Moderation of Amyloid-ß Deposition on the Effect of Cholinesterase Inhibitors on Cognition in Mild Cognitive Impairment.

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-ß (Aß) deposition, a hallmark of Alzheimer's disease; this Aß heterogeneity may explain inconsistent results. Objective: This study aimed to assess whether Aß 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 Aß status, was associated with more cognitive decline over the 2-year period. Conclusions: Aß pathology does not appear to moderate ChEI effects on cognitive decline in MCI.

Moderation of thyroid hormones for the relationship between amyloid and tau pathology.

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 (Aß) and tau deposition measured by positron emission tomography (PET). Given the well-known relationship between Aß and tau pathology in AD, we additionally examined the moderating effects of thyroid hormone levels on the association between Aß 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 [11C]-Pittsburgh compound B (PiB)- PET and [18F] AV-1451 PET. RESULTS: No associations were found between either thyroid hormones or TSH and Aß and tau deposition on PET. However, fT4 (p = 0.002) and fT3 (p = 0.001) exhibited significant interactions with Aß on tau deposition: The sensitivity analyses conducted after the removal of an outlier showed that the interaction effect between fT4 and Aß deposition was not significant, whereas the interaction between fT3 and Aß deposition remained significant. However, further subgroup analyses demonstrated a more pronounced positive relationship between Aß 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 Aß on tau deposition. CONCLUSION: Our findings suggest that serum thyroid hormones may moderate the relationship between cerebral Aß and tau pathology. Higher levels of serum thyroid hormones could potentially accelerate the Aß-dependent tau deposition in the brain. Further replication studies in independent samples are needed to verify the current results.

Plasma Leptin and Alzheimer Protein Pathologies Among Older Adults.

Importance: Many epidemiologic studies have suggested that low levels of plasma leptin, a major adipokine, are associated with increased risk of Alzheimer disease (AD) dementia and cognitive decline. Nevertheless, the mechanistic pathway linking plasma leptin and AD-related cognitive decline is not yet fully understood. Objective: To examine the association of plasma leptin levels with in vivo AD pathologies, including amyloid-beta (Aß) and tau deposition, through both cross-sectional and longitudinal approaches among cognitively unimpaired older adults. Design, Setting, and Participants: This was a longitudinal cohort study from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer Disease. Data were collected from January 1, 2014, to December 31, 2020, and data were analyzed from July 11 to September 6, 2022. The study included a total of 208 cognitively unimpaired participants who underwent baseline positron emission tomography (PET) scans for brain Aß deposition. For longitudinal analyses, 192 participants who completed both baseline and 2-year follow-up PET scans for brain Aß deposition were included. Exposure: Plasma leptin levels as assessed by enzyme-linked immunosorbent assay. Main Outcomes and Measures: Baseline levels and longitudinal changes of global Aß and AD-signature region tau deposition measured by PET scans. Results: Among the 208 participants, the mean (SD) age was 66.0 (11.3) years, 114 were women (54.8%), and 37 were apolipoprotein E ε4 carriers (17.8%). Lower plasma leptin levels had a significant cross-sectional association with greater brain Aß deposition (ß = -0.04; 95% CI, -0.09 to 0.00; P = .046), while there was no significant association between plasma leptin levels and tau deposition (ß = -0.02; 95% CI, -0.05 to 0.02; P = .41). In contrast, longitudinal analyses revealed that there was a significant association between lower baseline leptin levels and greater increase of tau deposition over 2 years (ß = -0.06; 95% CI, -0.11 to -0.01; P = .03), whereas plasma leptin levels did not have a significant association with longitudinal change of Aß deposition (ß = 0.006; 95% CI, 0.00-0.02; P = .27). Conclusions and Relevance: The present findings suggest that plasma leptin may be protective for the development or progression of AD pathology, including both Aß and tau deposition.

Association between brain amyloid deposition and longitudinal changes of white matter hyperintensities.

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 (Aß) 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 Aß 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 Aß or tau deposition and WMH volume were examined using multiple linear regression analysis. In this analysis, baseline Aß 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 Aß or tau deposition for 2 years as dependent variables to investigate whether WMH volume could precede AD pathologies. RESULTS: Baseline Aß 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 Aß or tau deposition for 2 years. We also found a significant interaction effect between baseline Aß deposition and sex on longitudinal change of WMH volume. Subsequent subgroup analyses showed that high baseline Aß deposition was associated with increase of WMH volume over 2 years in female, but not in male. CONCLUSIONS: Our findings suggest that Aß deposition accelerates cerebral WMHs, particularly in female, whereas white matter degeneration appears not influence on longitudinal Aß increase. The results also did not support any direction of influence between tau deposition and WMHs.

Development of a Cognitive Composite for Preclinical Alzheimer's Disease in Korean Older Adults.

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 Aß positive and negative group (p = 0.03). Linear mixed model analyses also showed that the Aß 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.

Body mass index and two-year change of in vivo Alzheimer's disease pathologies in cognitively normal older adults.

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 Aß 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 (ß, -0.018; 95% CI, -0.028 to -0.004; p = .008), In contrast, BMI was not related to two-year changes in global Aß deposition (ß, 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 (ß, -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.

Serum Adiponectin and In Vivo Brain Amyloid Deposition in Cognitively Normal Older Adults: A Cohort Study.

High blood adiponectin has been associated with Alzheimer's disease (AD) dementia and related cognitive decline. We aimed to investigate the association between serum adiponectin level and in vivo AD pathologies. Cross-sectional and longitudinal study designs for the data of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease, an ongoing prospective cohort study that began in 2014. A total of 283 cognitively normal older adults between 55 and 90 years of age were included in community and memory clinic setting. Participants underwent comprehensive clinical assessments, measurement of serum adiponectin level, and multimodal brain imaging, including Pittsburgh compound-B positron emission tomography (PET), AV-1451 PET, fluorodeoxyglucose (FDG)-PET, and MRI at baseline and 2-year follow-up. Serum adiponectin level was positively associated with global beta-amyloid protein (Aß) retention and change therein over 2 years, but not with other AD neuroimaging markers including tau deposition, AD-related neurodegeneration, and white matter hyperintensities. Blood adiponectin level is associated with increased brain amyloid deposition, which suggests that adiponectin may be a potential target for therapeutic and preventive strategies against AD.

Sex differences in the progression of glucose metabolism dysfunction in Alzheimer's disease.

Alzheimer's disease (AD) is a common neurodegenerative disease characterized by amyloid plaques and impaired brain metabolism. Because women have a higher prevalence of AD than men, sex differences are of great interest. Using cross-sectional and longitudinal data, we showed sex-dependent metabolic dysregulations in the brains of AD patients. Cohort 1 (South Korean, n = 181) underwent Pittsburgh compound B-PET, fluorodeoxyglucose-PET, magnetic resonance imaging, and blood biomarker (plasma tau and beta-amyloid 42 and 40) measurements at baseline and two-year follow-ups. Transcriptome analysis of data from Cohorts 2 and 3 (European, n = 78; Singaporean, n = 18) revealed sex differences in AD-related alterations in brain metabolism. In women (but not in men), all imaging indicators displayed consistent correlation curves with AD progression. At the two-year follow-up, clear brain metabolic impairment was revealed only in women, and the plasma beta-amyloid 42/40 ratio was a possible biomarker for brain metabolism in women. Furthermore, our transcriptome analysis revealed sex differences in transcriptomes and metabolism in the brains of AD patients as well as a molecular network of 25 female-specific glucose metabolic genes (FGGs). We discovered four key-attractor FGG genes (ALDOA, ENO2, PRKACB, and PPP2R5D) that were associated with amyloid/tau-related genes (APP, MAPT, BACE1, and BACE2). Furthermore, these genes successfully distinguished amyloid positivity in women. Understanding sex differences in the pathogenesis of AD and considering these differences will improve development of effective diagnostics and therapeutic treatments for AD.

Low Ankle-Brachial Index Relates to Alzheimer-Signature Cerebral Glucose Metabolism in Cognitively Impaired Older Adults.

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 Aß 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.

The Effects of Depression and Fear in Dual-Income Parents on Work-Family Conflict During the COVID-19 Pandemic.

This study investigated depression and fear in dual-income parents during the COVID-19 pandemic as predictors of work-family conflict. Using a cross-sectional design, we recruited 214 dual-income parents aged 20 years or older with preschool and primary school children in Korea. Data were collected via an online survey. In the final model for hierarchical regression analysis, the strongest predictor of work-family conflict was depression (ß = .43, p < .001), followed by fear (ß = .23, p < .001), then weekly working hours (ß = .12, p < .05). The final model was statistically significant (F = 29.80, p < .001), with an explanatory power of 35%. These findings highlight the need to provide dual-income parents with government-led disaster psychological support during COVID-19, such as counseling, education, and mental health management services involving the psychological predictors of work-family conflict. Diverse systematic intervention programs and policy support should also be provided to help them resolve work-family conflict.

Enlarged perivascular spaces are associated with decreased brain tau deposition.

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 (Aß) 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 [11 C] Pittsburgh compound B and [18 F] 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, Aß-positive, or APOE4-positive individuals, but not significant in the cognitively normal, Aß-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 Aß 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.

Circadian rest-activity rhythm and longitudinal brain changes underlying late-life cognitive decline.

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 [11 C] Pittsburgh compound-B positron emission tomography (PET), [18 F] 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.

Synergistic interaction of high blood pressure and cerebral beta-amyloid on tau pathology.

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 ß-amyloid (Aß) and tau and also investigated whether a history of hypertension and current BP respectively affect the association between Aß 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 Aß and tau positron emission tomography (PET) (i.e., [11C]-Pittsburgh compound B and [18F] AV-1451 PET) were selected. History of hypertension and current BP were evaluated and cerebral Aß 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 Aß or tau deposition. However, the synergistic interaction effects of high current systolic (ß, 0.359; SE, 0.141; p = 0.014) and diastolic (ß, 0.696; SE, 0.158; p < 0.001) BP state with Aß deposition on tau deposition were significant, whereas there was no such effect for a history of hypertension (ß, 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 Aß 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.

Association of low meal frequency with decreased in vivo Alzheimer's pathology.

Little is known about the association between meal frequency and Alzheimer's disease (AD) in humans. We tested the hypothesis that low meal frequency (LMF) is associated with reduced in vivo AD pathology in human brain, and additionally investigated the mediation of serum ghrelin, a hunger-related hormone, for the association. A total of 411 non-demented older adults were systematically interviewed to identify their dietary patterns including meal frequency and underwent multi-modal neuroimaging for cerebral beta-amyloid (Aß) and tau deposition, glucose metabolism, and cerebrovascular injury. LMF (less than three meals a day) was significantly associated with lower Aß deposition compared to high meal frequency (HMF). In addition, both LMF and reduced Aß deposition were significantly related to elevated serum ghrelin. Our findings suggest that LMF may be related to the lower risk of AD through reduced brain amyloid deposition. Additionally, ghrelin appears mediate the association between LMF and lower amyloid deposition.

Behavioral and Psychological Symptoms and Associated Factors in Community-Dwelling Persons at the First Time of Dementia Diagnosis.

BACKGROUND: Community-dwelling residents at potential risk of dementia and their families have difficulty detecting symptoms of dementia during an outbreak of coronavirus disease-19 (COVID-19). We explored the characteristics of behavioral and psychological symptoms of dementia (BPSD) in community-dwelling persons at the first time of dementia diagnosis and identified their associated variables. METHODS: A cross-sectional study using secondary data of dementia diagnosis tests was conducted. Data were reported by professional nurses and clinicians from 355 persons at the first time of dementia diagnosis in South Korea. BPSD and their associated variables were measured with the Neuropsychiatric Inventory, the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-K) assessment handbook and electronic medical records. RESULTS: The most common symptoms were apathy/indifference (72.1%), followed by irritability/lability (42.8%) and depression/dysphoria (42.0%). Hierarchical regression analyses showed that the strongest factor associated with BPSD was dementia type (ß = -0.18, p = 0.001) mostly severer in frontotemporal dementia, followed by activities of daily living dependency (ß = 0.15, p = 0.033), and number of medications (ß = 0.10, p = 0.048). CONCLUSION: Providing information based on the study findings to families who are caring for persons at potential risk of dementia, may be able to detect dementia symptoms early and manage appropriate care.

Spouse bereavement and brain pathologies: A propensity score matching study.

AIM: Spouse bereavement is one of life's greatest stresses and has been suggested to trigger or accelerate cognitive decline and dementia. However, little information is available about the potential brain pathologies underlying the association between spouse bereavement and cognitive decline. We aimed to investigate that lifetime spouse bereavement is associated with in vivo human brain pathologies underlying cognitive decline. METHODS: A total of 319 ever-married older adults between the ages of 61 and 90 years underwent comprehensive clinical assessments and multimodal brain imaging including [11 C] Pittsburgh compound B-positron emission tomography (PET), AV-1451 PET, [18 F] fluorodeoxyglucose-PET, and magnetic resonance imaging. Participants were classified as experiencing no spouse bereavement or spouse bereavement, and comparisons using propensity score matching (59 cases and 59 controls) were performed. RESULTS: Spouse bereavement was significantly associated with higher cerebral white matter hyperintensity (WMH) volume compared with no spouse bereavement. Interaction and subsequent subgroup analyses showed that spouse bereavement was significantly associated with higher WMH in the older (>75 years) subgroup and among those with no- or low-skill occupations. In addition, spouse bereavement at 60 years or older affects WMH volume compared with no spouse bereavement, whereas spouse bereavement at younger than 60 years did not. No group differences were observed in other brain pathologies between spouse bereavement categories. CONCLUSIONS: The findings suggest that the spouse bereavement may contribute to dementia or cognitive decline by increasing cerebrovascular injury, particularly in older individuals and those with no- or low-skill occupations.

Application of QPLEXTM biomarkers in cognitively normal individuals across a broad age range and diverse regions with cerebral amyloid deposition.

The deposition of beta-amyloid (Aß) in the brain precedes the onset of symptoms such as cognitive impairment in Alzheimer's disease (AD); therefore, the early detection of Aß accumulation is crucial. We previously reported the applicability of the QPLEXTM Alz plus assay kit for the prescreening of Aß accumulation. Here, we tested the specific application of the kit in a large cohort of cognitively normal (CN) individuals of varying ages for the early detection of Aß accumulation. We included a total of 221 CN participants with or without brain Aß. The QPLEXTM biomarkers were characterized based on age groups (1st-3rd tertile) and across various brain regions with cerebral amyloid deposition. The 3rd tertile group (>65 years) was found to be the most suitable age group for the application of our assay kit. Receiver operating characteristic curve analysis showed that the area under the curve (AUC, discrimination power) was 0.878 with 69.7% sensitivity and 98.4% specificity in the 3rd tertile group. Additionally, specific correlations between biomarkers and cerebral amyloid deposition in four different brain regions revealed an overall correlation with general amyloid deposition, consistent with previous findings. Furthermore, the combinational panel with plasma Aß1-42 levels maximized the discrimination efficiency and achieved an AUC of 0.921 with 95.7% sensitivity and 67.3% specificity. Thus, we suggest that the QPLEXTM Alz plus assay is useful for prescreening brain Aß levels in CN individuals, especially those aged >65 years, to prevent disease progression via the early detection of disease initiation.

Functional Neural Correlates of Semantic Fluency Task Performance in Mild Cognitive Impairment and Alzheimer's Disease: An FDG-PET Study.

BACKGROUND: Total score (TS) of semantic verbal fluency test (SVFT) is generally used to interpret results, but it is ambiguous as to specific neural functions it reflects. Different SVFT strategy scores reflecting qualitative aspects are proposed to identify specific cognitive functions to overcome limitations of using the TS. OBJECTIVE: Functional neural correlates of the TS as well as the other strategy scores in subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia using Fluorine-18-Fluorodeoxyglucose positron emission tomography (FDG-PET). METHODS: Correlations between various SVFT scores (i.e., TS, mean cluster size, switching (SW), hard switching, cluster switching (CSW)) and cerebral glucose metabolism were explored using voxelwise whole-brain approach. Subgroup analyses were also performed based on the diagnosis and investigated the effects of disease severity on the associations. RESULTS: Significant positive correlation between TS and cerebral glucose metabolism was found in prefrontal, parietal, cingulate, temporal cortex, and subcortical regions. Significantly increased glucose metabolism associated with the SW were found in similar but smaller regions, mainly in the fronto-parieto-temporal regions. CSW was only correlated with the caudate. In the subgroup analysis conducted to assess different contribution of clinical severity, differential associations between the strategy scores and regional glucose metabolism were found. CONCLUSION: SW and CSW may reflect specific language and executive functions better than the TS. The SVFT is influenced by brain dysfunction due to the progression of AD, as demonstrated by the SW with larger involvement of temporal lobe for the AD, and CSW with significant association only for the MCI.

Cognitive reserve proxies, Alzheimer pathologies, and cognition.

This study aimed to explore the moderating effects of the frequently used cognitive reserve (CR) proxies [i.e., education, premorbid intelligence quotient (pIQ), occupational complexity (OC), and lifetime cognitive activity (LCA)] on the relationships between various in vivo Alzheimer's disease (AD) pathologies and cognition. In total, 351 [268 cognitively unimpaired (CU), 83 cognitive impaired (CI)] older adults underwent multi-modal brain imaging to measure AD pathologies and cognitive assessments, and information on CR proxies was obtained. For overall participants, only education moderated the relationship between Aß deposition and cognition. Education, pIQ, and LCA, but not OC, showed moderating effect on the relationship between AD-signature cerebral hypometabolism and cognition. In contrast, only OC had a moderating effect on the relationship between cortical atrophy of the AD-signature regions and cognition. Such moderation effects of the CR proxies were similarly observed in CI individuals, but most of them were not in CU individuals. The findings suggest that the proposed CR proxies have different moderating effects on the relationships between specific AD pathologies and cognition.

Serum zinc levels and in vivo beta-amyloid deposition in the human brain.

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 (Aß) 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 Aß retention. In addition, apolipoprotein E ε4 allele (APOE4) status moderated the association: the relationship between low zinc level and Aß 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.