| 11. |
- Chatterjee, P., et al.
(author)
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Serum Hepcidin Levels in Cognitively Normal Older Adults with High Neocortical Amyloid-beta Load
- 2020
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In: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 76:1, s. 291-301
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Journal article (peer-reviewed)abstract
- Background/Objective: Hepcidin, an iron-regulating hormone, suppresses the release of iron by binding to the iron exporter protein, ferroportin, resulting in intracellular iron accumulation. Given that iron dyshomeostasis has been observed in Alzheimer's disease (AD) together with elevated serum hepcidin levels, the current study examined whether elevated serum hepcidin levels are an early event in AD pathogenesis by measuring the hormone in cognitively normal older adults at risk of AD, based on high neocortical amyloid-beta load (NAL). Methods: Serum hepcidin levels in cognitively normal participants (n = 100) aged between 65-90 years were measured using ELISA. To evaluate NAL, all participants underwent 18F-florbetaben positron emission tomography. A standard uptake value ratio (SUVR)<1.35 was classified as low NAL (n = 65) and >= 1.35 (n = 35) was classified as high NAL. Results: Serum hepcidin was significantly higher in participants with high NAL compared to those with low NAL before and after adjusting for covariates: age, gender, and APOE epsilon 4 carriage (p < 0.05). A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished high from low NAL (area under the curve, AUC = 0.766), but was outperformed when serum hepcidin was added to the base model (AUC = 0.794) and further improved with plasma A beta(42/40) ratio (AUC = 0.829). Conclusion: The present findings indicate that serum hepcidin is increased in individuals at risk for AD and contribute to the body of evidence supporting iron dyshomeostasis as an early event of AD. Further, hepcidin may add value to a panel of markers that contribute toward identifying individuals at risk of AD; however, further validation studies are required.
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| 12. |
- Classon, Elisabet, et al.
(author)
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Montreal Cognitive Assessment: Normative Data for Cognitively Healthy Swedish 80-to 94-Year-Olds
- 2022
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In: Journal of Alzheimer's Disease. - : IOS PRESS. - 1387-2877 .- 1875-8908. ; 87:3, s. 1335-1344
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Journal article (peer-reviewed)abstract
- Background: The Montreal Cognitive Assessment (MoCA) is sensitive to cognitive impairment; however, it is also sensitive to demographic and socio-cultural factors. This necessitates reliable sub-population norms, but these are often lacking for older adults. Objective: To present demographically adjusted regression-based MoCA norms for cognitively healthy Swedish older adults. Methods: A pseudo-random sample of community-dwelling 80- to 94-year-olds, stratified by age and gender, was invited to the study. Initial telephone interviews and medical records searches (n = 218) were conducted to screen for cognitive impairment. N= 181 eligible participants were administered a protocol including the Swedish version of the MoCA and assessments of global cognition (Mini-Mental State Examination, MMSE) and depression (Patient Health Questionnaire-9, PHQ-9). Individuals scoring in the range of possible cognitive impairment on the MMSE or more than mild depression on the PHQ-9 were excluded (n = 23); three discontinued the test-session. Results: Norms were derived from the remaining n = 158. They were evenly distributed by gender, on average 85 years old, and with a mean education of 11 years. MoCA scores were independently influenced by age and education, together explaining 17.2% of the total variance. Higher age and lower education were associated with lower performance and 46% performed below the original cut-off (< 26/30). Conclusion: The negative impact of increasing age on MoCA performance continues linearly into the nineties in normal aging. Demographic factors should be considered when interpreting MoCA performance and a tool for computing demographically corrected standard scores is provided.
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| 13. |
- Cummings, J., et al.
(author)
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Cognitive Effects of the BET Protein Inhibitor Apabetalone: A Prespecified Montreal Cognitive Assessment Analysis Nested in the BETonMACE Randomized Controlled Trial
- 2021
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In: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 83:4, s. 1703-1715
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Journal article (peer-reviewed)abstract
- Background: Epigenetic changes may contribute importantly to cognitive decline in late life including Alzheimer's disease (AD) and vascular dementia (VaD). Bromodomain and extra-terminal (BET) proteins are epigenetic "readers" that may distort normal gene expression and contribute to chronic disorders. Objective: To assess the effects of apabetalone, a small molecule BET protein inhibitor, on cognitive performance of patients 70 years or older participating in a randomized trial of patients at high risk for major cardiovascular events (MACE). Methods: The Montreal Cognitive Assessment (MoCA) was performed on all patients 70 years or older at the time of randomization. 464 participants were randomized to apabetalone or placebo in the cognition sub-study. In a prespecified analysis, participants were assigned to one of three groups: MoCA score >= 26 (normal performance), MoCA score 25-22 (mild cognitive impairment), and MoCA score <= 21 (dementia). Exposure to apabetalone was equivalent in the treatment groups in each MoCA-defined group. Results: Apabetalone was associated with an increased total MoCA score in participants with baseline MoCA score of <= 21 (p = 0.02). There was no significant difference in change from baseline in the treatment groups with higher MoCA scores. In the cognition study, more patients randomized to apabetalone discontinued study drug for adverse effects (11.3% versus 7.9%). Conclusion: In this randomized controlled study, apabetalone was associated with improved cognition as measured by MoCA scores in those with baseline scores of 21 or less. BET protein inhibitors warrant further investigation for late life cognitive disorders.
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| 14. |
- de Crom, Tosca O E, et al.
(author)
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Air pollution and the risk of dementia : the Rotterdam study
- 2023
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 91:2, s. 603-613
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Journal article (peer-reviewed)abstract
- BACKGROUND: Exposure to air pollution has been suggested to increase the risk of dementia, but studies on this link often lack a detailed screening for dementia and data on important confounders.OBJECTIVE: To determine the association of exposure to air pollution with the risk of dementia and cognitive decline in the population-based Rotterdam Study.METHODS: Between 2009 and 2010, we determined air pollutant concentrations at participants residential addresses using land use regression models. Determined air pollutants include particulate matter <10μm (PM10) and <2.5μm (PM2.5), a proxy of elemental carbon (PM2.5 absorbance), nitrogen oxide (NOx), and nitrogen dioxide (NO2). As the individual air pollutant levels were highly correlated (r = 0.71-0.98), we computed a general marker covering all air pollutants based on a principal component analysis. We followed participants up for dementia until 2018 and determined cognitive performance during two subsequent examination rounds. Using Cox and linear mixed models, we related air pollution to dementia and cognitive decline.RESULTS: Of the 7,511 non-demented participants at baseline, 545 developed dementia during a median follow-up of 7 years. The general marker of all air pollutants was not associated with the risk of dementia (hazard ratio [95% confidence interval]: 1.04 [0.95-1.15]), neither were the individual air pollutants. Also, the general marker of all air pollutants or the individual air pollutant levels were not associated with cognitive decline.CONCLUSION: In this study, we found no clear evidence for an association between exposure to air pollution and the risk of dementia or cognitive decline.
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| 15. |
- Dentoni, Giacomo, et al.
(author)
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Mitochondrial Alterations in Neurons Derived from the Murine AppNL-F Knock-In Model of Alzheimer's Disease
- 2022
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 90:2, s. 565-583
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Journal article (peer-reviewed)abstract
- Background:Alzheimer’s disease (AD) research has relied on mouse models overexpressing human mutant A βPP; however, newer generation knock-in models allow for physiological expression of amyloid-β protein precursor (AβPP) containing familial AD mutations where murine AβPP is edited with a humanized amyloid-β (Aβ) sequence. The AppNL-F mouse model has shown substantial similarities to AD brains developing late onset cognitive impairment.Objective:In this study, we aimed to characterize mature primary cortical neurons derived from homozygous AppNL-F embryos, especially to identify early mitochondrial alterations in this model.Methods:Primary cultures of AppNL-F neurons kept in culture for 12–15 days were used to measure Aβ levels, secretase activity, mitochondrial functions, mitochondrial-ER contacts, synaptic function, and cell death.Results:We detected higher levels of Aβ42 released from AppNL-F neurons as compared to wild-type neurons. AppNL-F neurons, also displayed an increased Aβ42/Aβ40 ratio, similar to adult AppNL-F mouse brain. Interestingly, we found an upregulation in mitochondrial oxygen consumption with concomitant downregulation in glycolytic reserve. Furthermore, AppNL-F neurons were more susceptible to cell death triggered by mitochondrial electron transport chain inhibition. Juxtaposition between ER and mitochondria was found to be substantially upregulated, which may account for upregulated mitochondrial-derived ATP production. However, anterograde mitochondrial movement was severely impaired in this model along with loss in synaptic vesicle protein and impairment in pre- and post-synaptic function.Conclusion:We show that widespread mitochondrial alterations can be detected in AppNL-F neurons in vitro, where amyloid plaque deposition does not occur, suggesting soluble and oligomeric Aβ-species being responsible for these alterations.
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| 16. |
- Dong, Yi, et al.
(author)
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Plasma Amyloid-β, Total Tau, and Neurofilament Light Chain Across the Alzheimer's Disease Clinical Spectrum: A Population-Based Study
- 2023
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In: JOURNAL OF ALZHEIMERS DISEASE. - 1387-2877 .- 1875-8908. ; 96:2, s. 845-858
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Journal article (peer-reviewed)abstract
- Background: Plasma biomarkers have emerged as a promising approach for characterizing pathophysiology in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Objective: We aimed to characterize plasma biomarkers for AD and neurodegeneration across the AD clinical continuum, and to assess their ability to differentiate between AD, MCI, and normal cognition. Methods: This population-based study engaged 1,446 rural-dwelling older adults (age >= 60 years, 61.0% women) derived from MIND-China; of these, 402 were defined with MCI and 142 with AD. Plasma amyloid-beta (A beta), total tau (t-tau), and neurofilament light chain (NfL) concentrations were analyzed using the Simoa platform. Data were analyzed using linear and logistic regression models, and receiver operating characteristic (ROC) analysis. Results: Across the AD clinical spectrum, plasma A beta(40) and NfL increased, whereas A beta(42)/A beta(40) ratio decreased. Plasma t-tau was higher in people withADdementia than those with MCI or normal cognition. Plasma NfL outperformed other biomarkers in differentiating AD from normal cognition (area under the ROC curve [AUC] = 0.75), but all plasma biomarkers performed poorly to distinguish MCI from normal cognition (AUC <0.60). Plasma NfL in combination with age, sex, education, and APOE genotype yielded the AUC of 0.87 for differentiating between AD and normal cognition, 0.79 between AD and MCI, and 0.64 between MCI and normal cognition. Conclusions: In this Chinese population, AD plasma biomarkers vary by age, sex, and APOE genotype. Plasma A beta, t-tau, and NfL differ across the AD clinical spectrum, and plasma NfL appears to be superior to plasma A beta and t-tau for defining the clinical spectrum.
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| 17. |
- Edlund, Anna K., 1983-, et al.
(author)
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Plasma Apolipoprotein E3 and Glucose Levels Are Associated in APOE ɛ3/ɛ4 Carriers
- 2021
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 81:1, s. 339-354
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Journal article (peer-reviewed)abstract
- Background: Altered cerebral glucose metabolism, especially prominent in APOE ɛ4 carriers, occurs years prior to symptoms in Alzheimer’s disease (AD). We recently found an association between a higher ratio of plasma apolipoprotein E4 (apoE4) over apoE3, and cerebral glucose hypometabolism in cognitively healthy APOE ɛ3/ɛ4 subjects. Plasma apoE does not cross the blood-brain barrier, hence we speculate that apoE is linked to peripheral glucose metabolism which is known to affect glucose metabolism in the brain.Objective: Explore potential associations between levels of plasma insulin and glucose with previously acquired plasma apoE, cerebral metabolic rate of glucose (CMRgl), gray matter volume, and neuropsychological test scores.Methods: Plasma insulin and glucose levels were determined by ELISA and a glucose oxidase assay whereas apoE levels were earlier quantified by mass-spectrometry in 128 cognitively healthy APOE ɛ3/ɛ4 subjects. Twenty-five study subjects had previously undergone FDG-PET and structural MRI.Results: Lower plasma apoE3 associated with higher plasma glucose but not insulin in male subjects and subjects with a body mass index above 25. Negative correlations were found between plasma glucose and CMRgl in the left prefrontal and bilateral occipital regions. These associations may have functional implications since glucose levels in turn were negatively associated with neuropsychological test scores.Conclusion: Plasma apoE3 but not apoE4 may be involved in insulin-independent processes governing plasma glucose levels. Higher plasma glucose, which negatively affects brain glucose metabolism, was associated with lower plasma apoE levels in APOE ɛ3/ɛ4 subjects. High plasma glucose and low apoE levels may be a hazardous combination leading to an increased risk of AD.
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| 18. |
- Freak-Poli, Rosanne, et al.
(author)
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Loneliness, Not Social Support, Is Associated with Cognitive Decline and Dementia Across Two Longitudinal Population-Based Cohorts
- 2022
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 85:1, s. 295-308
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Journal article (peer-reviewed)abstract
- Background: Poor social health is likely associated with cognitive decline and risk of dementia; however, studies show inconsistent results. Additionally, few studies separate social health components or control for mental health.Objective: To investigate whether loneliness and social support are independently associated with cognitive decline and risk of dementia, and whether depressive symptoms confound the association.Methods: We included 4,514 participants from the population-based Rotterdam Study (RS; aged 71±7SD years) followed up to 14 years (median 10.8, interquartile range 7.4-11.6), and 2,112 participants from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K; aged 72±10SD years) followed up to 10 years (mean 5.9±1.6SD). At baseline, participants were free of major depression and scored on the Mini-Mental State Examination (MMSE) ≥26 for RS and ≥25 for SNAC-K. We investigated loneliness, perceived social support, and structural social support (specifically marital status and number of children). In both cohorts, dementia was diagnosed and cognitive function was repeatedly assessed with MMSE and a global cognitive factor (g-factor).Results: Loneliness was prospectively associated with a decline in the MMSE in both cohorts. Consistently, persons who were lonely had an increased risk of developing dementia (RS: HR 1.34, 95%CI 1.08-1.67; SNAC-K: HR 2.16, 95%CI 1.12-4.17). Adjustment for depressive symptoms and exclusion of the first 5 years of follow-up did not alter results. Neither perceived or structural social support was associated with cognitive decline or dementia risk.Conclusion: Loneliness, not social support, predicted cognitive decline and incident dementia independently of depressive symptoms.
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| 19. |
- Freak-Poli, Rosanne, et al.
(author)
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Loneliness, Not Social Support, Is Associated with Cognitive Decline and Dementia Across Two Longitudinal Population-Based Cohorts
- 2022
-
In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 85:1, s. 295-308
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Journal article (peer-reviewed)abstract
- Background: Poor social health is likely associated with cognitive decline and risk of dementia; however, studies show inconsistent results. Additionally, few studies separate social health components or control for mental health.Objective: To investigate whether loneliness and social support are independently associated with cognitive decline and risk of dementia, and whether depressive symptoms confound the association.Methods: We included 4,514 participants from the population-based Rotterdam Study (RS; aged 71 +/- 7SD years) followed up to 14 years (median 10.8, interquartile range 7.4-11.6), and 2,112 participants from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K; aged 72 +/- 10SD years) followed up to 10 years (mean 5.9 +/- 1.6SD). At baseline, participants were free of major depression and scored on the Mini-Mental State Examination (MMSE) >= 26 for RS and >= 25 for SNAC-K. We investigated loneliness, perceived social support, and structural social support (specifically marital status and number of children). In both cohorts, dementia was diagnosed and cognitive function was repeatedly assessed with MMSE and a global cognitive factor (g-factor).Results: Loneliness was prospectively associated with a decline in the MMSE in both cohorts. Consistently, persons who were lonely had an increased risk of developing dementia (RS: HR 1.34, 95% CI 1.08-1.67; SNAC-K: HR 2.16, 95% CI 1.12-4.17). Adjustment for depressive symptoms and exclusion of the first 5 years of follow-up did not alter results. Neither perceived or structural social support was associated with cognitive decline or dementia risk.Conclusion: Loneliness, not social support, predicted cognitive decline and incident dementia independently of depressive symptoms.
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| 20. |
- Ghani, Zartashia, 1980-, et al.
(author)
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Short Term Economic Evaluation of the Digital Platform "Support, Monitoring and Reminder Technology for Mild Dementia" (SMART4MD) for People with Mild Cognitive Impairment and their Informal Caregivers
- 2022
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 86:4, s. 1629-1641
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Journal article (peer-reviewed)abstract
- Background: A randomized controlled trial of the SMART4MD tablet application was conducted for persons with mild cognitive impairment (PwMCI) and their informal caregivers to improve or maintain quality of life. Objective: The objective was to conduct economic evaluation of SMART4MD compared to standard care in Sweden from a healthcare provider perspective based on a 6-month follow-up period. Methods: Three hundred forty-five dyads were enrolled: 173 dyads in the intervention group and 172 in standard care. The primary outcome measures for PwMCI and informal caregivers were quality-adjusted life years (QALY). The results are presented as incremental cost-effectiveness ratios, and confidence intervals are calculated using non-parametric bootstrap procedure. Results: For PwMCI, the mean difference in total costs between intervention and standard care was (sic)12 (95%CI: -2090 to 2115) (US$ =(sic) 1.19) and the mean QALY change was -0.004 (95%CI: -0.009 to 0.002). For informal caregivers, the cost difference was -(sic)539 (95%CI: -2624 to 1545) and 0.003 (95%CI: -0.002 to 0.008) for QALY. The difference in cost and QALY for PwMCI and informal caregivers combined was -(sic)527 (95%CI: -3621 to 2568) and -0.001 (95%CI: -0.008 to 0.006). Although generally insignificant differences, this indicates that SMART4MD, compared to standard care was: 1) more costly and less effective for PwMCI, 2) less costly and more effective for informal caregivers, and 3) less costly and less effective for PwMCI and informal caregivers combined. Conclusion: The cost-effectiveness of SMART4MD over 6 months is inconclusive, although the intervention might be more beneficial for informal caregivers than PwMCI.
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