although being very cautious, high blood glucose may relate to delayed brain tau deposition. [ABSTRACT FROM AUTHOR]