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Background: Clinical trial findings on cholinesterase inhibitors (ChEIs) for mild cognitive impairment (MCI) are inconclusive, offering limited support for their MCI treatment. Given that nearly half of amnestic MCI cases lack cerebral amyloid-β (Aβ) deposition, a hallmark of Alzheimer's disease; this Aβ heterogeneity may explain inconsistent results. Objective: This study aimed to assess whether Aβ deposition moderates ChEI effects on amnestic MCI cognition. Methods: We examined 118 individuals with amnestic MCI (ages 55–90) in a longitudinal cohort study. Baseline and 2-year follow-up assessments included clinical evaluations, neuropsychological testing, and multimodal neuroimaging. Generalized linear models were primarily analyzed to test amyloid positivity's moderation of ChEI effects on cognitive change over 2 years. Cognitive outcomes included Mini-Mental Status Examination score, the total score of the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery, and Clinical Dementia Rating-sum of boxes. Results: The analysis found no significant ChEI use x amyloid positivity interaction for all cognitive outcomes. ChEI use, irrespective of Aβ status, was associated with more cognitive decline over the 2-year period. Conclusions: Aβ pathology does not appear to moderate ChEI effects on cognitive decline in MCI. [ABSTRACT FROM AUTHOR]

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, [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. 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. [ABSTRACT FROM AUTHOR]

Background: As tracking subtle cognitive declines in the preclinical stage of Alzheimer's disease (AD) is difficult with traditional individual outcome measures, need for cognitive composite for preclinical AD is widely recognized. Objective: We aimed to develop culturally appropriate cognitive composite that sensitively identifies subtle cognitive decline of preclinical AD in Korean older adults. Methods: A total 225 cognitively normal elderly individuals from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease, were included. Tests of episodic memory, orientation, and executive function were carefully selected through review of previously established composites. Three candidate composites including Consortium to Establish a Registry for Alzheimer's Disease Word list recall (WLR), Logical memory (LM) II, and Mini-Mental status examination (MMSE) in common, and Letter fluency test (LF), category fluency test, or Stroop color and word test, were selected. Results: Student t-tests demonstrated that only the composite composed of WLR, LM II, MMSE, and LF (Composite 1) showed a significant difference in score decline over two-year follow-up period between Aβ positive and negative group (p = 0.03). Linear mixed model analyses also showed that the Aβ x time interaction effect was significant only for Composite 1 (p = 0.025). Based on the results, Composite 1 was chosen as the final cognitive composite for preclinical Alzheimer's disease (CPAD). Conclusions: CPAD can be used to assess subtle cognitive decline of preclinical AD in clinical research settings, especially in Korean older adults. It also may be used for monitoring progression or treatment benefits in clinical practices. [ABSTRACT FROM AUTHOR]

Background: As tracking subtle cognitive declines in the preclinical stage of Alzheimer's disease (AD) is difficult with traditional individual outcome measures, need for cognitive composite for preclinical AD is widely recognized. We aimed to develop culturally appropriate cognitive composite that sensitively identifies subtle cognitive decline of preclinical AD in Korean older adults. Method: A total 225 cognitively normal elderly individuals, who completed baseline and 2‐year follow‐up evaluation including clinical assessments and comprehensive neuropsychological tests and baseline amyloid positron emission tomography (PET) in the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE), were included. Tests of episodic memory, orientation, and executive function were carefully selected through review of previously established composite scores. Three candidate composites including Consortium to Establish a Registry for Alzheimer's Disease (CERAD) word list recall (WLR), logical memory (LM) II, and Mini‐mental status examination (MMSE) in common, and letter fluency test, category fluency test, or Stroop color and word test, were selected. Result: Student t‐tests demonstrated that only the composite composed of WLR, LM II, MMSE, and LF (Composite 1) showed a significant difference in score decline over two‐year follow‐up period between Aβ positive and negative group (P = 0.03). Linear mixed model analyses also showed that the Aβ x time interaction effect was significant only for Composite 1 (P = 0.026). In contrast, we did not find any significant results for other two candidate composites (Composite 2 and 3). Based on the results, Composite 1 was chosen as the final CPAD. Conclusion: CPAD can be used to assess subtle cognitive decline of preclinical AD in clinical research settings, especially in clinical trials with Korean older adults with preclinical AD. It also may be used for monitoring progression or treatment benefits in clinical practices. [ABSTRACT FROM AUTHOR]

Background: Ankle-brachial index (ABI), an indicator of atherosclerosis or arterial stiffness, has been associated with Alzheimer's disease (AD) dementia and related cognitive impairment. Nevertheless, only limited information is available regarding its contribution to brain alterations leading to cognitive decline in late-life. Objective: We aimed to investigate the relationship of ABI with in vivo AD pathologies and cerebrovascular injury in cognitively impaired older adults. Methods: Total 127 cognitively impaired (70 mild cognitive impairment and 57 AD dementia) individuals, who participated in an ongoing prospective cohort study, were included. All participants underwent comprehensive clinical and neuropsychological assessment, ABI measurement, apolipoprotein E (APOE) ɛ4 genotyping, and multi-modal brain imaging including [11C] Pittsburgh Compound B (PiB)-positron emission tomography (PET) and [18F] fludeoxyglucose (FDG)-PET, and MRI. Results: General linear model analysis showed significant relationship between ABI strata (low ABI: <1.00, normal ABI: 1.00–1.29, and high ABI: ≥1.30) and AD-signature region cerebral glucose metabolism (AD-CM), even after controlling age, sex, clinical dementia rating–sum of box, and APOE ɛ4 positivity (p = 0.029). Post hoc comparison revealed that low ABI had significantly lower AD-CM than middle and high ABI, while no difference of AD-CM was found between middle and high ABI. There was no significant difference of global Aβ deposition, AD-signature region cortical thickness, and white matter hyperintensity volume between the three ABI strata. Conclusion: Our findings suggest that lower ABI, likely related to atherosclerosis, may contribute to the aggravation of AD-related regional neurodegeneration in cognitively impaired older adults. [ABSTRACT FROM AUTHOR]

Aim: The neurobiological substrates underlying the relationship of circadian rest‐activity rhythm (RAR) alteration with accelerated late‐life cognitive decline are not clearly understood. In the present study, the longitudinal relationship of objectively measured circadian RAR with in vivo Alzheimer disease (AD) pathologies and cerebrovascular injury was investigated in older adults without dementia. Methods: The present study included 129 participants without dementia who participated in the KBASE (Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease) cohort. All participants underwent actigraphy at baseline and two consecutive [11C] Pittsburgh compound‐B positron emission tomography (PET), [18F] fluorodeoxyglucose‐PET, magnetic resonance imaging, and Mini‐Mental State Examination (MMSE) at baseline and at a 2‐year follow‐up assessment. The associations of circadian RAR with annualized change in neuroimaging measures including global amyloid‐beta retention, AD‐signature region cerebral glucose metabolism (AD‐CM), and white matter hyperintensity volume were examined. Results: Delayed acrophase at baseline was significantly associated with greater annualized decline of AD‐CM over a 2‐year period, but not with that of other neuroimaging measures. In contrast, other circadian RAR parameters at baseline had no association with annualized change of any neuroimaging measures. Annualized decline of AD‐CM was also significantly positively associated with the annual change in MMSE scores. Furthermore, a mediation analysis showed that greater reduction in AD‐CM mediated the effect of delayed acrophase at baseline on faster decline of MMSE score. Conclusion: The findings indicate that delayed acrophase in late life may cause or predict hypometabolism at AD‐signature brain regions, which underlies cognitive decline in the near future. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to investigate the associations of enlarged perivascular spaces (EPVS) in the basal ganglia (BG) and centrum semiovale (CSO) with beta‐amyloid (Aβ) and tau deposition in older adults with a diverse cognitive spectrum. Methods: A total of 163 (68 cognitively normal and 95 cognitively impaired) older participants underwent [11C] Pittsburgh compound B and [18F] AV‐1451 PET, and MRI. EPVS in the BG and CSO and other small vessel disease markers, such as white matter hyperintensities, lacunes, and deep and lobar microbleeds, were assessed. Results: Increased EPVS in the BG showed a significant association with lower cerebral tau deposition, even after controlling for other small vessel disease markers. Further exploratory analyses showed that this association was significant in cognitively impaired, Aβ‐positive, or APOE4‐positive individuals, but not significant in the cognitively normal, Aβ‐negative, or APOE4‐negative participants. In contrast to EPVS in the BG, EPVS in the CSO did not have any relationship with cerebral tau deposition. In addition, none of the two types of EPVS were associated with cerebral Aβ deposition. Conclusion: Brain tau deposition appears to be reduced with increased EPVS in the BG, especially in individuals with cognitive impairment, pathological amyloid burden, or genetic Alzheimer's disease risk. [ABSTRACT FROM AUTHOR]