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INTRODUCTION: Alzheimer's disease (AD) pathology is defined by β‐amyloid (Aβ) plaques and neurofibrillary tau, but Lewy bodies (LBs; 훼‐synuclein aggregates) are a common co‐pathology for which effective biomarkers are needed. METHODS: A validated α‐synuclein Seed Amplification Assay (SAA) was used on recent cerebrospinal fluid (CSF) samples from 1638 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, 78 with LB‐pathology confirmation at autopsy. We compared SAA outcomes with neuropathology, Aβ and tau biomarkers, risk‐factors, genetics, and cognitive trajectories. RESULTS: SAA showed 79% sensitivity and 97% specificity for LB pathology, with superior performance in identifying neocortical (100%) compared to limbic (57%) and amygdala‐predominant (60%) LB‐pathology. SAA+ rate was 22%, increasing with disease stage and age. Higher Aβ burden but lower CSF p‐tau181 associated with higher SAA+ rates, especially in dementia. SAA+ affected cognitive impairment in MCI and Early‐AD who were already AD biomarker positive. DISCUSSION: SAA is a sensitive, specific marker for LB‐pathology. Its increase in prevalence with age and AD stages, and its association with AD biomarkers, highlights the clinical importance of α‐synuclein co‐pathology in understanding AD's nature and progression. Highlights: SAA shows 79% sensitivity, 97% specificity for LB‐pathology detection in AD.SAA positivity prevalence increases with disease stage and age.Higher Aβ burden, lower CSF p‐tau181 linked with higher SAA+ rates in dementia.SAA+ impacts cognitive impairment in early disease stages.Study underpins need for wider LB‐pathology screening in AD treatment. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Cerebrovascular dysfunction is a pathological hallmark of Alzheimer's disease (AD). Nevertheless, detecting cerebrovascular changes within bulk tissues has limited our ability to characterize proteomic alterations from less abundant cell types. METHODS: We conducted quantitative proteomics on bulk brain tissues and isolated cerebrovasculature from the same individuals, encompassing control (N = 28), progressive supranuclear palsy (PSP) (N = 18), and AD (N = 21) cases. RESULTS: Protein co‐expression network analysis identified unique cerebrovascular modules significantly correlated with amyloid plaques, cerebrovascular amyloid angiopathy (CAA), and/or tau pathology. The protein products within AD genetic risk loci were concentrated within cerebrovascular modules. The overlap between differentially abundant proteins in AD cerebrospinal fluid (CSF) and plasma with cerebrovascular network highlighted a significant increase of matrisome proteins, SMOC1 and SMOC2, in CSF, plasma, and brain. DISCUSSION: These findings enhance our understanding of cerebrovascular deficits in AD, shedding light on potential biomarkers associated with CAA and vascular dysfunction in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We investigate pathological correlates of plasma phosphorylated tau 181 (p‐tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) across a clinically diverse spectrum of neurodegenerative disease, including normal cognition (NormCog) and impaired cognition (ImpCog). METHODS: Participants were NormCog (n = 132) and ImpCog (n = 461), with confirmed β‐amyloid (Aβ+/‐) status (cerebrospinal fluid, positron emission tomography, autopsy) and single molecule array plasma measurements. Logistic regression and receiver operating characteristic (ROC) area under the curve (AUC) tested how combining plasma analytes discriminated Aβ+ from Aβ‐. Survival analyses tested time to clinical dementia rating (global CDR) progression. RESULTS: Multivariable models (p‐tau+GFAP+NfL) had the best performance to detect Aβ+ in NormCog (ROCAUC = 0.87) and ImpCog (ROCAUC = 0.87). Survival analyses demonstrated that higher NfL best predicted faster CDR progression for both Aβ+ (hazard ratio [HR] = 2.94; p = 8.1e‐06) and Aβ‐ individuals (HR = 3.11; p = 2.6e‐09). DISCUSSION: Combining plasma biomarkers can optimize detection of Alzheimer's disease (AD) pathology across cognitively normal and clinically diverse neurodegenerative disease. Highlights: Participants were clinically heterogeneous, with autopsy‐ or biomarker‐confirmed Aβ.Combining plasma p‐tau181, GFAP, and NfL improved diagnostic accuracy for Aβ status.Diagnosis by plasma biomarkers is more accurate in amnestic AD than nonamnestic AD.Plasma analytes show independent associations with tau PET and post mortem Aβ/tau.Plasma NfL predicted longitudinal cognitive decline in both Aβ+ and Aβ‐ individuals. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Individuals in socioeconomically disadvantaged neighborhoods exhibit increased risk for impaired cognitive function. Whether this association relates to the major dementia‐related neuropathologies is unknown. METHODS: This cross‐sectional study included 469 autopsy cases from 2011 to 2023. The relationships between neighborhood disadvantage measured by Area Deprivation Index (ADI) percentiles categorized into tertiles, cognition evaluated by the last Mini‐Mental State Examination (MMSE) scores before death, and 10 dementia‐associated proteinopathies and cerebrovascular disease were assessed using regression analyses. RESULTS: Higher ADI was significantly associated with lower MMSE score. This was mitigated by increasing years of education. ADI was not associated with an increase in dementia‐associated neuropathologic change. Moreover, the significant association between ADI and cognition remained even after controlling for changes in major dementia‐associated proteinopathies or cerebrovascular disease. DISCUSSION: Neighborhood disadvantage appears to be associated with decreased cognitive reserve. This association is modified by education but is independent of the major dementia‐associated neuropathologies. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Variability in relationship of tau‐based neurofibrillary tangles (T) and neurodegeneration (N) in Alzheimer's disease (AD) arises from non‐specific nature of N, modulated by non‐AD co‐pathologies, age‐related changes, and resilience factors. METHODS: We used regional T‐N residual patterns to partition 184 patients within the Alzheimer's continuum into data‐driven groups. These were compared with groups from 159 non‐AD (amyloid "negative") patients partitioned using cortical thickness, and groups in 98 patients with ante mortem MRI and post mortem tissue for measuring N and T, respectively. We applied the initial T‐N residual model to classify 71 patients in an independent cohort into predefined groups. RESULTS: AD groups displayed spatial T‐N mismatch patterns resembling neurodegeneration patterns in non‐AD groups, similarly associated with non‐AD factors and diverging cognitive outcomes. In the autopsy cohort, limbic T‐N mismatch correlated with TDP‐43 co‐pathology. DISCUSSION: T‐N mismatch may provide a personalized approach for determining non‐AD factors associated with resilience/vulnerability in AD. [ABSTRACT FROM AUTHOR]

Introduction: The ATN framework provides an in vivo diagnosis of Alzheimer's disease (AD) using cerebrospinal fluid (CSF) biomarkers of pathologic amyloid plaques (A), tangles (T), and neurodegeneration (N). ATN is rarely evaluated in pathologically confirmed patients and its poor sensitivity to suspected non‐Alzheimer's pathophysiologies (SNAP), including frontotemporal lobar degeneration (FTLD), leads to misdiagnoses. We compared accuracy of ATN (ATNTAU) using CSF total tau (t‐tau) to a modified strategy (ATNNfL) using CSF neurofilament light chain (NfL) in an autopsy cohort. Methods: ATNTAU and ATNNfL were trained in an independent sample and validated in autopsy‐confirmed AD (n = 67) and FTLD (n = 27). Results: ATNNfL more accurately identified FTLD as SNAP (sensitivity = 0.93, specificity = 0.94) than ATNTAU (sensitivity = 0.44, specificity = 0.97), even in cases with co‐occurring AD and FTLD. ATNNfL misclassified fewer AD and FTLD as "Normal" (2%) than ATNTAU (14%). Discussion: ATNNfL is a promising diagnostic strategy that may accurately identify both AD and FTLD, even when pathologies co‐occur. [ABSTRACT FROM AUTHOR]

Introduction Neuropathologic assessment is the current “gold standard” for evaluating the Alzheimer's disease (AD), but there is no consensus on the methods used. Methods Fifteen unstained slides (8 brain regions) from each of the 14 cases were prepared and distributed to 10 different National Institute on Aging AD Centers for application of usual staining and evaluation following recently revised guidelines for AD neuropathologic change. Results Current practice used in the AD Centers Program achieved robustly excellent agreement for the severity score for AD neuropathologic change (average weighted κ = .88, 95% confidence interval: 0.77–0.95) and good-to-excellent agreement for the three supporting scores. Some improvement was observed with consensus evaluation but not with central staining of slides. Evaluation of glass slides and digitally prepared whole-slide images was comparable. Discussion AD neuropathologic evaluation as performed across AD Centers yields data that have high agreement with potential modifications for modest improvements. [ABSTRACT FROM AUTHOR]