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Introduction: Epidemiological studies indicate a link between attention-deficit/hyperactivity disorder (ADHD) and elevated risk of dementia. However, the impact of ADHD on cognition and Alzheimer's disease (AD) biomarkers in individuals with cognitive impairment remains unclear., Methods: We computed weighted ADHD polygenic risk scores (ADHD-PRS) in 938 cognitively impaired participants (674 mild cognitive impairment [MCI] and 264 dementia; mean age 73.5 years). A subset underwent cerebrospinal fluid (CSF) analysis for amyloid beta (Aβ) and phosphorylated tau, as well as fluorodeoxyglucose positron emission tomography ([ 18 F]FDG-PET)., Results: We observed lower executive function in individuals with high ADHD-PRS for both MCI and dementia participants. Higher levels of CSF phosphorylated tau, but not Aβ, were observed in dementia participants with higher ADHD-PRS. Increased ADHD-PRS was associated with glucose hypometabolism in the frontal and parietal cortices., Discussion: ADHD-PRS is associated with a more severe disease presentation in individuals with cognitive impairment due to dementia, characterized by impaired executive function, elevated tau pathology, and hypometabolism in the frontal and parietal cortices., Highlights: We calculated the genetic liability for attention-deficit/hyperactivity disorder (ADHD) using polygenic risk scores (ADHD-PRS). Elevated ADHD-PRS was associated with executive function deficits in individuals with mild cognitive impairment (MCI) or Alzheimer's disease (AD) dementia. Higher levels of cerebrospinal fluid (CSF) phosphorylated tau, but not amyloid beta (Aβ), were observed in dementia participants with higher ADHD-PRS. Higher ADHD-PRS was associated with brain hypometabolism in individuals with AD dementia. Hypometabolism in the parietal cortex mediated the effects of ADHD-PRS on executive function., (© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Brain glucose hypometabolism, indexed by the fluorodeoxyglucose positron emission tomography ([ 18 F]FDG-PET) imaging, is a metabolic signature of Alzheimer's disease (AD). However, the underlying biological pathways involved in these metabolic changes remain elusive., Methods: Here, we integrated [ 18 F]FDG-PET images with blood and hippocampal transcriptomic data from cognitively unimpaired (CU, n = 445) and cognitively impaired (CI, n = 749) individuals using modular dimension reduction techniques and voxel-wise linear regression analysis., Results: Our results showed that multiple transcriptomic modules are associated with brain [ 18 F]FDG-PET metabolism, with the top hits being a protein serine/threonine kinase activity gene cluster (peak-t (223)  = 4.86, P value < 0.001) and zinc-finger-related regulatory units (peak-t (223)  = 3.90, P value < 0.001)., Discussion: By integrating transcriptomics with PET imaging data, we identified that serine/threonine kinase activity-associated genes and zinc-finger-related regulatory units are highly associated with brain metabolic changes in AD., Highlights: We conducted an integrated analysis of system-based transcriptomics and fluorodeoxyglucose positron emission tomography ([ 18 F]FDG-PET) at the voxel level in Alzheimer's disease (AD). The biological process of serine/threonine kinase activity was the most associated with [ 18 F]FDG-PET in the AD brain. Serine/threonine kinase activity alterations are associated with brain vulnerable regions in AD [ 18 F]FDG-PET. Zinc-finger transcription factor targets were associated with AD brain [ 18 F]FDG-PET metabolism., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Plasma biomarkers of Alzheimer's disease and related dementias predict global cognitive performance and decline over time; it remains unclear how they associate with changes in different dementia syndromes affecting distinct cognitive domains., Methods: In a prospective study with repeated assessments of a randomly selected population-based cohort (n = 787, median age 73), we evaluated performance and decline in different cognitive domains over up to 8 years in relation to plasma concentrations of amyloid beta 42/40 (Aβ42/40) ratio, phosphorylated tau181 (p-tau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP)., Results: Cross-sectionally, memory showed the strongest associations with p-tau181, and attention, executive, and visuospatial functions with NfL. Longitudinally, memory decline was distinguishable with all biomarker profiles dichotomized according to data-driven cutoffs, most efficiently with Aβ42/40. GFAP and Aβ42/40 were the best discriminators of decline patterns in language and visuospatial functions, respectively., Discussion: These relatively non-invasive tests may be beneficial for clinical screening after replication in other populations and validation through neuroimaging or cerebrospinal fluid analysis., Highlights: We performed a prospective study with up to 8 years of repeated domain-specific cognitive assessments and baseline plasma Alzheimer's disease and related dementias biomarker measurements in a randomly selected population-based cohort. We considered distinct growth curves of trajectories of different cognitive domains and survival bias induced by missing data by adding quadratic time and applying joint modeling technique. Cross-sectionally, memory showed the strongest associations with plasma phosphorylated tau181, while attention, executive, and visuospatial functions were most strongly associated with neurofilament light chain. Longitudinally, memory and visuospatial declines were most efficiently distinguished by dichotomized amyloid beta 42/40 profile among all plasma biomarkers, while language was by dichotomized glial fibrillary acidic protein. These relatively non-invasive tests may be beneficial for clinical screening; however, they will need replication in other populations and validation through neuroimaging and/or cerebrospinal fluid assessments., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Detection of Alzheimer's disease (AD) pathophysiology among individuals with mild cognitive changes and those experiencing subjective cognitive decline (SCD) remains challenging. Plasma phosphorylated tau 217 (p-tau217) is one of the most promising of the emerging biomarkers for AD. However, accessible methods are limited., Methods: We employed a novel p-tau217 immunoassay (University of Gothenburg [UGOT] p-tau217) in four independent cohorts (n = 308) including a cerebrospinal fluid (CSF) biomarker-classified cohort (Discovery), two cohorts consisting mostly of cognitively unimpaired (CU) and mild cognitively impaired (MCI) participants (MYHAT and Pittsburgh), and a population-based cohort of individuals with SCD (Barcelonaβeta Brain Research Center's Alzheimer's At-Risk Cohort [β-AARC])., Results: UGOT p-tau217 showed high accuracy (area under the curve [AUC] = 0.80-0.91) identifying amyloid beta (Aβ) pathology, determined either by Aβ positron emission tomography or CSF Aβ42/40 ratio. In individuals experiencing SCD, UGOT p-tau217 showed high accuracy identifying those with a positive CSF Aβ42/40 ratio (AUC = 0.91)., Discussion: UGOT p-tau217 can be an easily accessible and efficient way to screen and monitor patients with suspected AD pathophysiology, even in the early stages of the continuum., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Plasma biomarkers-cost effective, non-invasive indicators of Alzheimer's disease (AD) and related disorders (ADRD)-have largely been studied in clinical research settings. Here, we examined plasma biomarker profiles and their associated factors in a population-based cohort to determine whether they could identify an at-risk group, independently of brain and cerebrospinal fluid biomarkers., Methods: We measured plasma phosphorylated tau181 (p-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and amyloid beta (Aβ)42/40 ratio in 847 participants from a population-based cohort in southwestern Pennsylvania., Results: K-medoids clustering identified two distinct plasma Aβ42/40 modes, further categorizable into three biomarker profile groups: normal, uncertain, and abnormal. In different groups, plasma p-tau181, NfL, and GFAP were inversely correlated with Aβ42/40, Clinical Dementia Rating, and memory composite score, with the strongest associations in the abnormal group., Discussion: Abnormal plasma Aβ42/40 ratio identified older adult groups with lower memory scores, higher dementia risks, and higher ADRD biomarker levels, with potential implications for population screening., Highlights: Population-based plasma biomarker studies are lacking, particularly in cohorts without cerebrospinal fluid or neuroimaging data. In the Monongahela-Youghiogheny Healthy Aging Team study (n = 847), plasma biomarkers associated with worse memory and Clinical Dementia Rating (CDR), apolipoprotein E ε4, and greater age. Plasma amyloid beta (Aβ)42/40 ratio levels allowed clustering participants into abnormal, uncertain, and normal groups. Plasma Aβ42/40 correlated differently with neurofilament light chain, glial fibrillary acidic protein, phosphorylated tau181, memory composite, and CDR in each group. Plasma biomarkers can enable relatively affordable and non-invasive community screening for evidence of Alzheimer's disease and related disorders pathophysiology., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Phosphorylated tau (p-tau) biomarkers have been recently proposed to represent brain amyloid-β (Aβ) pathology. Here, we evaluated the plasma biomarkers' contribution beyond the information provided by demographics (age and sex) to identify Aβ and tau pathologies in individuals segregated as cognitively unimpaired (CU) and impaired (CI)., Methods: We assessed 138 CU and 87 CI with available plasma p-tau231, 217 + , and 181, Aβ42/40, GFAP and Aβ- and tau-PET., Results: In CU, only plasma p-tau231 and p-tau217 + significantly improved the performance of the demographics in detecting Aβ-PET positivity, while no plasma biomarker provided additional information to identify tau-PET positivity. In CI, p-tau217 + and GFAP significantly contributed to demographics to identify both Aβ-PET and tau-PET positivity, while p-tau231 only provided additional information to identify tau-PET positivity., Discussion: Our results support plasma p-tau231 and p-tau217 + as state markers of early Aβ deposition, but in later disease stages they inform on tau tangle accumulation., Highlights: It is still unclear how much plasma biomarkers contribute to identification of AD pathology across the AD spectrum beyond the information already provided by demographics (age + sex). Plasma p-tau231 and p-tau217 + contribute to demographic information to identify brain Aβ pathology in preclinical AD. In CI individuals, plasma p-tau231 contributes to age and sex to inform on the accumulation of tau tangles, while p-tau217 + and GFAP inform on both Aβ deposition and tau pathology., (© 2023 the Alzheimer's Association.)

Introduction: Amyloid-β (Aβ) and tau can be quantified in blood. However, biological factors can influence the levels of brain-derived proteins in the blood. The blood-brain barrier (BBB) regulates protein transport between cerebrospinal fluid (CSF) and blood. BBB altered permeability might affect the relationship between brain and blood biomarkers., Methods: We assessed 224 participants in research (TRIAD, n = 96) and clinical (BIODEGMAR, n = 128) cohorts with plasma and CSF/positron emission tomography Aβ, p-tau, and albumin measures., Results: Plasma Aβ 42/40 better identified CSF Aβ 42/40 and Aβ-PET positivity in individuals with high BBB permeability. An interaction between plasma Aβ 42/40 and BBB permeability on CSF Aβ 42/40 was observed. Voxel-wise models estimated that the association of positron emission tomography (PET), with plasma Aβ was most affected by BBB permeability in AD-related brain regions. BBB permeability did not significantly impact the relationship between brain and plasma p-tau levels., Discussion: These findings suggest that BBB integrity may influence the performance of plasma Aβ, but not p-tau, biomarkers in research and clinical settings., Highlights: BBB permeability affects the association between brain and plasma Aβ levels. BBB integrity does not affect the association between brain and plasma p-tau levels. Plasma Aβ was most affected by BBB permeability in AD-related brain regions. BBB permeability increases with age but not according to cognitive status., (© 2023 the Alzheimer's Association.)