CSF Aβ42 Research Articles

Multimodal assessment predicts cognitive impairment after aneurysmal subarachnoid hemorrhage: a prospective cohort study.

Risk factors and mechanisms of cognitive impairment (CI) after aneurysmal subarachnoid hemorrhage (aSAH) are unclear. This study used a neuropsychological battery, MRI, ERP and CSF and plasma biomarkers to predict long-term cognitive impairment after aSAH. 214 patients hospitalized with aSAH (n=125) or unruptured intracranial aneurysms (UIA) (n=89) were included in this prospective cohort study. Neuropsychological tests were administered 7 to 24months post-discharge. MRI, ERP, and CSF and plasma biomarkers were used to predict long-term CI, and area under ROC curves were calculated. Patients with aSAH CI showed significant impairment across composite scores and cognitive domains on the neuropsychological battery vs. patients with aSAH No CI. On ALFF (MRI), the right medial orbitofrontal cortex (AUC=0.78), right inferior frontal gyrus (AUC=0.848), and right inferior parietal lobule (AUC=0.868) distinguished aSAH CI from aSAH No CI. For ERP, consistent changes were found across specific EEG electrodes (FP1, F3, CP1, FP2, F4, CP2), including increased PA, prolonged PL and decreased ITPC. ITPC showed the highest sensitivity for distinguishing aSAH CI from aSAH No CI, followed by PA. Channel F4 (ITPC, AUC=0.912, PA, AUC=0.846), corresponding to the right inferior frontal gyrus, was the most sensitive for detecting CI, followed by channel CP2 (ITPC, AUC=0.903, PA, AUC=0.806), corresponding to the right inferior parietal lobule. CSF (Aβ42, Aβ40, p-tau181/Aβ42, p-tau181/total-tau, total-tau) and plasma biomarkers (Aβ-40, p-tau181) were significantly associated with long-term CI. ALFF, ERP, and CSF and plasma Aβ and tau levels and ratios have clinical utility for evaluating and predicting long-term cognitive impairment following aSAH. MRI may reveal the pathogenesis of cognitive impairment following aSAH. ERP can be administered at the bedside offering sensitive, non-invasive, repeatable, and sustainable monitoring, which is particularly suitable for immobile coma patients. ERP may represent a promising method to monitor neural function and its outcomes.

Accuracy and clinical applicability of plasma tau 181 and 217 for Alzheimer's disease diagnosis in a memory clinic cohort.

Plasma tau phosphorylated at threonine 181 (p-tau181) and 217 (p-tau217) have demonstrated high accuracy for Alzheimer's disease (AD) diagnosis, defined by CSF/PET amyloid beta (Aβ) positivity, but most studies have been performed in research cohorts, limiting their generalizability. We studied plasma p-tau217 and p-tau181 for CSF Aβ status discrimination in a cohort of consecutive patients attending an academic memory clinic in Spain (July 2019-June 2024). All patients had CSF AD biomarkers performed as part of their routine clinical assessment. Aβ positivity was defined with a local cut-off of CSF Aβ1-42 < 600pg/mL; in patients with borderline Aβ1-42 values or when there was a mismatch between the Aβ and the T status (T + if CSF p-tau181 ≥ 65pg/mL), a ratio Aβ1-42/Aβ1-40 < 0.07 was used. Plasma p-tau217 and p-tau181 were measured retrospectively, from blood samples collected at first visit, with Fujirebio Lumipulse and Quanterix Simoa assays, respectively. We included 468 patients (mean age 67years, 50% female, 61% Aβ positive). Plasma p-tau217 outperformed plasma p-tau181 in discriminating CSF Aβ status (AUC 0.95 vs 0.90, p = 0.005). A 97.5% sensitivity and specificity plasma p-tau217 algorithm, classifying patients into three groups of Aβ probability (Low, Intermediate and High), resulted in 67% of patients in the Low and High groups, having their Aβ status predicted (as negative and positive, respectively) with 96% accuracy. The remaining 33% in the Intermediate group were candidates to undergo CSF/PET testing. A model with a 10% variation in p-tau217 levels yielded small changes in accuracy (95%). In conclusion, plasma p-tau217 could have discriminated CSF Aβ status in two-thirds of patients with very high accuracy in a memory clinic cohort. These results support the implementation of plasma p-tau217 as an initial diagnostic tool in memory clinics for AD diagnosis, reducing the need for more invasive/expensive testing.

Prospective memory performance and its resting-state functional connectivity correlates in individuals with memory complaints.

This study aimed to investigate prospective memory (PM) in patients with memory complaints but without dementia (PWD) and correlate findings with resting-state functional connectivity (rsFC) alterations. We hypothesized that PM impairment would be evident at a certain relatively early point in the continuum and specific rsFC patterns would be the neuroimaging signature of this impairment. Sixty PWD participated in the study. The Memory Screening Test for Intentions and the Virtual Week were used to assess PM. Using the participants' PM scores as a regressor, the rsFC for PM was analyzed by Network-Based Statistics (NBS). Participants were divided into high and low PM groups (HPMG, LPMG) according to their PM scores and then their neuropsychological scores, rsFC patterns, and CSF biomarker levels were compared. The effect of education on the relationship between connectivity and CSF Aβ42 level was examined by moderation analysis. Compared with HPMG, LPMG was impaired in both event- and time-based PM tasks, but the difference was more distinct in the event-based ones. While HPMG was more successful in event-based tasks than time-based ones, LPMG was not. As a result of NBS analysis, the middle frontal gyrus (MFG), supramarginal gyrus (SMG), and anterior cingulate cortex (ACC) were determined as central seeds. The HPMG's performance and connectivity were higher for most comparisons but had lower CSF Aβ42 than LPMG and therefore was closer to the positivity threshold. When the education level was at the mean and above, there was a negative correlation between CSF Aβ42 level and overall connectivity. The connectivities of MFG, SMG, and ACC play an important role in PM performance in the PWD. In more advanced PM impairment, the impairment of spontaneous processes is more prominent. At the onset of amyloidosis, the cognitive reserve may compensate for cognitive impairment by increasing connectivity.

Phase 2A Proof-of-Concept Double-Blind, Randomized, Placebo-Controlled Trial of Nicotinamide in Early Alzheimer Disease.

Nicotinamide is a coenzyme involved in cellular oxidation-reduction reactions that can inhibit Class III histone deacetylases (HDACs) or sirtuins. HDAC inhibition can affect numerous therapeutic pathways, including tau phosphorylation. We tested the hypothesis that nicotinamide treatment could reduce tau phosphorylation in early Alzheimer disease (AD). We performed a randomized, placebo-controlled, phase 2a proof-of-concept trial to evaluate the safety and tolerability of 48 weeks of treatment with 1,500 mg of nicotinamide twice a day. The primary outcome was level of tau phosphorylated at threonine 231 (p-tau231) in CSF. Prespecified secondary outcomes were levels of p-tau181, total tau, amyloid β40 (Aβ40), and Aβ42 in CSF and the clinical measures Alzheimer's Disease Assessment Scale (ADAS-cog13), Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale-Mild Cognitive Impairment (ADCS-ADL-MCI), and Clinical Dementia Rating Summary of Boxes (CDR-SB). Participants were recruited at 2 academic clinical centers. Enrollment criteria included diagnosis of mild cognitive impairment or mild dementia with CSF biomarker confirmation of AD. The Holm-Bonferroni procedure was used to control type I error within biomarker and clinical domains. Of 47 participants enrolled (mean age = 73.8 years; 43% female), 1 dropped out before treatment initiation and 6 before completion, including 2 in the nicotinamide and 4 in the placebo arm. Adverse events (AEs) were balanced by arm, with few attributed to treatment. Common AEs included infections and nervous system disorders. There was no statistically significant benefit of nicotinamide on the primary outcome of week 48 change from baseline in CSF p-tau231 (analysis of covariance; estimated mean difference in change between arms = -2.06, SE = 4.03; p = 0.61), with observed mean decline in CSF p-tau231 greater in the nicotinamide arm (-4.7 ± 14.5) than in the placebo arm (-2.3 ± 10.6). No significant effects of treatment were observed on secondary biomarker outcomes (CSF p-tau181, Aβ40, Aβ42, and total tau) in similar models (all p values >0.05), with observed mean changes in CSF p-tau181 (0.4 ± 29.8 vs 10.4 ± 41.8) and total tau (8.4 ± 228.6 vs 60.5 ± 237.5) favoring nicotinamide compared with placebo. At week 48, nicotinamide-treated participants experienced less decline on CDR-SB (mixed-effect model with repeated measures; estimate = -1.42, SE = 0.65; p = 0.03 unadjusted for multiple comparisons), without significant differences in cognitive (ADAS-cog; estimate = -1.93, SE = 1.93; p = 0.32) or functional (ADCS-ADL-MCI; estimate = -3.10, SE = 1.86; p = 0.10) outcomes. Nicotinamide was safe but did not alter AD biomarkers. This study provides Class I evidence that in patients with MCI or mild dementia with positive CSF AD biomarkers, 48 weeks of nicotinamide, 3,000 mg daily, is no better than placebo in reducing CSF p-tau231. ClinicalTrials.gov: NCT03061474.

Dispersion-based cognitive intra-individual variability in former American football players: Association with traumatic encephalopathy syndrome, repetitive head impacts, and biomarkers

Background: Exposure to repetitive head impacts (RHI), such as those experienced in American football, is linked to cognitive dysfunction later in life. Traumatic encephalopathy syndrome (TES) is a proposed clinical syndrome thought to be linked to neuropath­ology of chronic traumatic encephalopathy (CTE), a condition associated with RHI from football. Cognitive intra-individual variability (d-CIIV) measures test-score dispersion, indicating cognitive dysfunction. This study examined d-CIIV in former football players and its associations with TES diagnosis, RHI exposure, and DTI and CSF biomarkers. Methods: Data included 237 males (45–74 years) from DIAGNOSE CTE Research Project, including former professional and college football players (COL) (n = 173) and asymptomatic men without RHI or TBI (n = 55). Participants completed neuropsychological tests. TES diagnosis was based on 2021 NINDS TES criteria. Years of football play and a cumulative head impact index (CHII) measured RHI exposure. Lumipulse technology was used for CSF assays. DTI fractional anisotropy assessed white matter integrity. Coefficient of variation (CoV) measured d-CIIV. ANCOVA compared d-CIIV among groups (football versus control; TES-status). Pearson correlations and linear regressions tested associations between d-CIIV, RHI exposure, and CSF and DTI biomarkers. Results: Former professional players had higher d-CIIV than controls (F(7, 194) = 2.87, p = .007). d-CIIV was associated with TES diagnosis (F(8, 146) = 9.063, p < .001), with highest d-CIIV in TES Possible/Probable-CTE. Higher d-CIIV correlated with higher CHII scores (r = 0.19), reduced CSF Aβ1–42 (β = −0.302), increased p-tau181 (β = 0.374), and reduced DTI FA (β = −0.202). Conclusion: d-CIIV is linked to RHI exposure and TES diagnosis in former football players, with associated changes in CSF biomarkers and white matter integrity.

Increased cerebrospinal fluid and plasma apoE glycosylation is associated with reduced levels of Alzheimer's disease biomarkers.

The apolipoprotein E ( APOE ) ε4 allele is the strongest genetic risk factor for Alzheimer's disease (AD). ApoE is glycosylated with an O-linked Core-1 sialylated glycan at several sites, yet the impact and function of this glycosylation on AD biomarkers remains unclear. We examined apoE glycosylation in a cohort of cerebrospinal fluid (CSF, n=181) and plasma (n= 178) samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) stratified into 4 groups: cognitively normal (CN), Mild Cognitive Impairment (MCI), progressors and non-progressors based on delayed word recall performance over 4 years. We observed decreasing glycosylation from apoE2 > apoE3 > apoE4 in CSF, and in plasma (apoE3 > apoE4). ApoE glycosylation was reduced in the MCI compared with CN groups, and in progressors compared to non-progressors. In CSF, higher apoE glycosylation associated cross-sectionally with lower total tau (t-tau), p-tau181, and with higher Aβ 1-42 . Similar associations of apoE glycosylation with higher Aβ 1-42 were observed in plasma. In CSF, greater apoE4 glycosylation was associated with lower t-tau and p-tau181. Over a 6-year period, higher baseline levels of CSF apoE glycosylation predicted lower rates of increase in CSF t-tau and p-tau181 and lower rates of decrease in CSF Aβ 1-42 . These results indicate strong associations of apoE glycosylation with biomarkers of AD pathology independent of apoE genotype, warranting a deeper understanding of the functional role of apoE glycosylation on AD tau pathology.

Role of sleep and neurochemical biomarkers in synaptic plasticity related to neurological and psychiatric disorders: Ascoping review.

Sleep is vital for maintaining physical and mental well-being, impacting cognitive functions like memory and learning through neuroplasticity. Sleep disturbances prevalent in neurological and psychiatric disorders exacerbate cognitive decline, imposing societal burdens. Exploring the relationship between sleep and neuroplasticity elucidates the mechanisms influencing cognition, particularly amidst the prevalent sleep disturbances in these clinical populations. While existing reviews provide valuable insights, gaps remain in understanding the neurophysiological mechanisms underlying sleep and cognitive function. This scoping review aims to investigate the characteristic patterns of sleep parameters and neurochemical biomarkers in reflecting neuroplasticity changes related to neurological and psychiatric disorders and to explore how these markers interact and influence cognition at the molecular level. Studies involving adults and older adults were included, excluding animal models and the paediatric population. Selected studies explored the relationship between sleep parameter or neurochemical biomarker changes and cognitive impairment, reflecting underlying neuroplasticity changes. Peer-reviewed articles, clinical trials, theses, and dissertations in English were included while excluding secondary research and non-peer-reviewed sources. A three-step search strategy was executed following the updated Joanna Briggs Institute methodology for scoping reviews. Published studies were retrieved from nine databases, grey literature, expert recommendations, and hand-searching of the included studies' bibliography. A basic qualitative content synthesis of 34 studies was conducted per JBI's scoping review guidance. Slow-wave and Rapid-Eye Movement sleep, sleep spindles, sleep cycle disruption, K-Complex(KC) density, Hippocampal sEEG, BDNF, IL-6, iNOS mRNA expression, plasma serotonin, CSF Aβ-42, t-tau and p-tau proteins, and serum cortisol revealed associations with cognitive dysfunction. Examining the relationship between sleep parameters, neurochemical biomarkers, and cognitive function reveals neuronal mechanisms that guide potential therapeutic interventions and enhance quality patient care.

Lumipulse-Measured Cerebrospinal Fluid Biomarkers for the Early Detection of Alzheimer Disease.

CSF biomarkers of Aβ42 and phosphorylated tau (p-tau181) are used clinically for the detection of Alzheimer disease (AD) pathology during life. CSF biomarker validation studies have largely used clinical diagnoses and/or amyloid PET imaging as the reference standard. The few existing CSF-to-autopsy studies have been restricted to late-stage AD. This CSF-to-autopsy study investigated associations between CSF biomarkers of AD and AD neuropathologic changes among brain donors who had normal cognition at the time of lumbar puncture (LP). This was a retrospective study of brain donors from the National Alzheimer's Coordinating Center who had normal cognition at the time of LP and who had measurements of CSF Aβ42 and p-tau181 performed with Lumipulse assays. All brain donors were from Washington University Knight ADRC. Staging of AD neuropathologic change (ADNC) was made based on National Institute on Aging-Alzheimer's Association criteria. For this study, participants were divided into 2 categories: "AD-" (no AD/low ADNC) and "AD+" (intermediate/high ADNC). Accuracy of each biomarker for discriminating AD status was evaluated using area under the curve (AUC) statistics generated using predicted probabilities from binary logistic regressions that controlled for age, sex, APOE ε4, and interval between LP and death. The average age at LP was 79.3 years (SD = 5.6), and the average age at death was 87.1 years (SD = 6.5). Of the 49 brain donors, 24 (49%) were male and 47 (95.9%) were White. 20 (40.8%) had autopsy-confirmed AD. The average interval from LP until death was 7.76 years (SD = 4.31). CSF p-tau181/Aβ42 was the optimal predictor of AD, having excellent discrimination accuracy (AUC = 0.97, 95% CI 0.94-1.00, p = 0.003). CSF p-tau181 alone had the second-best discrimination accuracy (AUC = 0.92, 95% CI 0.84-1.00, p = 0.001), followed by CSF Aβ42 alone (AUC = 0.92, 95% CI 0.85-1.00, p = 0.007), while CSF t-tau had the numerically lowest discrimination accuracy (AUC = 0.87, 95% CI 0.76-0.97, p = 0.005). Effects remained after controlling for prevalent comorbid neuropathologies. CSF p-tau181/Aβ42 was strongly associated with CERAD ratings of neuritic amyloid plaque scores and Braak staging of NFTs. This study supports Lumipulse-measured CSF Aβ42 and p-tau181 and, particularly, the ratio of p-tau181 to Aβ42, for the early detection of AD pathophysiologic processes. This study provides Class II evidence that Lumipulse measures of p-tau181/Aβ42 in the CSF accurately discriminated cognitively normal participants with and without Alzheimer disease neuropathologic change.

Amyloid-Related Imaging Abnormalities (ARIA) in Clinical Trials of Gantenerumab in Early Alzheimer Disease

Data from 2 phase 3 studies of gantenerumab, GRADUATE I/II, and their open-label extensions represent a resource to further characterize amyloid-related imaging abnormalities (ARIA), including long-term sequelae. To describe the characteristics of ARIA and risk factors and clinical consequences of ARIA-edema (ARIA-E). Secondary data collection from the GRADUATE I/II phase 3 randomized, double-blind, placebo-controlled, 116-week parallel-group studies and their open-label extensions, including PostGraduate, with up to 210 (mean, 125) weeks of total gantenerumab treatment were conducted between 2018 and 2023. The study included multicenter trials at 288 sites across 30 countries. GRADUATE I/II enrolled 985 and 980 participants, respectively, with early symptomatic Alzheimer disease (AD) and amyloid-beta (Aβ) pathology who were aged 50 to 90 years. PostGraduate enrolled 1382 participants (671 previously randomized to gantenerumab). Data were analyzed from November 2, 2022, to October 10, 2023. GRADUATE I/II participants were randomized 1:1 to gantenerumab or placebo. Nine-month uptitration was used to mitigate ARIA risk. Postbaseline safety monitoring, including brain magnetic resonance imaging (MRI) findings, and adverse events and cognitive assessments. The safety-evaluable MRI population of GRADUATE I/II comprised 1939 participants (mean age, 71.7 years; 1105 female [57.0%]). Severity of AD-related Aβ neuropathology (lower cerebrospinal fluid [CSF] Aβ42, hazard ratio [HR] for CSF Aβ42: 0.4; 95% CI, 0.2-0.7) and comorbid cerebrovascular pathology (Fazekas score: HR, 1.6; 95% CI, 1.3-2.0; total superficial siderosis count: HR, 1.9; 95% CI, 1.3-2.6; total microhemorrhage count: HR, 1.3; 95% CI, 1.0-1.5) may be important baseline risk factors for ARIA-E, in addition to apolipoprotein E (APOE) ε4 status (APOE ε4 heterozygous carrier: HR, 2.0; 95% CI, 1.4-2.8 and APOE ε4 homozygous carrier: HR, 4.7; 95% CI, 3.2-6.7). At the group level, ARIA-E did not impact long-term cognitive and functional performance (relative difference in adjusted means for Clinical Dementia Rating-Sum of Boxes was -9% in pooled GRADUATE analysis at week 116 and when censored at first ARIA-E). While taking gantenerumab, ARIA-E and ARIA-hemosiderin occurred in 24.9% (247 of 993) and 22.9% (227 of 993) participants, respectively; first ARIA-E occurred by week 64 in 86.2% (213 of 247) of participants with ARIA-E. Narratives are provided for all serious symptomatic ARIA-E cases. These results show that in addition to APOE ε4 allele count, severity of Aβ neuropathology and comorbid cerebrovascular pathology may be relevant for clinicians prescribing anti-Aβ monoclonal antibodies for early AD and developing individualized safety monitoring plans. Evaluation of these risk factors in other anti-Aβ monoclonal antibodies is recommended. ClinicalTrials.gov Identifiers: NCT03444870, NCT03443973, NCT04374253.

Alzheimer's Disease : Current Landscape and Future Directions

Introduction: Alzheimer's disease (AD) is the most prevalent form of dementia, constituting up to 72% of cases, and poses a significant financial burden on global healthcare. The aging population is expected to triple the cost of dementia to over $600 billion in the US alone by 2050. Dementia, a major cause of dependency and dysfunction, accounted for 11.4% of all reported deaths in Britain and Wales in 2022. Recent studies suggest a potential decline in dementia incidence, especially in males in Occident countries, possibly linked to better management of vascular risk. While 89% of dementia costs are attributed to high-income countries, middle and low-income nations face significant challenges in addressing the epidemiology of dementia. The prevalence of AD in developing nations is estimated at 3.4%, varying widely. Women exhibit a 1.17 times higher age-specific global prevalence compared to men, and their age-normalized death rate is also higher, suggesting factors beyond life expectancy contribute to their vulnerability. AD primarily affects individuals aged 75 or older, with 80% of cases in this age group. Acetylcholinesterase inhibitors are commonly used in all stages of dementia, though their efficacy in mild cognitive impairment and prodromal AD is uncertain. Distinguishing AD from depression symptoms can be challenging. The pathological features of AD involve neurofibrillary tangles (NFTs) and senile plaques, leading to neural and synaptic loss. Multiple mechanisms contribute to AD pathogenesis, including amyloid/tau toxicity and oxidative stress. Diagnosis : traditionally relies on clinical criteria, but biomarkers like CSF Aβ and tau proteins, as well as blood-based biomarkers, have shown promise in early detection. Noveltrearment: Promising treatment options include anti-amyloid monoclonal antibodies like aducanumab, lecanemab, and gantenerumab, with varying degrees of success in clinical trials. Donanemab, targeting a specific type of Aβ, has shown significant slowing of mental degradation in early-stage patients.

CSF and Plasma Biomarkers in Patients With Iatrogenic Cerebral Amyloid Angiopathy.

Recently, a subset of patients affected by cerebral amyloid angiopathy (CAA) distinguished by atypical juvenile onset and a hypothesized iatrogenic origin (iatrogenic CAA, iCAA) has emerged. β-Amyloid (Aβ) accumulation evidenced by amyloid PET positivity or CSF Aβ decrease was included in the iCAA diagnostic criteria. Conversely, diagnostic criteria for sporadic CAA (sCAA) do not involve biomarker analysis. The aim of this study was to assess CSF and plasma levels of Aβ and tau in iCAA and sCAA cohorts. Patients affected by probable or possible CAA according to established criteria (Boston 2.0) were prospectively recruited at Fondazione IRCCS Carlo Besta and San Gerardo dei Tintori from May 2021 to January 2024. Patients with probable and possible iCAA or sCAA with available plasma and/or CSF samples were included. Clinical and neurologic data were collected, and levels of Aβ40, Aβ42, total tau, and phospho-tau (p-tau) were assessed in CSF and plasma by SiMoA and Lumipulse. 21 patients with iCAA (72% male, mean age at symptom onset 50 years [36-74]) and 32 patients with sCAA (44% male, mean age at symptom onset 68 years [52-80]) were identified. Cognitive impairment and cardiovascular risk factors in the sCAA cohort were more common compared with the iCAA cohort. Patients with sCAA and iCAA showed similar CSF levels for Aβ40 (p = 0.5 [sCAA, 95% CI 2,604-4,228; iCAA, 95% CI 1,958-3,736]), Aβ42 (p = 0.7 [sCAA, 95% CI 88-157; iCAA, 95% CI 83-155]), and total tau (p = 0.08 [sCAA, 95% CI 80-134; iCAA, 95% CI 37-99]). Plasma levels of Aβ40 (p = 0.08, 95% CI 181-222), Aβ42 (p = 0.3, 95% CI 6-8), and total tau (p = 0.4, 95% CI 3-6) were not statistically different in patients with sCAA compared with iCAA ones (Aβ40, 95% CI 153-193; Aβ42, 95% CI 6-7 and total tau, 95% CI 2-4). Despite presenting with a younger age at onset, fewer cardiovascular risk factors, and lower cognitive impairment, patients with iCAA demonstrated Aβ and tau levels comparable with elderly patients with sCAA, supporting a common molecular paradigm between the 2 CAA forms.

Association of Vascular Risk Factors and Cerebrovascular Pathology With Alzheimer Disease Pathologic Changes in Individuals Without Dementia.

Vascular risk factors (VRFs) and cerebral small vessel disease (cSVD) are common in patients with Alzheimer disease (AD). It remains unclear whether this coexistence reflects shared risk factors or a mechanistic relationship and whether vascular and amyloid pathologies have independent or synergistic influence on subsequent AD pathophysiology in preclinical stages. We investigated links between VRFs, cSVD, and amyloid levels (Aβ1-42) and their combined effect on downstream AD biomarkers, that is, CSF hyperphosphorylated tau (P-tau181), atrophy, and cognition. This retrospective study included nondemented participants (Clinical Dementia Rating < 1) from the European Prevention of Alzheimer's Dementia (EPAD) cohort and assessed VRFs with the Framingham risk score (FRS) and cSVD features on MRI using visual scales and white matter hyperintensity volumes. After preliminary linear analysis, we used structural equation modeling (SEM) to create a "cSVD severity" latent variable and assess the direct and indirect effects of FRS and cSVD severity on Aβ1-42, P-tau181, gray matter volume (baseline and longitudinal), and cognitive performance (baseline and longitudinal). A total cohort of 1,592 participants were evaluated (mean age = 65.5 ± 7.4 years; 56.16% F). We observed positive associations between FRS and all cSVD features (all p < 0.05) and a negative association between FRS and Aβ1-42 (β = -0.04 ± 0.01). All cSVD features were negatively associated with CSF Aβ1-42 (all p < 0.05). Using SEM, the cSVD severity fully mediated the association between FRS and CSF Aβ1-42 (indirect effect: β = -0.03 ± 0.01), also when omitting vascular amyloid-related markers. We observed a significant indirect effect of cSVD severity on P-tau181 (indirect effect: β = 0.12 ± 0.03), baseline and longitudinal gray matter volume (indirect effect: β = -0.10 ± 0.03; β = -0.12 ± 0.05), and baseline cognitive performance (indirect effect: β = -0.16 ± 0.03) through CSF Aβ1-42. In a large nondemented population, our findings suggest that cSVD is a mediator of the relationship between VRFs and CSF Aβ1-42 and affects downstream neurodegeneration and cognitive impairment. We provide evidence of VRFs indirectly affecting the pathogenesis of AD, highlighting the importance of considering cSVD burden in memory clinics for AD risk evaluation and as an early window for intervention. These results stress the role of VRFs and cerebrovascular pathology as key biomarkers for accurate design of anti-amyloid clinical trials and offer new perspectives for patient stratification.

Core CSF Biomarker Profile in Cerebral Amyloid Angiopathy: Updated Meta-Analysis.

There is a clear need to characterize and validate molecular biomarkers of cerebral amyloid angiopathy (CAA), in an effort to improve diagnostics, especially in the context of patients with Alzheimer disease (AD) receiving immunotherapies (for whom underlying CAA is the driver of amyloid-related imaging abnormalities). We performed an updated meta-analysis of 5 core CSF biomarkers (Aβ42, Aβ40, Aβ438, total tau [T-tau], and phosphorylated tau [P-tau]) to assess which of these are most altered in sporadic CAA. We systematically searched PubMed for eligible studies reporting data on CSF biomarkers reflecting APP metabolism (Aβ42, Aβ40, Aβ38), neurodegeneration (T-tau), and tangle pathology (P-tau), in symptomatic sporadic CAA cohorts (based on the Boston criteria) vs control groups and/or vs patients with AD. Biomarker performance was assessed in random-effects meta-analysis based on ratio of mean (RoM) biomarker concentrations in (1) patients with CAA to controls and (2) CAA to patients with AD. RoM >1 indicates higher biomarker concentration in CAA vs comparison population, and RoM <1 indicates higher concentration in comparison groups. 8 studies met inclusion criteria: a total of 11 CAA cohorts (n = 289), 9 control cohorts (n = 310), and 8 AD cohorts (n = 339). Overall included studies were of medium quality based on our assessment tools. CAA to controls had lower mean level of all amyloid markers with CSF Aβ42, Aβ40, and Aβ38 RoMs of 0.46 (95% CI 0.38-0.55, p < 0.0001), 0.70 (95% CI 0.63-0.78, p < 0.0001), and 0.71 (95% CI 0.56-0.89, p = 0.003), respectively. CSF T-tau and P-tau RoMs of patients with CAA to controls were both greater than 1: 1.56 (95% CI 1.32-1.84, p < 0.0001) and 1.31 (95% CI 1.13-1.51, p < 0.0001), respectively. Differentiation between CAA and AD was strong for CSF Aβ40 (RoM 0.76, 95% CI 0.69-0.83, p < 0.0001) and Aβ38 (RoM 0.55, 95% CI 0.38-0.81, p < 0.0001), but not Aβ42 (RoM 1.00; 95% CI 0.81-1.23, p = 0.970). For T-tau and P-tau, average CSF ratios in patients with CAA vs AD were 0.64 (95% CI 0.58-0.71, p < 0.0001) and 0.64 (95% CI 0.58-0.71, p < 0.0001), respectively. Specific CSF patterns of Aβ42, Aβ40, Aβ38, T-tau, and P-tau might serve as molecular biomarkers of CAA, in research and clinical settings, offering the potential to improve the clinical diagnostic approach pathway in specific scenarios.

Clarifying the association of CSF Aβ, tau, BACE1, and neurogranin with AT(N) stages in Alzheimer disease.

Current AT(N) stratification for Alzheimer's disease (AD) accounts for complex combinations of amyloid (A), tau proteinopathy (T) and neurodegeneration (N) signatures. Understanding the transition between these different stages is a major challenge, especially in view of the recent development of disease modifying therapy. This is an observational study, CSF levels of Tau, pTau181, pTau217, Aβ38/40/42, sAPPα/β, BACE1 and neurogranin were measured in the BALTAZAR cohort of cognitively impaired patients and in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Biomarkers levels were related to the AT(N) framework. (A) and (T) were defined in BALTAZAR with CSF Aβ42/40 ratio and pTau217 respectively, and in ADNI with amyloid and tau PET. (N) was defined using total CSF tau in both cohorts. As expected, CSF Aβ42 decreased progressively with the AD continuum going from the A-T-N- to the A + T + N + profile. On the other hand, Tau and pTau181 increased progressively with the disease. The final transition from A + T + N- to A + T + N + led to a sharp increase in Aβ38, Aβ42 and sAPP levels. Synaptic CSF biomarkers BACE1 and neurogranin, were lowest in the initial A + T-N- stage and increased with T + and N + . CSF pTau181 and total tau were closely related in both cohorts. The early transition to an A + phenotype (A + T-N-) primarily impacts synaptic function. The appearance of T + and then N + is associated with a significant and progressive increase in pathological Alzheimer's disease biomarkers. Our main finding is that CSF pTau181 is an indicator of N + rather than T + , and that N + is associated with elevated levels of BACE1 protein and beta-amyloid peptides. This increase may potentially fuel the amyloid cascade in a positive feedback loop. Overall, our data provide further insights into understanding the interconnected pathological processes of amyloid, tau, and neurodegeneration underlying Alzheimer's disease.

Increases in amyloid-β42 slow cognitive and clinical decline in Alzheimer's disease trials.

Positive effects of new anti-amyloid-β (Aβ) monoclonal antibodies in Alzheimer's disease (AD) have been attributed to brain amyloid reduction. However, most anti-Aβ antibodies also increase the CSF levels of the 42-amino acid isoform (Aβ42). We evaluated the associations of changes in CSF Aβ42 and brain Aβ-PET with cognitive and clinical end points in randomized trials of anti-Aβ drugs that lowered (β- and γ-secretase inhibitors) or increased CSF Aβ42 levels (anti-Aβ monoclonal antibodies) to test the hypothesis that post-treatment increases in CSF Aβ42 levels are independently associated with cognitive and clinical outcomes. From long-term (≥12 months) randomized placebo-controlled clinical trials of anti-Aβ drugs published until November 2023, we calculated the post-treatment versus baseline difference in ADAS-Cog (cognitive subscale of the Alzheimer's Disease Assessment Scale) and CDR-SB (Clinical Dementia Rate-Sum of Boxes) and z-standardized changes in CSF Aβ42 and Aβ-PET Centiloids (CL). We estimated the effect size [regression coefficients (RCs) and confidence intervals (CIs)] and the heterogeneity (I2) of the associations between AD biomarkers and cognitive and clinical end points using random-effects meta-regression models. We included 25 966 subjects with AD from 24 trials. In random-effects analysis, increases in CSF Aβ42 were associated with slower decline in ADAS-Cog (RC: -0.55; 95% CI: -0.89, -0.21, P = 0.003, I2 = 61.4%) and CDR-SB (RC: -0.16; 95% CI: -0.26, -0.06, P = 0.002, I2 = 34.5%). Similarly, decreases in Aβ-PET were associated with slower decline in ADAS-Cog (RC: 0.69; 95% CI: 0.48, 0.89, P < 0.001, I2 = 0%) and CDR-SB (RC: 0.26; 95% CI: 0.18, 0.33, P < 0.001, I2 = 0%). Sensitivity analyses yielded similar results. Higher CSF Aβ42 levels after exposure to anti-Aβ drugs are independently associated with slowing cognitive impairment and clinical decline. Increases in Aβ42 may represent a mechanism of potential benefit of anti-Aβ monoclonal antibodies in AD.

Plasma P-tau217 Demonstrates Excellent Diagnostic and Prognostic Performance as a Blood-Based Biomarker for Alzheimer Disease in Older Adults

Abstract Background There has been unprecedented progress in the development of blood-based biomarkers (BBMs such as p-tau217 to detect Alzheimer Disease (AD) pathology – characterised by the accumulation of Amyloid-Beta (Aβ) and hyper-phosphorylated tau (T). However, BBM performance in “real-world” memory clinic contexts remains unclear. Methods Using high-sensitivity immunoassays, plasma p-tau217 was assessed in 554 participants. Two cohorts were studied: (i) a memory clinic validation cohort of 108 older adults (69 ± 6.5 years; 54.6% female) with early cognitive symptoms and paired plasma/cerebrospinal fluid (CSF) at time of diagnostic Lumbar Puncture (LP) and (ii) a broader replication cohort of 446 individuals ranging from cognitively-unimpaired middle-aged adults to older adults with established AD with 18-month follow-up. Plasma P-tau217 performance was examined against clinically established CSF Aβ+/T+ cut-offs using Area-Under the Curve (AUC) analysis. Plasma cut-offs were optimised vs CSF based on maximal Youden index. Results In the memory clinic cohort, plasma p-tau217 exhibited excellent performance for the detection of Aβ pathology (AUC: 0.91, 0.86-0.97). Plasma p-tau217 was nearly 4-fold higher in Aβ+ (13.89; 7.36-19.0pg/mL) vs Aβ- (3.72; 2.80-4.09pg/mL, U = 230, p&amp;lt;0.001) participants. Plasma p-tau217 was superior in the identification of Aβ vs T pathology (p&amp;lt;0.05, DeLong Test) and outperformed p-tau181 and other BBMs(all p&amp;lt;0.05, DeLong Test). In the replication cohort, plasma p-tau217 maintained &amp;gt;90% accuracy for clinical AD and was significantly associated with clinically meaningful cognitive decline over 18 months (Odds Ratio 1.40; 1.06-1.85, p=0.02). In the initial memory clinic cohort, application of plasma p-tau217 as a diagnostic test would have reduced the need for LPs by over half (56.5%). Conclusion Plasma p-217 demonstrates excellent diagnostic and prognostic performance in older adults with AD, representing an amyloid-responsive measure which also predicts meaningful cognitive decline in established AD. Incorporation of plasma p-tau217 in memory clinic settings may substantially reduce the need for over half of diagnostic LPs.

APOE contributes to longitudinal impulse control disorders progression in Parkinson’s disease

BackgroundImpulse control disorders (ICDs) are an increasingly recognized complication in Parkinson disease (PD). The pathogenesis of ICDs is currently unclear. Few genetic studies have been conducted in this area.ObjectiveWe aimed to ascertain the correlation between APOE and ICDs, and identify clinical predictors of ICDs in PD.MethodsThis study included 287 PD patients from the Parkinson’s Progression Markers Initiative. They were followed up to investigate the progression of ICDs over a period of 5 years. The cumulative incidence of ICDs and potential risk factors were evaluated using Kaplan-Meier and Cox regression analyses.Results44.3% (31/70) patients with APOE ɛ4 and 32.3% (70/217) patients without APOE ɛ4 developed ICDs during the five-year follow up period. There were significant differences between the PD with and without ICDs development group in age, MSEADLG score, ESS score, GDS score, and STAI score at baseline. In multivariable Cox regression analysis, APOE ε4 (HR = 1.450, p = 0.048) and STAI score (HR = 1.017, p = 0.001) were predictors of the development of ICDs. Patients with APOE ɛ4 group showed significantly lower CSF Aβ42 and CSF α-syn level than patients without APOE ɛ4 group at baseline. In patients with APOE ɛ4 group, the “low α-syn level” group and the “low ptau/tau ratio” group had a significantly higher incidence of ICDs, respectively.ConclusionsThis study provides important insights into the potential role of the APOE gene in the development of ICDs in PD. Further studies are needed to confirm our findings and to investigate the underlying mechanisms in more detail.

Impact of excessive daytime sleepiness on the progression of freezing of gait in de novo Parkinson’s disease: a cohort study

BackgroundExcessive daytime sleepiness (EDS) and freezing of gait (FOG) are prevalent non-motor and motor symptoms in patients with Parkinson’s disease (PD), significantly impacting their quality of life. However, the correlation between EDS and FOG progression in de novo PD patients remains controversial.MethodsA total of 328 participants from the Parkinson’s Progression Markers Initiative (PPMI) were divided into two groups: 43 with EDS (EDS group) and 285 without EDS (nEDS group). The cumulative incidence of FOG was assessed at the 5-year follow-up using Kaplan–Meier and log-rank tests. Multivariate Cox proportional hazards models were used to assess the impact of EDS on FOG progression in PD patients, with validation for robustness through sensitivity and subgroup analyses.ResultsThe EDS group experienced a higher incidence of FOG throughout the 5-year follow-up than did the nEDS group. Multivariate Cox proportional hazards models showed significantly association between EDS severity and enhanced risk of developing FOG (HR = 1.076, 95% CI:1.007 ~ 1.149, P = 0.031). For sensitivity analysis, parallel analyses were performed by substituting the independent variable with categorical variables, which yielded analogous outcomes (HR = 1.837, 95% CI:1.063 ~ 3.174, P = 0.029). Furthermore, subgroup analyses based on sex, age, TD/PIGD classification, depressive symptoms, cognitive impairment, mean caudate nucleus uptake level, mean putamen nucleus uptake level and CSF Aβ-42 level revealed no significant interactions between subgroups (all P values for interaction were > 0.05).ConclusionEDS is a potential prognosis factor for the progression of FOG in patients with PD.

CSF α-Synuclein Seed Amplification Assay in Patients With Atypical Parkinsonian Disorders.

There is no disease-modifying treatment of corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), 2 disorders characterized by their striking phenotypic, and, in CBS, pathologic heterogeneity. Seed amplification assays (SAAs) could enable the detection of neuropathologic processes, such as α-synuclein (αSyn) copathology, that affect the success of future disease-modifying treatment strategies. The primary objective was to assess possible αSyn copathology in CBS and PSP, as detected in CSF using an αSyn SAA (αSyn-SAA). Secondary objectives were to evaluate the association of αSyn-SAA positivity with other biomarkers including of Alzheimer disease (AD), and with clinical presentation. We hypothesized that αSyn-SAA positivity would be detectable in CBS and PSP and that it would be associated with AD biomarker positivity and β-amyloid (Aβ) 42 levels, neurodegeneration as assessed by neurofilament light chain (NfL) levels, and symptoms associated with synucleinopathies. This cross-sectional observational study included patients clinically diagnosed with CBS and PSP who underwent a lumbar puncture between 2012 and 2021 (Toronto Western Hospital, Canada). CSF was tested for αSyn-SAA positivity, AD biomarkers, and NfL levels. Clinical data were derived from medical records. We tested the CSF of 40 patients with CBS (19 female patients, 65.9 ± 8.6 years) and 28 with PSP (13 female patients, 72.5 ± 8.7 years old), mostly White (n = 50) or Asian (n = 14). αSyn-SAA positivity was observed in 35.9% patients with CBS and 28.6% with PSP. In young-onset, but not late-onset patients, αSyn-SAA positivity and AD positivity were associated (odds ratio [OR] 8.8, 95% CI 1.2-82.6, p < 0.05). A multivariable linear regression analysis showed a significant interaction of αSyn-SAA status by age at onset on CSF Aβ42 levels (β = 0.3 ± 0.1, p < 0.05). Indeed, age at onset was positively related to Aβ42 levels only in αSyn-SAA-positive patients, as shown by slope comparison. A logistic regression analysis also suggested that REM sleep behavior disorder was associated with αSyn-SAA positivity (OR 60.2, 95% CI 5.2-1,965.8; p < 0.01). We detected a frequency of αSyn-SAA positivity in CBS and PSP in line with pathologic studies, highlighting the usefulness of SAAs for in vivo detection of otherwise undetectable neuropathologic processes. Our results also suggest that AD status (specifically low Aβ42) and older age at onset may contribute to αSyn-SAA positivity. This opens new perspectives for the stratification of patients in clinical trials.

Predicting Cognitive Decline in Amyloid-Positive Patients With Mild Cognitive Impairment or Mild Dementia.

Cognitive decline rates in Alzheimer disease (AD) vary greatly. Disease-modifying treatments may alter cognitive decline trajectories, rendering their prediction increasingly relevant. We aimed to construct clinically applicable prediction models of cognitive decline in amyloid-positive patients with mild cognitive impairment (MCI) or mild dementia. From the Amsterdam Dementia Cohort, we selected amyloid-positive participants with MCI or mild dementia and at least 2 longitudinal Mini-Mental State Examination (MMSE) measurements. Amyloid positivity was based on CSF AD biomarker concentrations or amyloid PET. We used linear mixed modeling to predict MMSE over time, describing trajectories using a cubic time curve and interactions between linear time and the baseline predictors age, sex, baseline MMSE, APOE ε4 dose, CSF β-amyloid (Aβ) 1-42 and pTau, and MRI total brain and hippocampal volume. Backward selection was used to reduce model complexity. These models can predict MMSE over follow-up or the time to an MMSE value. MCI and mild dementia were modeled separately. Internal 5-fold cross-validation was performed to calculate the explained variance (R2). In total, 961 participants were included (age 65 ± 7 years, 49% female), 310 had MCI (MMSE 26 ± 2) and 651 had mild dementia (MMSE 22 ± 4), with 4 ± 2 measurements over 2 (interquartile range 1-4) years. Cognitive decline rates increased over time for both MCI and mild dementia (model comparisons linear vs squared vs cubic time fit; p < 0.05 favoring a cubic fit). For MCI, backward selection retained age, sex, and CSF Aβ1-42 and pTau concentrations as time-varying effects altering the MMSE trajectory. For mild dementia, retained time-varying effects were Aβ1-42, age, APOE ε4, and baseline MMSE. R2 was 0.15 for the MCI model and 0.26 for mild dementia in internal cross-validation. A hypothetical patient with MCI, baseline MMSE 28, and CSF Aβ1-42 of 925 pg/mL was predicted to reach an MMSE of 20 after 6.0 years (95% CI 5.4-6.7) and after 8.6 years with a hypothetical treatment reducing decline by 30%. We constructed models for MCI and mild dementia that predict MMSE over time. These models could inform patients about their potential cognitive trajectory and the remaining uncertainty and aid in conversations about individualized potential treatment effects.