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Background: Altered thyroid hormone levels have been associated with increased risk of Alzheimer's disease (AD) dementia and related cognitive decline. However, the neuropathological substrates underlying the link between thyroid hormones and AD dementia are not yet fully understood. We first investigated the association between serum thyroid hormone levels and in vivo AD pathologies including both beta-amyloid (Aβ) and tau deposition measured by positron emission tomography (PET). Given the well-known relationship between Aβ and tau pathology in AD, we additionally examined the moderating effects of thyroid hormone levels on the association between Aβ and tau deposition., Methods: This cross-sectional study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) cohort. This study included a total of 291 cognitively normal adults aged 55 to 90. All participants received comprehensive clinical assessments, measurements for serum total triiodothyronine (T3), free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH), and brain imaging evaluations including [ 11 C]-Pittsburgh compound B (PiB)- PET and [ 18 F] AV-1451 PET., Results: No associations were found between either thyroid hormones or TSH and Aβ and tau deposition on PET. However, fT4 (p = 0.002) and fT3 (p = 0.001) exhibited significant interactions with Aβ on tau deposition: The sensitivity analyses conducted after the removal of an outlier showed that the interaction effect between fT4 and Aβ deposition was not significant, whereas the interaction between fT3 and Aβ deposition remained significant. However, further subgroup analyses demonstrated a more pronounced positive relationship between Aβ and tau in both the higher fT4 and fT3 groups compared to the lower group, irrespective of outlier removal. Meanwhile, neither T3 nor TSH had any interaction with Aβ on tau deposition., Conclusion: Our findings suggest that serum thyroid hormones may moderate the relationship between cerebral Aβ and tau pathology. Higher levels of serum thyroid hormones could potentially accelerate the Aβ-dependent tau deposition in the brain. Further replication studies in independent samples are needed to verify the current results., (© 2024. The Author(s).)

Background: Growing evidence suggests that not only cerebrovascular disease but also Alzheimer's disease (AD) pathological process itself cause cerebral white matter degeneration, resulting in white matter hyperintensities (WMHs). Some preclinical evidence also indicates that white matter degeneration may precede or affect the development of AD pathology. This study aimed to clarify the direction of influence between in vivo AD pathologies, particularly beta-amyloid (Aβ) and tau deposition, and WMHs through longitudinal approach., Methods: Total 282 older adults 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, [ 11 C] Pittsburgh Compound B PET for measuring Aβ deposition, [ 18 F] AV-1451 PET for measuring tau deposition, and MRI scans with fluid-attenuated inversion recovery image for measuring WMH volume. The relationships between Aβ or tau deposition and WMH volume were examined using multiple linear regression analysis. In this analysis, baseline Aβ or tau were used as independent variables, and change of WMH volume over 2 years was used as dependent variable to examine the effect of AD pathology on increase of WMH volume. Additionally, we set baseline WMH volume as independent variable and longitudinal change of Aβ or tau deposition for 2 years as dependent variables to investigate whether WMH volume could precede AD pathologies., Results: Baseline Aβ deposition, but not tau deposition, had significant positive association with longitudinal change of WMH volume over 2 years. Baseline WMH volume was not related with any of longitudinal change of Aβ or tau deposition for 2 years. We also found a significant interaction effect between baseline Aβ deposition 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, but not in male., Conclusions: Our findings suggest that Aβ deposition accelerates cerebral WMHs, particularly in female, whereas white matter degeneration appears not influence on longitudinal Aβ increase. The results also did not support any direction of influence between tau deposition and WMHs., (© 2024. The Author(s).)

Background: White matter (WM) microstructural changes in the hippocampal cingulum bundle (CBH) in Alzheimer's disease (AD) have been described in cohorts of largely European ancestry but are lacking in other populations., Methods: We assessed the relationship between CBH WM integrity and cognition or amyloid burden in 505 Korean older adults aged ≥ 55 years, including 276 cognitively normal older adults (CN), 142 with mild cognitive impairment (MCI), and 87 AD patients, recruited as part of the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (KBASE) at Seoul National University., Results: Compared to CN, AD and MCI subjects showed significantly higher RD, MD, and AxD values (all p-values < 0.001) and significantly lower FA values (left p ≤ 0.002, right p ≤ 0.015) after Bonferroni adjustment for multiple comparisons. Most tests of cognition and mood (p < 0.001) as well as higher medial temporal amyloid burden (p < 0.001) were associated with poorer WM integrity in the CBH after Bonferroni adjustment., Conclusion: These findings are consistent with patterns of WM microstructural damage previously reported in non-Hispanic White (NHW) MCI/AD cohorts, reinforcing existing evidence from predominantly NHW cohort studies., (© 2023. The Author(s).)

Background: Low body mass index (BMI) or underweight status in late life is associated with an increased risk of dementia or Alzheimer's disease (AD). However, the relationship between late-life BMI and prospective longitudinal changes of in-vivo AD pathology has not been investigated., Methods: This prospective longitudinal study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE). A total of 194 cognitive normal older adults were included in the analysis. BMI at baseline was measured, and two-year changes in brain Aβ and tau deposition on PET imaging were used as the main outcomes. Linear mixed-effects (LME) models were used to examine the relationships between late-life BMI and longitudinal change in AD neuropathological biomarkers., Results: A lower BMI at baseline was significantly associated with a greater increase in tau deposition in AD-signature region over 2 years (β, -0.018; 95% CI, -0.028 to -0.004; p = .008), In contrast, BMI was not related to two-year changes in global Aβ deposition (β, 0.0002; 95% CI, -0.003 to 0.002, p = .671). An additional exploratory analysis for each sex showed lower baseline BMI was associated with greater increases in tau deposition in males (β, -0.027; 95% CI, -0.046 to -0.009; p = 0.007), but not in females., Discussion: The findings suggest that lower BMI in late-life may predict or contribute to the progression of tau pathology over the subsequent years in cognitively unimpaired older adults., (© 2023. The Author(s).)

Background: Hypertension has been associated with Alzheimer's disease (AD) dementia as well as vascular dementia. However, the underlying neuropathological changes that link hypertension to AD remain poorly understood. In our study, we examined the relationships of a history of hypertension and high current blood pressure (BP) with in vivo AD pathologies including β-amyloid (Aβ) and tau and also investigated whether a history of hypertension and current BP respectively affect the association between Aβ and tau deposition., Methods: This cross-sectional study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease, a prospective cohort study. Cognitively normal older adults who underwent both Aβ and tau positron emission tomography (PET) (i.e., [ 11 C]-Pittsburgh compound B and [ 18 F] AV-1451 PET) were selected. History of hypertension and current BP were evaluated and cerebral Aβ and tau deposition measured by PET were used as main outcomes. Generalized linear regression models were used to estimate associations., Results: A total of 68 cognitively normal older adults (mean [SD] age, 71.5 [7.4] years; 40 women [59%]) were included in the study. Neither a history of hypertension nor the current BP exhibited a direct association with Aβ or tau deposition. However, the synergistic interaction effects of high current systolic (β, 0.359; SE, 0.141; p = 0.014) and diastolic (β, 0.696; SE, 0.158; p < 0.001) BP state with Aβ deposition on tau deposition were significant, whereas there was no such effect for a history of hypertension (β, 0.186; SE, 0.152; p = 0.224)., Conclusions: The findings suggest that high current BP, but not a history of hypertension, synergistically modulate the relationship between cerebral Aβ and tau deposition in late-life. In terms of AD prevention, the results support the importance of strict BP control in cognitively normal older adults with hypertension., (© 2022. The Author(s).)

Background: Despite the known associations between zinc levels and Alzheimer's disease (AD) dementia and related cognitive impairment, the underlying neuropathological links remain poorly understood. We tested the hypothesis that serum zinc level is associated with cerebral beta-amyloid protein (Aβ) deposition. Additionally, we explored associations between serum zinc levels and other AD pathologies [i.e., tau deposition and AD-signature cerebral glucose metabolism (AD-CM)] and white matter hyperintensities (WMHs), which are measures of cerebrovascular injury., Methods: A total of 241 cognitively normal older adults between 55 and 90 years of age were enrolled. All the participants underwent comprehensive clinical assessments, serum zinc level measurement, and multimodal brain imaging, including Pittsburgh compound B-positron emission tomography (PET), AV-1451 PET, fluorodeoxyglucose (FDG)-PET, and magnetic resonance imaging. Zinc levels were stratified into three categories: < 80 μg/dL (low), 80 to 90 μg/dL (medium), and > 90 μg/dL (high)., Results: A low serum zinc level was significantly associated with increased Aβ retention. In addition, apolipoprotein E ε4 allele (APOE4) status moderated the association: the relationship between low zinc level and Aβ retention was significant only in APOE4 carriers. Although a low zinc level appeared to reduce AD-CM, the relationship became insignificant on sensitivity analysis including only individuals with no nutritional deficiency. The serum zinc level was associated with neither tau deposition nor the WMH volume., Conclusions: Our findings suggest that decreased serum zinc levels are associated with elevation of brain amyloid deposition. In terms of AD prevention, more attention needs to be paid to the role of zinc., (© 2021. The Author(s).)

Background: Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by the hallmark finding of cerebral amyloid deposition. Many researchers have tried to predict the existence of cerebral amyloid deposition by using easily accessible blood plasma samples, but the effectiveness of such strategies remains controversial., Methods: We developed a new multiplex kit, the QPLEX™ Alz plus assay kit, which uses proteomics-based blood biomarkers to prescreen for cerebral amyloid deposition. A total of 300 participants who underwent Pittsburgh compound B (PiB)-positron emission tomography (PET) which allows imaging of cerebral amyloid deposition were included in this study. We compared the levels of QPLEX™ biomarkers between patients who were classified as PiB-negative or PiB-positive, regardless of their cognitive function. Logistic regression analysis followed by receiver operating characteristic (ROC) curve analysis was performed. The kit accuracy was tested using a randomized sample selection method., Results: The results obtained using our assay kit reached 89.1% area under curve (AUC) with 80.0% sensitivity and 83.0% specificity. Further validation of the QPLEX™ Alz plus assay kit using a randomized sample selection method showed an average accuracy of 81.5%., Conclusions: Our QPLEX™ Alz plus assay kit provides preliminary evidence that it can be used as blood marker to predict cerebral amyloid deposition but independent validation is needed.

Introduction: Although the heritability of sporadic Alzheimer's disease (AD) is estimated to be 60-80%, addressing the genetic contribution to AD risk still remains elusive. More specifically, it remains unclear whether genetic variants are able to affect neurodegenerative brain features that can be addressed by in vivo imaging techniques., Methods: Targeted sequencing analysis of the coding and UTR regions of 132 AD susceptibility genes was performed. Neuroimaging data using 11 C-Pittsburgh Compound B positron emission tomography (PET), 18 F-fluorodeoxyglucose PET, and MRI that are available from the KBASE (Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's disease) cohort were acquired. A total of 557 participants consisted of 336 cognitively normal (CN) adults, 137 mild cognitive impairment (MCI), and 84 AD dementia (ADD) groups., Results: We called 5391 high-quality single nucleotide variants (SNVs) on AD susceptibility genes and selected significant associations between variants and five in vivo AD pathologies: (1) amyloid β (Aβ) deposition, (2) AD-signature region cerebral glucose metabolism (AD-Cm), (3) posterior cingulate cortex (PCC) cerebral glucose metabolism (PCC-Cm), (4) AD-signature region cortical thickness (AD-Ct), and (5) hippocampal volume (Hv). The association analysis for common variants (allele frequency (AF) > 0.05) yielded several novel loci associated with Aβ deposition (PIWIL1-rs10848087), AD-Cm (NME8-rs2722372 and PSEN2-rs75733498), AD-Ct (PSEN1-rs7523) and, Hv (CASS4-rs3746625). Meanwhile, in a gene-based analysis for rare variants (AF < 0.05), cases carrying rare variants in LPL, FERMT2, NFAT5, DSG2, and ITPR1 displayed associations with the neuroimaging features. Exploratory voxel-based brain morphometry between the variant carriers and non-carriers was performed subsequently. Finally, we document a strong association of previously reported APOE variants with the in vivo AD pathologies and demonstrate that the variants exert a causal effect on AD susceptibility via neuroimaging features., Conclusions: This study provides novel associations of genetic factors to Aβ accumulation and AD-related neurodegeneration to influence AD susceptibility.

Background: To clarify whether atherosclerosis of the carotid and intracranial arteries is related to Alzheimer's disease (AD) pathology in vivo, we investigated the associations of carotid and intracranial artery stenosis with cerebral beta-amyloid (Aβ) deposition and neurodegeneration in middle- and old-aged individuals. Given different variations of the pathologies between cognitive groups, we focused separately on cognitively normal (CN) and cognitively impaired (CI) groups., Methods: A total of 281 CN and 199 CI (mild cognitive impairment and AD dementia) subjects underwent comprehensive clinical assessment, [ 11 C] Pittsburgh compound B-positron emission tomography, and magnetic resonance (MR) imaging including MR angiography. We evaluated extracranial carotid and intracranial arteries for the overall presence, severity (i.e., number and degree of narrowing), and location of stenosis., Results: We found no associations between carotid and intracranial artery stenosis and cerebral Aβ burden in either the CN or the CI group. In terms of neurodegeneration, exploratory univariable analyses showed associations between the presence and severity of stenosis and regional neurodegeneration biomarkers (i.e., reduced hippocampal volume [HV] and cortical thickness in the AD-signature regions) in both the CN and CI groups. In confirmatory multivariable analyses controlling for demographic covariates and diagnosis, the association between number of stenotic intracranial arteries ≥ 2 and reduced HV in the CI group remained significant., Conclusions: Neither carotid nor intracranial artery stenosis appears to be associated with brain Aβ burden, while intracranial artery stenosis is related to amyloid-independent neurodegeneration, particularly hippocampal atrophy.

Background: Very little is known for the direction or causality of the relationship between lifetime sleep experiences and in vivo Alzheimer's disease (AD) pathologies. This study aimed to examine the relationship between sleep experiences during the young adulthood, midlife, and late-life periods and in vivo cerebral beta-amyloid (Aβ) deposition and AD signature regional neurodegeneration in cognitively normal (CN) old adults., Methods: This study included 202 CN old adults who participated in the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) study. All participants underwent a comprehensive clinical assessment, [ 11 C] Pittsburgh Compound B positron emission tomography (PET), [ 18 F] Fluorodeoxyglucose-PET, and magnetic resonance imaging. The quality and duration of sleep were assessed for the following age periods: 20-30s, 40-50s, and the most recent month. All analyses were adjusted for age, gender, education, apolipoprotein E ε4 status, vascular risk score, Hamilton Depression Rating Scale score, and use of sleep medication., Results: Bad sleep quality and short sleep duration during midlife were significantly associated with increased Aβ deposition and AD signature regional hypometabolism, respectively. Although current bad sleep quality appeared to be associated with increased Aβ accumulation, this association disappeared after controlling for the effects of midlife sleep quality. Neither the quality nor duration of sleep during young adulthood was related to Aβ burden or neurodegeneration., Conclusions: Bad sleep quality during midlife increases pathological Aβ deposition in the brain, while short sleep duration during the same period accelerates regional hypometabolism.

Background: Recently, the field of gene-gene or gene-environment interaction research appears to have gained growing interest, although it is seldom investigated in Alzheimer's disease (AD). Hence, the current study aims to investigate interaction effects of the key genetic and environmental risks-the apolipoprotein ε4 allele (APOE4) and family history of late-onset AD (FH)-on AD-related brain changes in cognitively normal (CN) middle-aged and older adults., Methods: [ 11 C] Pittsburg compound-B (PiB) positron emission tomography (PET) imaging as well as [ 18 F] fluoro-2-deoxyglucose (FDG) PET that were simultaneously taken with T1-weighted magnetic resonance imaging (MRI) were obtained from 268 CNs from the Korean Brain Aging Study for Early Diagnosis and Prediction of AD (KBASE). Composite standardized uptake value ratios were obtained from PiB-PET and FDG-PET images in the AD signature regions of interests (ROIs) and analyzed. Voxel-wise analyses were also performed to examine detailed regional changes not captured by the ROI analyses., Results: A significant synergistic interaction effect was found between the APOE4 and FH on amyloid-beta (Aβ) deposition in the AD signature ROIs as well as other regions. Synergistic interaction effects on cerebral glucose metabolism were observed in the regions not captured by the AD signature ROIs, particularly in the medial temporal regions., Conclusions: Strong synergistic effects of APOE4 and FH on Aβ deposition and cerebral glucose metabolism in CN adults indicate possible gene-to-gene or gene-to-environment interactions that are crucial for pathogenesis of AD involving Aβ. Other unspecified risk factors-genes and/or environmental-that are captured by the positive FH status might either coexpress or interact with APOE4 to alter AD-related brain changes in CN. Healthy people with both FH and APOE4 need more attention for AD prevention.

Background: The present study investigated the relationships between thyroid hormone serum levels or thyroid-stimulating hormone (TSH) and two Alzheimer's disease (AD)-specific biomarkers, cerebral amyloid beta (Aβ) burden and glucose metabolism, in AD-signature brain regions in cognitively normal (CN) middle-aged and older individuals., Methods: This study assessed 148 CN individuals who received comprehensive clinical and neuropsychological assessments that included 11 C-Pittsburgh Compound B (PiB)-positron emission tomography (PET) scans, 18 F-deoxyglucose (FDG)-PET scans, and the quantification of serum triiodothyronine (T3), free T3, free thyroxine (fT4), and TSH levels., Results: All participants were clinically euthyroid. Independent negative associations were found between serum fT4 levels and global cerebral Aβ deposition after controlling for the effects of age, gender, and the apolipoprotein E ε4 (APOEε4) genotype. Although serum TSH levels were not associated with global cerebral Aβ deposition, they had a significant negative association with glucose metabolism in the precuneus/posterior cingulate cortex after controlling for age, gender, and the APOEε4 genotype. No other thyroid hormones exhibited relationships with either brain Aβ burden or glucose metabolism., Conclusions: Even in a clinical euthyroid state, low serum fT4 and high serum TSH levels appear to be differentially associated with AD-specific brain changes.

Background: Plasma β-amyloid (Aβ) is a potential candidate for an Alzheimer's disease (AD) biomarker because blood is an easily accessible bio-fluid, which can be collected routinely, and Aβ is one of the major hallmarks of AD pathogenesis in the brain. However, the association between plasma Aβ levels and AD diagnosis is still unclear due to the instability and inaccurate measurements of plasma Aβ levels in the blood of patients with AD. If a consistent value of plasma Aβ from the blood can be obtained, this might help determine whether plasma Aβ is a potential biomarker for AD diagnosis., Methods: We predicted the brain amyloid deposit by measuring the plasma Aβ levels. This cross-sectional study included 353 participants (215 cognitively normal, 79 with mild cognitive impairment, and 59 with AD dementia) who underwent Pittsburgh-compound B positron emission tomography (PiB-PET) scans. We treated a mixture of protease inhibitors and phosphatase inhibitors (MPP) and detected plasma Aβ42 and Aβ40 (MPP-Aβ42 and MPP-Aβ40) in a stable manner using xMAP technology., Results: MPP-Aβ40 and MPP-Aβ42/40 (MPP-Aβs) were significantly different between subjects with positive amyloid deposition (PiB+) and those with negative amyloid deposition (PiB-) (P < 0.0001). Furthermore, MPP-Aβ40 (P < 0.0001, r = 0.23) and MPP-Aβ42/40 ratio (P < 0.0001, r = -0.23) showed significant correlation with global PiB deposition (standardized uptake value ratio). In addition, our integrated multivariable (MPP-Aβ42/40, gender, age, and apolipoprotein E genotypes) logistic regression model proposes a new standard for the prediction of cerebral amyloid deposition., Conclusions: MPP-Aβ might be one of the potential blood biomarkers for the prediction of PiB-PET positivity in the brain.