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INTRODUCTION: We examined the relationship between sedentary behavior (SB), moderate‐to‐vigorous physical activity (MVPA), and white matter hyperintensity (WMH) volumes, a common magnetic resonance imaging (MRI) marker associated with risk of neurodegenerative disease in middle‐aged to older adults. METHODS: We used data from the UK Biobank (n = 14,415; 45 to 81 years) that included accelerometer‐derived measures of SB and MVPA, and WMH volumes from MRI. RESULTS: Both MVPA and SB were associated with WMH volumes (βMVPA = −0.03 [−0.04, −0.01], p < 0.001; βSB = 0.02 [0.01, 0.03], p = 0.007). There was a significant interaction between SB and MVPA on WMH volumes (βSB×MVPA = −0.015 [−0.028, −0.001], pSB×MVPA = 0.03) where SB was positively associated with WMHs at low MVPA, and MVPA was negatively associated with WMHs at high SB. DISCUSSION: While this study cannot establish causality, the results highlight the potential importance of considering both MVPA and SB in strategies aimed at reducing the accumulation of WMH volumes in middle‐aged to older adults. Highlights: SB is associated with greater WMH volumes and MVPA is associated with lower WMH volumes.Relationships between SB and WMH are strongest at low levels of MVPA.Associations between MVPA and WMH are strongest at high levels of SB.Considering both SB and MVPA may be effective strategies for reducing WMHs [ABSTRACT FROM AUTHOR]

Introduction: This study examined plasma glial fibrillary acidic protein (GFAP) as a biomarker of cognitive impairment due to Alzheimer's disease (AD) with and against plasma neurofilament light chain (NfL), and phosphorylated tau (p‐tau)181+231. Methods: Plasma samples were analyzed using Simoa platform for 567 participants spanning the AD continuum. Cognitive diagnosis, neuropsychological testing, and dementia severity were examined for cross‐sectional and longitudinal outcomes. Results: Plasma GFAP discriminated AD dementia from normal cognition (adjusted mean difference = 0.90 standard deviation [SD]) and mild cognitive impairment (adjusted mean difference = 0.72 SD), and demonstrated superior discrimination compared to alternative plasma biomarkers. Higher GFAP was associated with worse dementia severity and worse performance on 11 of 12 neuropsychological tests. Longitudinally, GFAP predicted decline in memory, but did not predict conversion to mild cognitive impairment or dementia. Discussion: Plasma GFAP was associated with clinical outcomes related to suspected AD and could be of assistance in a plasma biomarker panel to detect in vivo AD. [ABSTRACT FROM AUTHOR]

Key Points: Question: Is there an association between sedentary behavior and risk of all-cause dementia in older adults? Findings: In this retrospective study of prospectively collected data of 49 841 adults participating in the UK Biobank, more time spent in sedentary behaviors (determined through a machine learning–based analysis of wrist-worn accelerometer data) was significantly associated with higher risk of incident dementia. Meaning: Among older adults, more time spent in sedentary behaviors was associated with higher risk of incident all-cause dementia. Importance: Sedentary behavior is associated with cardiometabolic disease and mortality, but its association with dementia is unclear. Objective: To investigate whether accelerometer-assessed sedentary behavior is associated with incident dementia. Design, Setting, and Participants: A retrospective study of prospectively collected data from the UK Biobank including 49 841 adults aged 60 years or older without a diagnosis of dementia at the time of wearing the wrist accelerometer and living in England, Scotland, or Wales. Follow-up began at the time of wearing the accelerometer (February 2013 to December 2015) and continued until September 2021 in England, July 2021 in Scotland, and February 2018 in Wales. Exposures: Mean daily sedentary behavior time (included in the primary analysis) and mean daily sedentary bout length, maximum daily sedentary bout length, and mean number of daily sedentary bouts (included in the secondary analyses) were derived from a machine learning–based analysis of 1 week of wrist-worn accelerometer data. Main Outcome and Measures: Incident all-cause dementia diagnosis from inpatient hospital records and death registry data. Cox proportional hazard models with linear and cubic spline terms were used to assess associations. Results: A total of 49 841 older adults (mean age, 67.19 [SD, 4.29] years; 54.7% were female) were followed up for a mean of 6.72 years (SD, 0.95 years). During this time, 414 individuals were diagnosed with incident all-cause dementia. In the fully adjusted models, there was a significant nonlinear association between time spent in sedentary behavior and incident dementia. Relative to a median of 9.27 hours/d for sedentary behavior, the hazard ratios (HRs) for dementia were 1.08 (95% CI, 1.04-1.12, P <.001) for 10 hours/d, 1.63 (95% CI, 1.35-1.97, P <.001) for 12 hours/d, and 3.21 (95% CI, 2.05-5.04, P <.001) for 15 hours/d. The adjusted incidence rate of dementia per 1000 person-years was 7.49 (95% CI, 7.48-7.49) for 9.27 hours/d of sedentary behavior, 8.06 (95% CI, 7.76-8.36) for 10 hours/d, 12.00 (95% CI, 10.00-14.36) for 12 hours/d, and 22.74 (95% CI, 14.92-34.11) for 15 hours/d. Mean daily sedentary bout length (HR, 1.53 [95% CI, 1.03-2.27], P =.04 and 0.65 [95% CI, 0.04-1.57] more dementia cases per 1000 person-years for a 1-hour increase from the mean of 0.48 hours) and maximum daily sedentary bout length (HR, 1.15 [95% CI, 1.02-1.31], P =.02 and 0.19 [95% CI, 0.02-0.38] more dementia cases per 1000 person-years for a 1-hour increase from the mean of 1.95 hours) were significantly associated with higher risk of incident dementia. The number of sedentary bouts per day was not associated with higher risk of incident dementia (HR, 1.00 [95% CI, 0.99-1.01], P =.89). In the sensitivity analyses, after adjustment for time spent in sedentary behavior, the mean daily sedentary bout length and the maximum daily sedentary bout length were no longer significantly associated with incident dementia. Conclusions and Relevance: Among older adults, more time spent in sedentary behaviors was significantly associated with higher incidence of all-cause dementia. Future research is needed to determine whether the association between sedentary behavior and risk of dementia is causal. This study of prospectively collected data from the UK Biobank investigates whether accelerometer-assessed sedentary behavior is associated with incident dementia in adults aged 60 years or older without a diagnosis of dementia at the time of wearing the wrist accelerometer. [ABSTRACT FROM AUTHOR]

Introduction: We examined the ability of plasma hyperphosphorylated tau (p‐tau)181 to detect cognitive impairment due to Alzheimer's disease (AD) independently and in combination with plasma total tau (t‐tau) and neurofilament light (NfL). Methods: Plasma samples were analyzed using the Simoa platform for 235 participants with normal cognition (NC), 181 with mild cognitive impairment due to AD (MCI), and 153 with AD dementia. Statistical approaches included multinomial regression and Gaussian graphical models (GGMs) to assess a network of plasma biomarkers, neuropsychological tests, and demographic variables. Results: Plasma p‐tau181 discriminated AD dementia from NC, but not MCI, and correlated with dementia severity and worse neuropsychological test performance. Plasma NfL similarly discriminated diagnostic groups. Unlike plasma NfL or t‐tau, p‐tau181 had a direct association with cognitive diagnosis in a bootstrapped GGM. Discussion: These results support plasma p‐tau181 for the detection of AD dementia and the use of blood‐based biomarkers for optimal disease detection. [ABSTRACT FROM AUTHOR]

Background: In Alzheimer's disease (AD), plasma biomarkers of neurodegeneration and phosphorylated tau have initial support for their relationship to clinical diagnosis and cognitive outcomes over time (total tau [t‐tau], neurofilament light [NfL], and p‐tau). To date, only one study has assessed a network model with these data. Here, we assessed the network relations (i.e., conditional dependencies) between diagnostic variables, plasma biomarkers, neuropsychological test performance, and demographic variables using a Gaussian graphical model (GGM) with participants from the Boston University (BU) Alzheimer's Disease Research Center (ADRC) Longitudinal Clinical Core Registry. Method: The sample included individuals with normal cognition (n=235), MCI due to AD (n=181), and AD dementia (n=153). Participants completed a comprehensive battery of neuropsychological tests to assess global cognition, attention, executive function, episodic memory, and language abilities. Diagnoses were adjudicated during multidisciplinary diagnostic consensus conferences. Plasma samples were analyzed using the Simoa technique. Regularized GGMs were estimated with Pearson, polychoric, and polyserial correlations depending on whether the variables were continuous, ordinal, or mixed. Network stability was assessed with a non‐parametric bootstrap of standardized edge weights and a person‐dropping bootstrap of centrality measures with 10,000 samples. Latent dimensions were estimated with Markov chain Monte Carlo (MCMC) simulation. Result: Assessment of the model suggested adequate fit, χ2(184, N = 569) = 620.46, EBIC = 27,444.53, RMSEA = 0.06, TLI = 0.95. Metrics of strength, closeness centrality, and expected influence met established thresholds of stability. Among biomarkers, diagnosis was connected to p‐tau181, βz = 0.07, 95% CI [0.01, 0.12]. Assessment of network centrality suggested that p‐tau181 ranked relatively highly for betweenness centrality and expected influence and NfL ranked highly for betweenness centrality. In contrast, t‐tau was not connected to any functional or diagnostic variable and did not rank highly for centrality. The biomarker variables loaded similarly on the two latent dimensions and were clustered near consensus conference diagnosis. Conclusion: Unlike t‐tau, plasma biomarkers p‐tau181 and NfL were influential as "central junctions" for other connections in a network of diagnostic, biomarker, and demographic data. The findings support recent research that posits p‐tau181 and NfL reflect distinct aspects of AD progression (respectively, AD pathology and neurodegeneration). [ABSTRACT FROM AUTHOR]

Introduction: We examined the relationship between sedentary behavior (SB), moderate-to-vigorous physical activity (MVPA), and white matter hyperintensity (WMH) volumes, a common magnetic resonance imaging (MRI) marker associated with risk of neurodegenerative disease in middle-aged to older adults., Methods: We used data from the UK Biobank ( n  = 14,415; 45 to 81 years) that included accelerometer-derived measures of SB and MVPA, and WMH volumes from MRI., Results: Both MVPA and SB were associated with WMH volumes (β MVPA  = -0.03 [-0.04, -0.01], p  < 0.001; β SB  = 0.02 [0.01, 0.03], p  = 0.007). There was a significant interaction between SB and MVPA on WMH volumes (β SB×MVPA  = -0.015 [-0.028, -0.001], p SB×MVPA  = 0.03) where SB was positively associated with WMHs at low MVPA, and MVPA was negatively associated with WMHs at high SB., Discussion: While this study cannot establish causality, the results highlight the potential importance of considering both MVPA and SB in strategies aimed at reducing the accumulation of WMH volumes in middle-aged to older adults., Highlights: SB is associated with greater WMH volumes and MVPA is associated with lower WMH volumes.Relationships between SB and WMH are strongest at low levels of MVPA.Associations between MVPA and WMH are strongest at high levels of SB.Considering both SB and MVPA may be effective strategies for reducing WMHs., Competing Interests: The authors declare no conflict of interest. Author disclosures are available in the Supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Plasma-to-autopsy studies are essential for validation of blood biomarkers and understanding their relation to Alzheimer's disease (AD) pathology. Few such studies have been done on phosphorylated tau (p-tau) and those that exist have made limited or no comparison of the different p-tau variants. This study is the first to use immunoprecipitation mass spectrometry (IP-MS) to compare the accuracy of eight different plasma tau species in predicting autopsy-confirmed AD. The sample included 123 participants (AD = 69, non-AD = 54) from the Boston University Alzheimer's disease Research Center who had an available ante-mortem plasma sample and donated their brain. Plasma samples proximate to death were analyzed by targeted IP-MS for six different tryptic phosphorylated (p-tau-181, 199, 202, 205, 217, 231), and two non-phosphorylated tau (195-205, 212-221) peptides. NIA-Reagan Institute criteria were used for the neuropathological diagnosis of AD. Binary logistic regressions tested the association between each plasma peptide and autopsy-confirmed AD status. Area under the receiver operating curve (AUC) statistics were generated using predicted probabilities from the logistic regression models. Odds Ratio (OR) was used to study associations between the different plasma tau species and CERAD and Braak classifications. All tau species were increased in AD compared to non-AD, but p-tau217, p-tau205 and p-tau231 showed the highest fold-changes. Plasma p-tau217 (AUC = 89.8), p-tau231 (AUC = 83.4), and p-tau205 (AUC = 81.3) all had excellent accuracy in discriminating AD from non-AD brain donors, even among those with CDR < 1). Furthermore, p-tau217, p-tau205 and p-tau231 showed the highest ORs with both CERAD (OR p-tau217  = 15.29, OR p-tau205  = 5.05 and OR p-tau231  = 3.86) and Braak staging (OR p-tau217  = 14.29, OR p-tau205  = 5.27 and OR p-tau231  = 4.02) but presented increased levels at different amyloid and tau stages determined by neuropathological examination. Our findings support plasma p-tau217 as the most promising p-tau species for detecting AD brain pathology. Plasma p-tau231 and p-tau205 may additionally function as markers for different stages of the disease., (© 2023. The Author(s).)

Introduction: This study examined plasma glial fibrillary acidic protein (GFAP) as a biomarker of cognitive impairment due to Alzheimer's disease (AD) with and against plasma neurofilament light chain (NfL), and phosphorylated tau (p-tau) 181+231 ., Methods: Plasma samples were analyzed using Simoa platform for 567 participants spanning the AD continuum. Cognitive diagnosis, neuropsychological testing, and dementia severity were examined for cross-sectional and longitudinal outcomes., Results: Plasma GFAP discriminated AD dementia from normal cognition (adjusted mean difference = 0.90 standard deviation [SD]) and mild cognitive impairment (adjusted mean difference = 0.72 SD), and demonstrated superior discrimination compared to alternative plasma biomarkers. Higher GFAP was associated with worse dementia severity and worse performance on 11 of 12 neuropsychological tests. Longitudinally, GFAP predicted decline in memory, but did not predict conversion to mild cognitive impairment or dementia., Discussion: Plasma GFAP was associated with clinical outcomes related to suspected AD and could be of assistance in a plasma biomarker panel to detect in vivo AD., Competing Interests: The authors MA, MAS, TKK, HJA, BF, YT, BM, JNP, EGS, IS, LAF, GRJ, KWT, AEB, MKO, LEG, NWK, RK, TDS, ACM, WQ, and JM have no competing interests to declare. HZ has served on scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant, on advisory boards, or on data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. NJA has given lectures in symposia sponsored by Eli‐Lily. AEB has served as a consultant or on advisory boards for Eli Lilly and Roche Pharmaceuticals and has received grant monies from Cumulus Neuroscience, VoxNeuro, Bristol Myers Squibb, and Cyclerion. He receives publishing royalties from Elsevier and Oxford University Press. RA serves on the scientific advisory board of Signant Health, as consultant to Biogen, and has given a lecture in a symposium sponsored by Eisai. RAS has served as a consultant to Biogen and Lundbeck. He receives royalties for published neuropsychological tests from Psychological Assessment Resources, Inc. MLA has received honorarium from the Michael J. Fox Foundation for services unrelated to this study. He receives royalties from Oxford University Press., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: We examined the ability of plasma hyperphosphorylated tau (p-tau) 181 to detect cognitive impairment due to Alzheimer's disease (AD) independently and in combination with plasma total tau (t-tau) and neurofilament light (NfL)., Methods: Plasma samples were analyzed using the Simoa platform for 235 participants with normal cognition (NC), 181 with mild cognitive impairment due to AD (MCI), and 153 with AD dementia. Statistical approaches included multinomial regression and Gaussian graphical models (GGMs) to assess a network of plasma biomarkers, neuropsychological tests, and demographic variables., Results: Plasma p-tau 181 discriminated AD dementia from NC, but not MCI, and correlated with dementia severity and worse neuropsychological test performance. Plasma NfL similarly discriminated diagnostic groups. Unlike plasma NfL or t-tau, p-tau 181 had a direct association with cognitive diagnosis in a bootstrapped GGM., Discussion: These results support plasma p-tau 181 for the detection of AD dementia and the use of blood-based biomarkers for optimal disease detection., (© 2021 the Alzheimer's Association.)