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INTRODUCTION: From an ongoing multicenter effort toward differentiation of Parkinsonian spectrum disorders (PSD) from other types of neurodegenerative disorders, the sleep biomarker non-rapid-eye-movement sleep with hypertonia (NRH) emerged. METHODS: This study included in the PSD group patients with dementia with Lewy bodies/Parkinson disease dementia (DLB/PDD = 16), Parkinson disease (PD = 16), and progressive supranuclear palsy (PSP = 13). The non-PSD group included patients with Alzheimer disease dementia (AD = 24), mild cognitive impairment (MCI = 35), and a control group with normal cognition (CG = 61). In-home, multi-night Sleep Profiler studies were conducted in all participants. Automated algorithms detected NRH, characterized by elevated frontopolar electromyographic power. Between-group differences in NRH were evaluated using Logistic regression, Mann-Whitney U and Chi-squared tests. RESULTS: NRH was greater in the PSD group compared to non-PSD (13.9 ± 11.0% vs. 3.1 ± 4.7%, P

Background: Abnormal cerebrospinal fluid (CSF)/serum albumin ratio (Qalb) levels have been observed in patients with cognitive impairment. Few studies have specifically focused on Lewy Body Disease (LBD), and the results were controversial. Thus, we conducted this systematic review and meta-analysis to investigate Qalb levels in patients with LBD by including data from different studies. Method: We systematically searched PubMed, Embase, Cochrane Library, and Web of Science databases for a collection of studies containing studies comparing Qalb levels in patients with LBD and healthy controls (including healthy controls and other dementia subtypes). In the initial search, 86 relevant papers were retrieved. Standardized mean differences (SMD) in Qalb levels were calculated using a random effects model. Results: A total of 13 eligible studies were included. Mean Qalb levels were significantly higher in patients with LBD compared to healthy older adults [standardized mean difference (SMD): 2.95, 95% confidence interval (CI): 0.89-5.00, Z = 2.81, p = 0.005]; and were significantly higher in patients with LBD than in patients with Alzheimer's disease (AD) (SMD: 1.13, 95% CI: 0.42-1.83, Z = 3.15, p = 0.002);whereas mean Qalb levels were significantly higher in patients with frontotemporal lobar degeneration (FTLD) compared to those with AD (SMD: 1.13, 95% CI, 0.14-2.13, Z = 2.24, p = 0.03). Conclusion: Qalb levels were significantly elevated in LBD patients compared with normal older adults and were higher than those in AD patients and FTLD patients, which helped in the differential diagnosis of LBD from other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation and Alzheimer's disease (AD) co-pathology may contribute to disease progression and severity in dementia with Lewy bodies (DLB). This study aims to clarify whether a different pattern of neuroinflammation, such as alteration in microglial and astroglial morphology and distribution, is present in DLB cases with and without AD co-pathology. Methods: The morphology and load (% area of immunopositivity) of total (Iba1) and reactive microglia (CD68 and HLA-DR), reactive astrocytes (GFAP) and proteinopathies of alpha-synuclein (KM51/pser129), amyloid-beta (6 F/3D) and p-tau (AT8) were assessed in a cohort of mixed DLB + AD (n = 35), pure DLB (n = 15), pure AD (n = 16) and control (n = 11) donors in limbic and neocortical brain regions using immunostaining, quantitative image analysis and confocal microscopy. Regional and group differences were estimated using a linear mixed model analysis. Results: Morphologically, reactive and amoeboid microglia were common in mixed DLB + AD, while homeostatic microglia with a small soma and thin processes were observed in pure DLB cases. A higher density of swollen astrocytes was observed in pure AD cases, but not in mixed DLB + AD or pure DLB cases. Mixed DLB + AD had higher CD68-loads in the amygdala and parahippocampal gyrus than pure DLB cases, but did not differ in astrocytic loads. Pure AD showed higher Iba1-loads in the CA1 and CA2, higher CD68-loads in the CA2 and subiculum, and a higher astrocytic load in the CA1-4 and subiculum than mixed DLB + AD cases. In mixed DLB + AD cases, microglial load associated strongly with amyloid-beta (Iba1, CD68 and HLA-DR), and p-tau (CD68 and HLA-DR), and minimally with alpha-synuclein load (CD68). In addition, the highest microglial activity was found in the amygdala and CA2, and astroglial load in the CA4. Confocal microscopy demonstrated co-localization of large amoeboid microglia with neuritic and classic-cored plaques of amyloid-beta and p-tau in mixed DLB + AD cases. Conclusions: In conclusion, microglial activation in DLB was largely associated with AD co-pathology, while astrocytic response in DLB was not. In addition, microglial activity was high in limbic regions, with prevalent AD pathology. Our study provides novel insights into the molecular neuropathology of DLB, highlighting the importance of microglial activation in mixed DLB + AD. [ABSTRACT FROM AUTHOR]

Background: Diffusion‐weighted magnetic resonance imaging (dMRI) examines tissue microstructure integrity in vivo. Prior dementia with Lewy bodies (DLB) diffusion tensor imaging studies yielded mixed results. Objective: We employed free‐water (FW) imaging to assess DLB progression and correlate with clinical decline in DLB. Methods: Baseline and follow‐up MRIs were obtained at 12 and/or 24 months for 27 individuals with DLB or mild cognitive impairment with Lewy bodies (MCI‐LB). FW was analyzed using the Mayo Clinic Adult Lifespan Template. Primary outcomes were FW differences between baseline and 12 or 24 months. To compare FW change longitudinally, we included 20 cognitively unimpaired individuals from the Alzheimer's Disease Neuroimaging Initiative. Results: We followed 23 participants to 12 months and 16 participants to 24 months. Both groups had worsening in Montreal Cognitive Assessment (MoCA) and Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) scores. We found significant FW increases at both time points compared to baseline in the insula, amygdala, posterior cingulum, parahippocampal, entorhinal, supramarginal, fusiform, retrosplenial, and Rolandic operculum regions. At 24 months, we found more widespread microstructural changes in regions implicated in visuospatial processing, motor, and cholinergic functions. Between‐group analyses (DLB vs. controls) confirmed significant FW changes over 24 months in most of these regions. FW changes were associated with longitudinal worsening of MDS‐UPDRS and MoCA scores. Conclusions: FW increased in gray and white matter regions in DLB, likely due to neurodegenerative pathology associated with disease progression. FW change was associated with clinical decline. The findings support dMRI as a promising tool to track disease progression in DLB. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The brain- and body-first models of Lewy body disorders predict that aggregated alpha-synuclein pathology usually begins in either the olfactory system or the enteric nervous system. In both scenarios the pathology seems to arise in structures that are closely connected to the outside world. Environmental toxicants, including certain pesticides, industrial chemicals, and air pollution are therefore plausible trigger mechanisms for Parkinson's disease and dementia with Lewy bodies. Here, we propose that toxicants inhaled through the nose can lead to pathological changes in alpha-synuclein in the olfactory system that subsequently spread and give rise to a brain-first subtype of Lewy body disease. Similarly, ingested toxicants can pass through the gut and cause alpha-synuclein pathology that then extends via parasympathetic and sympathetic pathways to ultimately produce a body-first subtype. The resulting spread can be tracked by the development of symptoms, clinical assessments, in vivo imaging, and ultimately pathological examination. The integration of environmental exposures into the brain-first and body-first models generates testable hypotheses, including on the prevalence of the clinical conditions, their future incidence, imaging patterns, and pathological signatures. The proposed link, though, has limitations and leaves many questions unanswered, such as the role of the skin, the influence of the microbiome, and the effects of ongoing exposures. Despite these limitations, the interaction of exogenous factors with the nose and the gut may explain many of the mysteries of Parkinson's disease and open the door toward the ultimate goal –prevention. [ABSTRACT FROM AUTHOR]

Background: Attention-deficit/hyperactivity disorder (ADHD), a common neurodevelopmental condition now recognized to persist into older adulthood, has been postulated to be a risk factor for neurocognitive disorders given the overlap in clinical features and neurobiology, as well as the complex interplay between ADHD and known risk factors for dementia. Studies have emerged assessing this relationship, but there has not yet been a comprehensive systematic review addressing this topic. Objective: To assess whether ADHD is a risk factor for neurocognitive disorders and to explore possible mechanisms for such an association. Methods: A systematic review of the literature was conducted using Medline, Embase, and PsycINFO from inception until June 4, 2023. Studies were included if they assessed whether or how ADHD may be a risk factor for neurocognitive disorders. Studies were excluded if they were not primary literature, not published in a peer-reviewed journal, not in English, and/or used non-human subjects. Study quality was assessed using the QualSyst tool. Results: Sixteen studies met inclusion criteria. Seven studies found a positive association between ADHD and neurocognitive disorders (all-cause dementia in four studies, Alzheimer's disease in three studies, Lewy body dementia in two studies, and mild cognitive impairment in one study). Four studies did not find an association. Five studies pertained to possible mechanisms for an association, including genetics, with minimal significant findings. Conclusions: ADHD may be a risk factor for certain neurocognitive disorders, although the evidence base is limited, and the absolute risk is small. Possible explanations include genetic and lifestyle factors. [ABSTRACT FROM AUTHOR]

Aims: Hirano bodies (HBs) are eosinophilic pathological structures with two morphological phenotypes commonly found in the hippocampal CA1 region in Alzheimer's disease (AD). This study evaluated the prevalence and distribution of HBs in AD and other neurodegenerative diseases. Methods: This cross‐sectional study systematically evaluated HBs in a cohort of 193 cases with major neurodegenerative diseases, including AD (n = 91), Lewy body disease (LBD, n = 87), progressive supranuclear palsy (PSP, n = 36), multiple system atrophy (MSA, n = 14) and controls (n = 26). The prevalence, number and morphology of HBs in the stratum lacunosum (HBL) and CA1 pyramidal cell layer were examined. In addition, we investigated the presence of HBs in five additional hippocampal subregions. Results: The morphological types of HBs in CA1 were divided into three, including a newly discovered type, and were evaluated separately, with their morphology confirmed in three dimensions: (1) classic rod‐shaped HB (CHB), (2) balloon‐shaped HB (BHB) and the newly described (3) string‐shaped HB (SHB). The prevalence of each HB type differed between disease groups: Compared with controls, for CHB in AD, AD + LBD, PSP and corticobasal degeneration, for BHB in AD + LBD and PSP, and SHB in AD + LBD and PSP were significantly increased. Regression analysis showed that CHBs were independently associated with higher Braak NFT stage, BHBs with LBD and TDP‐43 pathology, SHBs with higher Braak NFT stage, PSP and argyrophilic grain disease and HBLs with MSA. Conclusions: This study demonstrates that HBs are associated with diverse neurodegenerative diseases and shows that morphological types appear distinctively in various conditions. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Little is known regarding quality of life (QoL) in dementia with Lewy bodies (DLB), particularly in advanced stages. METHODS: Dyads of individuals with moderate–advanced DLB and their primary caregivers were recruited from specialty clinics, advocacy organizations, and research registries. The study collected demographics, disease‐related measures, and measures of patient/caregiver experiences. RESULTS: The Quality of Life in Alzheimer's Disease (QoL‐AD) was completed by the person with DLB and the caregiver (proxy) in 61 dyads; 85 dyads had only a proxy‐completed QoL‐AD. Patient‐ and proxy‐reported scores were moderately correlated (r = 0.57, P < 0.0001). Worse patient‐reported QoL correlated with daytime sleepiness, autonomic symptom burden, and behavioral symptoms. Proxy ratings correlated with dementia severity, daytime sleepiness, behavioral symptoms, dependence in activities of daily living, and caregiver experience measures. DISCUSSION: Patient‐ and proxy‐reported quality of life (QoL) should be assessed separately in advanced DLB. Some symptoms associated with QoL have available therapeutic options. Research is needed regarding strategies to optimally improve QoL in DLB. Highlights: Patient and proxy quality of life (QoL) ratings had moderate correlation in advanced dementia with Lewy bodies.Daytime sleepiness affected patient‐ and proxy‐reported QoL.Behavioral symptoms affected patient‐ and proxy‐reported QoL.Autonomic symptom burden affected patient‐reported QoL.Dementia severity, dependence, and caregiver experiences affected proxy ratings. [ABSTRACT FROM AUTHOR]

Lewy body diseases (LBDs) feature α-synuclein (α-syn)-containing Lewy bodies, with misfolded α-syn potentially propagating as seeds. Using a seeding amplification assay, we previously reported distinct α-syn seeding in LBD cases based on the area under seeding curves. This study revealed that LBD cases showing different α-syn seeding kinetics have distinct proteomics profiles, emphasizing disruptions in mitochondria and lipid metabolism in high-seeder cases. Though the mechanisms underlying LBD development are intricate, the factors influencing α-syn seeding activity remain elusive. To address this and complement our previous findings, we conducted targeted transcriptome analyses in the substantia nigra using the nanoString nCounter assay together with histopathological evaluations in high (n = 4) and low (n = 3) nigral α-syn seeders. Neuropathological findings (particularly the substantia nigra) were consistent between these groups and were characterized by neocortical LBD associated with Alzheimer's disease neuropathologic change. Among the 1811 genes assessed, we identified the top 20 upregulated and downregulated genes and pathways in α-syn high seeders compared with low seeders. Notably, alterations were observed in genes and pathways related to transmembrane transporters, lipid metabolism, and the ubiquitin–proteasome system in the high α-syn seeders. In conclusion, our findings suggest that the molecular behavior of α-syn is the driving force in the neurodegenerative process affecting the substantia nigra through these identified pathways. These insights highlight their potential as therapeutic targets for attenuating LBD progression. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The extent to which the Big Five personality traits and subjective well‐being (SWB) are discriminatory predictors of clinical manifestation of dementia versus dementia‐related neuropathology is unclear. METHODS: Using data from eight independent studies (Ntotal= 44,531; Ndementia= 1703; baseline Mage= 49 to 81 years, 26 to 61% female; Mfollow‐up range = 3.53 to 21.00 years), Bayesian multilevel models tested whether personality traits and SWB differentially predicted neuropsychological and neuropathological characteristics of dementia. RESULTS: Synthesized and individual study results indicate that high neuroticism and negative affect and low conscientiousness, extraversion, and positive affect were associated with increased risk of long‐term dementia diagnosis. There were no consistent associations with neuropathology. DISCUSSION: This multistudy project provides robust, conceptually replicated and extended evidence that psychosocial factors are strong predictors of dementia diagnosis but not consistently associated with neuropathology at autopsy. Highlights: N(+), C(−), E(−), PA(−), and NA(+) were associated with incident diagnosis.Results were consistent despite self‐report versus clinical diagnosis of dementia.Psychological factors were not associated with neuropathology at autopsy.Individuals with higher conscientiousness and no diagnosis had less neuropathology.High C individuals may withstand neuropathology for longer before death. [ABSTRACT FROM AUTHOR]

ABSTRACT Dementia is one of the growing diseases in the world and has different types based on its definition. The Montreal Cognitive Assessment (MoCA) test has been employed to screen patients with dementia, cognitive impairment, and disruption of daily activities. Objective: This study examined the diagnostic value of the total MoCA score and its subscores in differentiating Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy body (DLB), and vascular dementia (VaD). Methods: A total of 241 patients (AD=110, FTD=90, DLB=28, and VaD=13) and 59 healthy persons, who were referred to a dementia clinic with memory impairment in Firoozgar Hospital, were included in this study. MoCA tests were performed in all patients and normal persons. Results: By using the receiver operating characteristic (ROC) curve and measuring the area under the curve (AUC) for the total MoCA score in each group, AUC was 0.616, 0.681, 0.6117, and 0.583 for differentiating AD, FTD, DLB, and VaD patients, respectively. Among the groups, just the VaD group showed no significant usefulness in using the total MoCA score to differentiate it. To compare MoCA subscores, AD patients had higher scores in digit span, literal fluency, and abstraction but lower delayed recall scores compared with FTD patients. Conclusion: The total MoCA score and its subscores could not differentiate people with different types of dementia in the setting of screening.

Background: The postmortem diagnostic of individuals having suffered presumptive neurodegenerative disease comprises exclusion of a prion disease, extensive brain sampling and histopathological evaluation, which are resource-intensive and time consuming. To exclude prion disease and to achieve prompt accurate preliminary diagnosis, we developed a fast-track procedure for the histopathological assessment of brains from patients with suspected neurodegenerative disease. Methods: Based on the screening of two brain regions (frontal cortex and cerebellum) with H&E and six immunohistochemical stainings in 133 brain donors, a main histopathological diagnosis was established and compared to the final diagnosis made after a full histopathological work-up according to our brain bank standard procedure. Results: In over 96 % of cases there was a concordance between the fast-track and the final main neuropathological diagnosis. A prion disease was identified in four cases without prior clinical suspicion of a prion infection. Conclusion: The fast-track screening approach relying on two defined, easily accessible brain regions is sufficient to obtain a reliable tentative main diagnosis in individuals with neurodegenerative disease and thus allows for a prompt feedback to the physicians. However, a more thorough histological work-up taking into account the clinical history and the working diagnosis from fast-track screening is necessary for accurate staging and for assessment of co-pathologies.

3R/4R-tau species are found in Alzheimer disease (AD) and ∼50% of Lewy body dementias at autopsy (LBD+tau); 4R-tau accumulations are found in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Digital image analysis techniques can elucidate patterns of tau pathology more precisely than traditional methods but repeatability across centers is unclear. We calculated regional percentage areas occupied by tau pathological inclusions from the middle frontal cortex (MFC), superior temporal cortex (STC), and angular gyrus (ANG) from cases from the University of Pennsylvania and the University of California San Diego with AD, LBD+tau, PSP, or CBD (n = 150) using QuPath. In both cohorts, AD and LBD+tau had the highest grey and white matter tau burden in the STC (p ≤ 0.04). White matter tau burden was relatively higher in 4R-tauopathies than 3R/4R-tauopathies (p

Background and objectivePatients with dementia with Lewy bodies perform worse than those with Alzheimer disease (AD) on tests of visual perception, but the clinical utility of these tests remains unknown because studies often had clinically diagnosed groups that may inadvertently cross-contaminate Lewy body disease (LBD) with pure AD pathology, used experimental tests not easily adaptable for clinical use, and had no way to examine relationships between the severity of LBD pathology and degree of cognitive impairment. Therefore, we sought to determine whether performance on a widely used clinical test of visuoperceptual ability effectively differentiates between patients with autopsy-confirmed LBD or AD and correlates with the severity of LBD pathology.MethodsPatients with mild to moderate dementia (n = 42) and cognitively healthy controls (n = 22) performed a Fragmented Letters Test in which they identified letters of the alphabet that were randomly visually degraded by 70% and additional visuospatial and episodic memory tests. At autopsy, dementia cases were confirmed to have LBD (n = 19), all with concomitant AD, or only AD (n = 23). Severity of α-synuclein pathology in the hippocampus and neocortex was rated on an ordinal scale.ResultsPatients with LBD performed worse than those with AD (B = -2.80 ± 0.91, p = 0.009) and healthy controls (B = -3.34 ± 1.09, p = 0.01) on the Fragmented Letters Test after adjustment for age, sex, education, Mini-Mental State Examination score, and ability to name intact letters. Patients with AD did not differ from controls (B = -0.55 ± 1.08, p = 0.87). The test effectively distinguished between patients with LBD or AD with 73% sensitivity and 87% specificity, and the area under the curve in receiver operating characteristic analyses was 0.85 (95% CI 0.72-0.95), higher than for standard tests of visuospatial ability (Block Design; 0.72; CI 0.35-0.75) or memory (California Verbal Learning Test, trials 1-5; 0.55; CI 0.57-0.88). Fragmented Letters Test scores were negatively correlated with LBD pathology density ratings in hippocampus and neocortical regions (Spearman rs = -0.53 to -0.69).DiscussionFragmented Letters Test performance can effectively differentiate patients with LBD pathology from those with only AD pathology at a mild to moderate stage of dementia, even when LBD occurs with significant concomitant AD pathology, and may also be useful for gauging the severity of cortical α-synuclein pathology in those with LBD.

Associations between age-related neuropathological lesions and adult-onset lifetime major depressive disorder (a-MDD), late-life MDD (LLD), or depressive symptoms close to death (DS) were examined in a large community sample of non-demented older adults. Seven hundred forty-one individuals (age at death = 72.2 ± 11.7 years) from the Biobank for Aging Studies were analyzed. a-MDD was present in 54 (7.3%) participants, LLD in 80 (10.8%), and DS in 168 (22.7%). After adjustment for covariates and compared to controls, a-MDD, LDD and DS were associated with small vessel disease (p = 0.039, p = 0.003, and p = 0.003 respectively); LLD, and DS were associated with brain infarcts (p = 0.012, p = 0.018, respectively) and Lewy body disease (p = 0.043, p = 0.002, respectively). DS was associated with beta-amyloid plaque burden (p = 0.027) and cerebral amyloid angiopathy (p = 0.035) in cognitively normal individuals (Clinical Dementia Rating scale = 0). Vascular brain pathology was the strongest correlate of clinical depictions of depression in the absence of dementia, corroborating the vascular hypothesis of depression. Lewy body pathology underlay DS. An older adult with DS or LLD should be monitored for possible cognitive decline or neurodegenerative disorders.

Abstract Background The relationship between cerebrospinal fluid pressure (CSFP) and cognition has received little research attention. The purpose of this study was to explore the relationship between CSFP and cognition in patients with Alzheimer’s disease (AD) and patients with Lewy body dementia (LBD). Method We included 178 participants, including 137 patients with AD and 41 patients with LBD (including dementia with Lewy bodies (DLBs) and Parkinson’s disease dementia (PDD)). CSFP was measured by lumbar puncture, and a patient-reported history and laboratory test data were collected. Logistic and linear regression analyses were used to evaluate the associations between CSFP and cognition, the cerebrospinal fluid (CSF) / serum albumin ratio (Qalb), and CSF biomarkers of AD. Results The mean age of the included patients was 63.58 ± 8.77 years old, and the mean CSFP was 121 ± 33.72 mmH2O. A total of 76.9% of the patients had a CSFP distribution of [90–170) mmH2O, 46 patients (25.8%) had severe dementia, 83 patients (46.6%) had moderate dementia, 28 patients (15.7%) had mild dementia, and 21 patients (11.8%) had mild cognitive impairment (MCI) (including 16 patients with MCI due to AD and 5 patients with MCI due to LBD). In all patients (p value

BackgroundLewy body (LB) dementias have limited clinical diagnostic accuracy because of frequent copathologies contributing to clinical heterogeneity. Although sex differences in clinical prevalence and frequency of pure LB pathology were shown, differences for clinicopathological correlations are less known.ObjectiveThe aim of this study was to determine sex differences for clinical associations of Alzheimer's disease (AD) copathology in those with LB pathology.MethodsData were from National Alzheimer's Coordinating Center for 223 women and 468 men with limbic or neocortical LB, separated into two groups as those with high likelihood and low/intermediate likelihood for LB clinical phenotype based on pathology. Clinical associations of sex and interaction of sex and pathology for the clinical phenotype were analyzed.ResultsMore severe AD copathology was associated with worse cognitive decline and lower likelihood of LB disease clinical phenotype. Women with more severe AD copathology and tau had worse cognitive decline and higher likelihood of AD clinical phenotype than men. Men with more severe AD copathology had lower likelihood of LB clinical phenotype than women. Interaction of sex and pathology was more pronounced in those aged between 70 and 80 years.ConclusionsAD copathology reduces the likelihood of LB clinical phenotype for both women and men; however, men may be at higher risk for LB disease underdiagnosis and women at higher risk for dementia. The use of both LB and AD biomarkers, even when LB or AD pathology is not clinically expected, is necessary for the accurate clinical diagnosis of both LB diseases and AD. © 2022 International Parkinson and Movement Disorder Society.

The APOE locus is strongly associated with risk for developing Alzheimer's disease and dementia with Lewy bodies. In particular, the role of the APOE ε4 allele as a putative driver of α-synuclein pathology is a topic of intense debate. Here, we performed a comprehensive evaluation in 2466 dementia with Lewy bodies cases versus 2928 neurologically healthy, aged controls. Using an APOE-stratified genome-wide association study approach, we found that GBA is associated with risk for dementia with Lewy bodies in patients without APOE ε4 (P = 6.58 × 10-9, OR = 3.41, 95% CI = 2.25-5.17), but not with dementia with Lewy bodies with APOE ε4 (P = 0.034, OR = 1.87, 95%, 95% CI = 1.05-3.37). We then divided 495 neuropathologically examined dementia with Lewy bodies cases into three groups based on the extent of concomitant Alzheimer's disease co-pathology: pure dementia with Lewy bodies (n = 88), dementia with Lewy bodies with intermediate Alzheimer's disease co-pathology (n = 66) and dementia with Lewy bodies with high Alzheimer's disease co-pathology (n = 341). In each group, we tested the association of the APOE ε4 against the 2928 neurologically healthy controls. Our examination found that APOE ε4 was associated with dementia with Lewy bodies + Alzheimer's disease (P = 1.29 × 10-32, OR = 4.25, 95% CI = 3.35-5.39) and dementia with Lewy bodies + intermediate Alzheimer's disease (P = 0.0011, OR = 2.31, 95% CI = 1.40-3.83), but not with pure dementia with Lewy bodies (P = 0.31, OR = 0.75, 95% CI = 0.43-1.30). In conclusion, although deep clinical data were not available for these samples, our findings do not support the notion that APOE ε4 is an independent driver of α-synuclein pathology in pure dementia with Lewy bodies, but rather implicate GBA as the main risk gene for the pure dementia with Lewy bodies subgroup.

Dementia with Lewy bodies (DLB) is one of the most common degenerative dementias after Alzheimer's disease (AD) dementia. DLB is under-diagnosed across populations but may be particularly missed in older Black adults. The object of this review was to examine key features of DLB and potential associations with race in order to hypothesize why DLB may be under-diagnosed in Black adults in the U.S. In terms of dementia, symptoms associated with high rates of co-pathology (e.g., AD, vascular disease) in older Black adults may obscure the clinical picture that might suggest Lewy body pathology. Research also suggests that clinicians may be predisposed to give AD dementia diagnoses to Black adults, potentially missing contributions of Lewy body pathology. Hallucinations in Black adults may be misattributed to AD or primary psychiatric disease rather than Lewy body pathology. Research on the prevalence of REM sleep behavior in diverse populations is lacking, but REM sleep behavior disorder could be under-diagnosed in Black adults due to sleep patterns or reporting by caregivers who are not bed partners. Recognition of parkinsonism could be reduced in Black adults due to clinician biases, cultural effects on self-report, and potentially underlying differences in the frequency of parkinsonism. These considerations are superimposed on structural and systemic contributions to health (e.g., socioeconomic status, education, structural racism) and individual-level social exposures (e.g., social interactions, discrimination). Improving DLB recognition in Black adults will require research to investigate reasons for diagnostic disparities and education to increase identification of core symptoms in this population. [ABSTRACT FROM AUTHOR]

Background and purpose: Visual hallucinations are a common, potentially distressing experience of people with Lewy body disease (LBD). The underlying brain changes giving rise to visual hallucinations are not fully understood, although previous models have posited that alterations in the connectivity between brain regions involved in attention and visual processing are critical. Methods: Data from 41 people with LBD and visual hallucinations, 48 with LBD without visual hallucinations and 60 similarly aged healthy comparator participants were used. Connections were investigated between regions in the visual cortex and ventral attention, dorsal attention and default mode networks. Results: Participants with visual hallucinations had worse cognition and motor function than those without visual hallucinations. In those with visual hallucinations, reduced functional connectivity within the ventral attention network and from the visual to default mode network was found. Connectivity strength between the visual and default mode network correlated with the number of correct responses on a pareidolia task, and connectivity within the ventral attention network with visuospatial performance. Conclusions: Our results add to evidence of dysfunctional connectivity in the visual and attentional networks in those with LBD and visual hallucinations. [ABSTRACT FROM AUTHOR]

Objective: Dementia with Lewy bodies (DLB) is the second most common dementia. Advancing our limited understanding of its molecular pathogenesis is essential for identifying novel biomarkers and therapeutic targets for DLB. DLB is an α-synucleinopathy, and small extracellular vesicles (SEV) from people with DLB can transmit α-synuclein oligomerisation between cells. Post-mortem DLB brains and serum SEV from those with DLB share common miRNA signatures, and their functional implications are uncertain. Hence, we aimed to investigate potential targets of DLB-associated SEV miRNA and to analyse their functional implications. Methods: We identified potential targets of six previously reported differentially expressed miRNA genes in serum SEV of people with DLB (MIR26A1 , MIR320C2 , MIR320D2 , MIR548BA , MIR556 , and MIR4722) using miRBase and miRDB databases. We analysed functional implications of these targets using EnrichR gene set enrichment analysis and analysed their protein interactions using Reactome pathway analysis. Results: These SEV miRNA may regulate 4278 genes that were significantly enriched among the genes involved in neuronal development, cell-to-cell communication, vesicle-mediated transport, apoptosis, regulation of cell cycle, post-translational protein modifications, and autophagy lysosomal pathway, after Benjamini-Hochberg false discovery rate correction at 5%. The miRNA target genes and their protein interactions were significantly associated with several neuropsychiatric disorders and with multiple signal transduction, transcriptional regulation, and cytokine signalling pathways. Conclusion: Our findings provide in-silico evidence that potential targets of DLB-associated SEV miRNAs may contribute to Lewy pathology by transcriptional regulation. Experimental validation of these dysfunctional pathways is warranted and could lead to novel therapeutic avenues for DLB. [ABSTRACT FROM AUTHOR]

In 36 normal controls (NC), 37 patients with Alzheimer's disease (AD) without parkinsonism (ADP-), 31 AD with parkinsonism (ADP+), and 40 AD with dementia with Lewy bodies (ADDLB), dual-phase dopamine transporter (DAT) positron emission tomography (PET) were performed to evaluate the diagnostic performance of DAT and early-to-delayed uptake ratios (E/Ds) in the anterior caudate (AC), posterior caudate (PC), anterior putamen (AP), posterior putamen (PP), and substantia nigra (SN) to differentiate ADP+/ADDLB from NC, and their effects on parkinsonism and cognition. DAT-SN and E/D-PP showed higher accuracies to differentiate ADP+/ADDLB from NC than DAT-PP. Among AD patients, lower DAT in the putamen and PC and higher E/Ds in the striatum were associated with severe parkinsonism, while higher E/Ds in the putamen, PC, and SN were associated with executive dysfunction. Our results suggest that decreased DAT-SN and increased E/D-PP could be biomarkers differentiating ADP+/ADDLB from pure AD and controls. Meanwhile, increased E/Ds in the putamen could reflect the severity of DLB presenting with parkinsonism and executive dysfunction among AD patients. • Dopamine transporter (DAT) was measured in AD patients with LBD features (AD/LBD). • Perfusion/dopamine mismatch was measured with early/delayed uptake (E/D) ratios. • Nigral DAT had a higher accuracy than putamen DAT for the diagnosis of AD/LBD. • Nigral and putamen E/D ratios had a better diagnostic accuracy than putamen DAT. • Decreased nigral DAT and increased putamen E/D ratio may be biomarkers for AD/LBD. [ABSTRACT FROM AUTHOR]

Background: The relationship between cerebrospinal fluid pressure (CSFP) and cognition has received little research attention. The purpose of this study was to explore the relationship between CSFP and cognition in patients with Alzheimer's disease (AD) and patients with Lewy body dementia (LBD). Method: We included 178 participants, including 137 patients with AD and 41 patients with LBD (including dementia with Lewy bodies (DLBs) and Parkinson's disease dementia (PDD)). CSFP was measured by lumbar puncture, and a patient-reported history and laboratory test data were collected. Logistic and linear regression analyses were used to evaluate the associations between CSFP and cognition, the cerebrospinal fluid (CSF) / serum albumin ratio (Qalb), and CSF biomarkers of AD. Results: The mean age of the included patients was 63.58 ± 8.77 years old, and the mean CSFP was 121 ± 33.72 mmH2O. A total of 76.9% of the patients had a CSFP distribution of [90–170) mmH2O, 46 patients (25.8%) had severe dementia, 83 patients (46.6%) had moderate dementia, 28 patients (15.7%) had mild dementia, and 21 patients (11.8%) had mild cognitive impairment (MCI) (including 16 patients with MCI due to AD and 5 patients with MCI due to LBD). In all patients (p value < 0.001) and in patients with AD (p value = 0.01), the mean cerebrospinal fluid pressure (CSFP) was higher in patients with MCI than in patients with dementia. In multivariate analysis, in all patients (OR: 6.37, 95% confidential interval (CI): 1.76–23.04, p = 0.005) and patients with AD (odds ratio (OR): 5.43, 95% CI: 1.41–20.87, p = 0.005), a CSFP in the lowest quartile ([50–90) mmH2O) was associated with a higher level of severe dementia than a CSFP in the highest quartile ([170–210) mmH2O). In addition, there was a significant linear correlation between CSFP and the Mini-Mental State Examination (MMSE) score in all patients with dementia (r = 0.43, p = 0.04, Durbin-Watson test (D-W test) = 0.75). Conclusion: In patients with AD, the mean cerebrospinal fluid pressure was higher in patients with MCI than in patients with dementia, and the decrease in CSFP was related to a more serious dementia level. However, no such relationship was found in patients with LBD. [ABSTRACT FROM AUTHOR]

Rare and common GBA variants are risk factors for both Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). However, the degree to which GBA variants are associated with neuropathological features in Lewy body disease (LBD) is unknown. Herein, we assessed 943 LBD cases and examined associations of 15 different neuropathological outcomes with common and rare GBA variants. Neuropathological outcomes included LBD subtype, presence of a high likelihood of clinical DLB (per consensus guidelines), LB counts in five cortical regions, tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen, ventrolateral substantia nigra neuronal loss, Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, phospho-ubiquitin (pS65-Ub) level, TDP-43 pathology, and vascular disease. Sequencing of GBA exons revealed a total of 42 different variants (4 common [MAF > 0.5%], 38 rare [MAF < 0.5%]) in our series, and 165 cases (17.5%) had a copy of the minor allele for ≥ 1 variant. In analysis of common variants, p.L483P was associated with a lower Braak NFT stage (OR = 0.10, P < 0.001). In gene-burden analysis, presence of the minor allele for any GBA variant was associated with increased odds of a high likelihood of DLB (OR = 2.00, P < 0.001), a lower Braak NFT stage (OR = 0.48, P < 0.001), a lower Thal amyloid phase (OR = 0.55, P < 0.001), and a lower pS65-Ub level (β: −0.37, P < 0.001). Subgroup analysis revealed that GBA variants were most common in LBD cases with a combination of transitional/diffuse LBD and Braak NFT stage 0-II or Thal amyloid phase 0–1, and correspondingly that the aforementioned associations of GBA gene-burden with a decreased Braak NFT stage and Thal amyloid phase were observed only in transitional or diffuse LBD cases. Our results indicate that in LBD, GBA variants occur most frequently in cases with greater LB pathology and low AD pathology, further informing disease–risk associations of GBA in PD, PD dementia, and DLB. [ABSTRACT FROM AUTHOR]

Dementia with Lewy bodies is characterized by a high burden of autonomic dysfunction and Lewy pathology in peripheral organs and components of the sympathetic and parasympathetic nervous system. Parasympathetic terminals may be quantified with 18F-fluoroetoxybenzovesamicol, a PET tracer that binds to the vesicular acetylcholine transporter in cholinergic presynaptic terminals. Parasympathetic imaging may be useful for diagnostics, improving our understanding of autonomic dysfunction and for clarifying the spatiotemporal relationship of neuronal degeneration in prodromal disease. Therefore, we aimed to investigate the cholinergic parasympathetic integrity in peripheral organs and central autonomic regions of subjects with dementia with Lewy bodies and its association with subjective and objective measures of autonomic dysfunction. We hypothesized that organs with known parasympathetic innervation, especially the pancreas and colon, would have impaired cholinergic integrity. To achieve these aims, we conducted a cross-sectional comparison study including 23 newly diagnosed non-diabetic subjects with dementia with Lewy bodies (74 ± 6 years, 83% male) and 21 elderly control subjects (74 ± 6 years, 67% male). We obtained whole-body images to quantify PET uptake in peripheral organs and brain images to quantify PET uptake in regions of the brainstem and hypothalamus. Autonomic dysfunction was assessed with questionnaires and measurements of orthostatic blood pressure. Subjects with dementia with Lewy bodies displayed reduced cholinergic tracer uptake in the pancreas (32% reduction, P = 0.0003) and colon (19% reduction, P = 0.0048), but not in organs with little or no parasympathetic innervation. Tracer uptake in a region of the medulla oblongata overlapping the dorsal motor nucleus of the vagus correlated with autonomic symptoms (rs = −0.54, P = 0.0077) and changes in orthostatic blood pressure (rs = 0.76, P < 0.0001). Tracer uptake in the pedunculopontine region correlated with autonomic symptoms (rs = −0.52, P = 0.0104) and a measure of non-motor symptoms (rs = −0.47, P = 0.0230). In conclusion, our findings provide the first imaging-based evidence of impaired cholinergic integrity of the pancreas and colon in dementia with Lewy bodies. The observed changes may reflect parasympathetic denervation, implying that this process is initiated well before the point of diagnosis. The findings also support that cholinergic denervation in the brainstem contributes to dysautonomia. [ABSTRACT FROM AUTHOR]

Aim: Clinical studies reported that patients with schizophrenia are at a higher risk of developing dementia than people without schizophrenia. However, early neuropathological studies have shown that the incidence of Alzheimer's disease (AD) in schizophrenia patients does not differ from that in controls. These inconsistent results may be attributable to the inclusion of non‐AD dementia, but there have been few clinicopathological studies in older patients with schizophrenia based on the current neuropathological classification. This study aimed to investigate the neuropathological basis of incident dementia in older patients with schizophrenia. Methods: We systematically examined 32 brains of old patients with schizophrenia using standardized pathological methods. The severity of dementia‐related neuropathologies was analyzed using standardized semiquantitative assessments. After excluding patients who fulfilled the neuropathological criteria, clinicopathological variables were compared between patients with and without incident dementia to identify potential differences. Results: Seven patients fulfilled the pathological criteria for AD (n = 3), argyrophilic grain disease (AGD) (n = 2), dementia with Lewy bodies (n = 1), and AGD/progressive supranuclear palsy (n = 1). Among 25 patients for whom a neuropathological diagnosis was not obtained, 10 had dementia, but the clinicopathological findings did not differ from the remaining 15 patients without dementia. Conclusion: Two types of older schizophrenia patient present dementia: patients with co‐existing neurodegenerative disease and patients who do not meet pathological criteria based on the current classification. To understand the neurobiological aspects of incident dementia in older patients with schizophrenia, further clinicopathological studies are needed that do not simply analyze incident dementia as a comorbidity of conventional dementia‐related neuropathologies. [ABSTRACT FROM AUTHOR]

Lewy body disease (LBD) is characterized by the appearance of Lewy neurites and Lewy bodies, which are predominantly composed of α‐synuclein. Notably, the cardiac plexus (CP) is one of the main targets of LBD research. Although previous studies have reported obvious differences in the frequency of Lewy body pathology (LBP) in the CP, none of them have confirmed whether LBP preferably appears in any part of the CP. Thus, we aimed to clarify the emergence and/or propagation of LBP in the CP. In this study, 263 consecutive autopsy cases of patients aged ≥50 years were included, with one region per case selected from three myocardial perfusion areas (MPAs) and subjected to proteinase K and then immunohistochemically stained with anti‐α‐synuclein antibodies to assess LBP. We stained all three MPAs in 17 cases with low‐density LBP and observed the actual distribution of LBP. LBP were identified in the CP in 20.2% (53/263) of patients. Moreover, we found that LBP may appear in only one region of MPAs, mainly in the young‐old group (35.3% (6/17) of patients). These findings suggest that it is possible to underestimate LBP in the CP, especially in the young‐old group, by restricting the search to only one of the three MPAs. [ABSTRACT FROM AUTHOR]

This study investigated the molecular spectrum of amyloid‐beta (Aβ) in neurodegenerative diseases beyond Alzheimer's disease (AD). We analyzed Aβ deposition in the temporal cortex and striatum in 116 autopsies, including Lewy body disease (LBD; N = 51), multiple system atrophy (MSA; N = 10), frontotemporal lobar degeneration‐TDP‐43 (FTLD‐TDP; N = 16), and progressive supranuclear palsy (PSP; N = 39). The LBD group exhibited the most Aβ deposition in the temporal cortex and striatum (90/76%, respectively), followed by PSP (69/28%), FTLD‐TDP (50/25%), and the MSA group (50/10%). We conducted immunohistochemical analysis using antibodies targeting eight Aβ epitopes in the LBD and PSP groups. Immunohistochemical findings were evaluated semi‐quantitatively and quantitatively using digital pathology. Females with LBD exhibited significantly more severe Aβ deposition, particularly Aβ42 and Aβ43, along with significantly more severe tau pathology. Furthermore, a quantitative analysis of all Aβ peptides in the LBD group revealed an association with the APOE‐ε4 genotypes. No significant differences were observed between males and females in the PSP group. Finally, we compared striatal Aβ deposition in cases with LBD (N = 15), AD without α‐synuclein pathology (N = 6), and PSP (N = 5). There were no differences in the pan‐Aβ antibody (6F/3D)‐immunolabeled deposition burden among the three groups, but the deposition burden of peptides with high aggregation capacity, especially Aβ43, was significantly higher in the AD and LBD groups than in the PSP group. Furthermore, considerable heterogeneity was observed in the composition of Aβ peptides on a case‐by‐case basis in the AD and LBD groups, whereas it was relatively uniform in the PSP group. Cluster analysis further supported these findings. Our data suggest that the type of concomitant proteinopathies influences the spectrum of Aβ deposition, impacted also by sex and APOE genotypes. [ABSTRACT FROM AUTHOR]

Human neurodegenerative diseases associated with the misfolding of the alpha-synuclein (aS) protein (synucleinopathies) are similar to prion diseases to the extent that lesions are spread by similar molecular mechanisms. In a transgenic mouse model (M83) overexpressing a mutated (A53T) form of human aS, we had previously found that Protein Misfolding Cyclic Amplification (PMCA) triggered the aggregation of aS, which is associated with a high resistance to the proteinase K (PK) digestion of both human and murine aS, a major hallmark of the disease-associated prion protein. In addition, PMCA was also able to trigger the aggregation of murine aS in C57Bl/6 mouse brains after seeding with sick M83 mouse brains. Here, we show that intracerebral inoculations of M83 mice with C57Bl/6-PMCA samples strikingly shortens the incubation period before the typical paralysis that develops in this transgenic model, demonstrating the pathogenicity of PMCA-aggregated murine aS. In the hind brain regions of these sick M83 mice containing lesions with an accumulation of aS phosphorylated at serine 129, aS also showed a high PK resistance in the N-terminal part of the protein. In contrast to M83 mice, old APPxM83 mice co-expressing human mutated amyloid precursor and presenilin 1 proteins were seen to have an aggregation of aS, especially in the cerebral cortex, hippocampus and striatum, which also contained the highest load of aS phosphorylated at serine 129. This was proven by three techniques: a Western blot analysis of PK-resistant aS; an ELISA detection of aS aggregates; or the identification of aggregates of aS using immunohistochemical analyses of cytoplasmic/neuritic aS deposits. The results obtained with the D37A6 antibody suggest a higher involvement of murine aS in APPxM83 mice than in M83 mice. Our study used novel tools for the molecular study of synucleinopathies, which highlight similarities with the molecular mechanisms involved in prion diseases. [ABSTRACT FROM AUTHOR]

Background and purpose: White matter hyperintensities (WMHs) are associated with cognitive deficits and worse clinical outcomes in dementia, but rare studies have been carried out of cognitive impairment in Lewy body disease (CI‐LB) patients. The objective was to investigate the associations between WMHs and clinical manifestations in patients with CI‐LB. Methods: In this retrospective multicentre cohort study, 929 patients (486 with dementia with Lewy bodies [DLB], 262 with Parkinson's disease dementia [PDD], 74 with mild cognitive impairment [MCI] with Lewy bodies [MCI‐LB] and 107 with Parkinson's disease with MCI [PD‐MCI]) were analysed from 22 memory clinics between January 2018 and June 2022. Demographic and clinical data were collected by reviewing medical records. WMHs were semi‐quantified according to the Fazekas method. Associations between WMHs and clinical manifestations were investigated by multivariate linear or logistic regression models. Results: Dementia with Lewy bodies patients had the highest Fazekas scores compared with PDD, MCI‐LB and PD‐MCI. Multivariable regressions showed the Fazekas score was positively associated with the scores of Unified Parkinson's Disease Rating Scale Part III (p = 0.001), Hoehn−Yahn stage (p = 0.004) and total Neuropsychiatric Inventory (p = 0.001) in MCI‐LB and PD‐MCI patients. In patients with DLB and PDD, Fazekas scores were associated with the absence of rapid eye movement sleep behaviour disorder (p = 0.041) and scores of Unified Parkinson's Disease Rating Scale Part III (p < 0.001), Hoehn−Yahn stage (p < 0.001) and the Montreal Cognitive Assessment (p = 0.014). Conclusion: White matter hyperintensity burden of DLB was higher than for PDD, MCI‐LB and PD‐MCI. The greater WMH burden was significantly associated with poorer cognitive performance, worse motor function and more severe neuropsychiatric symptoms in CI‐LB. [ABSTRACT FROM AUTHOR]

Dysregulation of autophagic pathways leads to accumulation of abnormal proteins and damaged organelles in many neurodegenerative disorders, including Parkinson's disease (PD) and Lewy body dementia (LBD). Autophagy-related dysfunction may also trigger secretion and spread of misfolded proteins, such as α-synuclein (α-syn), the major misfolded protein found in PD/LBD. However, the mechanism underlying these phenomena remains largely unknown. Here, we used cell-based models, including human induced pluripotent stem cell-derived neurons, CRISPR/Cas9 technology, and male transgenic PD/LBD mice, plus vetting in human postmortem brains (both male and female). We provide mechanistic insight into this pathologic pathway. We find that aberrant S-nitrosylation of the autophagic adaptor protein p62 causes inhibition of autophagic flux and intracellular buildup of misfolded proteins, with consequent secretion resulting in cell-to-cell spread. Thus, our data show that pathologic protein S-nitrosylation of p62 represents a critical factor not only for autophagic inhibition and demise of individual neurons, but also for α-syn release and spread of disease throughout the nervous system.SIGNIFICANCE STATEMENT In Parkinson's disease and Lewy body dementia, dysfunctional autophagy contributes to accumulation and spread of aggregated α-synuclein. Here, we provide evidence that protein S-nitrosylation of p62 inhibits autophagic flux, contributing to α-synuclein aggregation and spread.

ObjectiveThis study aimed to compare causes of death in the most prevalent neuropathologically diagnosed dementias.MethodsWe analyzed causes of death in a community-based cohort of participants aged 50 or older, submitted to full-body autopsy and a comprehensive neuropathologic examination of the brain. Individuals with Alzheimer disease (AD), vascular dementia (VaD), mixed dementia (AD+VaD), or dementia with Lewy bodies (DLBs) were compared with individuals with no dementia.ResultsIn a sample of 920 individuals, 456 had no dementia, 147 had AD, 120 had VaD, 53 had DLB, and 37 had AD+VaD. Pneumonia as the cause of death was more frequent in the AD (P=0.023), AD+VaD (P=0.046), and DLB (P=0.043) groups. In addition, VaD (P=0.041) and AD+VaD (P=0.028) groups had a higher frequency of atherosclerosis as detected by full-body autopsy.ConclusionOur findings highlight the importance of preventive measures regarding atherosclerosis and pneumonia in patients with dementia. Moreover, because of cognitive impairment, these patients may not fully account for symptoms to make early detection and diagnosis possible. These results confirm findings from previous studies that were based on clinical data, with added accuracy provided by neuropathologic diagnosis and full-body autopsy reports.

Plasma biomarkers related to amyloid, tau, and neurodegeneration (ATN) show great promise for identifying these pathological features of Alzheimer's Disease (AD) as shown by recent clinical studies and selected autopsy studies. We have evaluated ATN plasma biomarkers in a series of 312 well-characterized longitudinally followed research subjects with plasma available within 5 years or less before autopsy and examined these biomarkers in relation to a spectrum of AD and related pathologies. Plasma Aβ42, Aβ40, total Tau, P-tau181, P-tau231 and neurofilament light (NfL) were measured using Single molecule array (Simoa) assays. Neuropathological findings were assessed using standard research protocols. Comparing plasma biomarkers with pathology diagnoses and ratings, we found that P-tau181 (AUC = 0.856) and P-tau231 (AUC = 0.773) showed the strongest overall sensitivity and specificity for AD neuropathological change (ADNC). Plasma P-tau231 showed increases at earlier ADNC stages than other biomarkers. Plasma Aβ42/40 was decreased in relation to amyloid and AD pathology, with modest diagnostic accuracy (AUC = 0.601). NfL was increased in non-AD cases and in a subset of those with ADNC. Plasma biomarkers did not show changes in Lewy body disease (LBD), hippocampal sclerosis of aging (HS) or limbic-predominant age-related TDP-43 encephalopathy (LATE) unless ADNC was present. Higher levels of P-tau181, 231 and NfL predicted faster cognitive decline, as early as 10 years prior to autopsy, even among people with normal cognition or mild cognitive impairment. These results support plasma P-tau181 and 231 as diagnostic biomarkers related to ADNC that also can help to predict future cognitive decline, even in predementia stages. Although NfL was not consistently increased in plasma in AD and shows increases in several neurological disorders, it had utility to predict cognitive decline. Plasma Aβ42/40 as measured in this study was a relatively weak predictor of amyloid pathology, and different assay methods may be needed to improve on this. Additional plasma biomarkers are needed to detect the presence and impact of LBD and LATE pathology.