Microglial Activation, Tau Pathology, and Neurodegeneration Biomarkers Predict Longitudinal Cognitive Decline in Alzheimer's Disease Continuum.

Inflammatory changes are among the key markers of Alzheimer's disease (AD) related pathological changes. Pro-inflammatory analytes have been related to cognitive decline while others have been related to attenuating neuronal death. Among them, changes in cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and soluble tumor necrosis factor receptor 2 (sTNFR2) have been described as impacting favorable clinical outcomes in AD. We therefore evaluate the effect of CSF sTREM2 and sTNFR2 when taken together on AD biomarkers and longitudinal clinical decline to understand their relative role on impacting AD clinical biomarkers and subsequent clinical outcomes. This longitudinal observational cohort study included 168 amyloid-positive (A+) and p-tau-positive (T+) participants with mild cognitive impairment (MCI) or AD dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with 109 of them having concomitant CSF sTREM2 and sTNFR2 data and 48 A+ T+ participants with MCI from a tertiary memory clinic cohort. An exploratory analysis was performed using data from 86 cognitively normal (CN) participants from ADNI with 72 of them having concomitant CSF AD biomarkers and CSF sTREM2 and sTNFR2 data. General linear models were used to evaluate the effect of sTREM2 and sTNFR2 levels on baseline CSF Aβ42, t-tau, and p-tau, and a linear mixed-effects model was used to assess longitudinal cognitive change after controlling for well-known covariates. Among ADNI A+ T+ MCI and AD dementia participants, CSF sTNFR2 had a stronger association, than CSF sTREM2, with CSF t-tau and p-tau. This was replicated among A+ T+ MCI participants from the memory clinic cohort. On the contrary, among A+ T+ CN participants, CSF sTREM2 explained significant variance in CSF t-tau and p-tau, while CSF sTNFR2 did not. When the effects of CSF sTNFR2 and t-tau on longitudinal cognitive change were taken into account, higher CSF sTREM2 predicted slower cognitive decline in A+ T+ AD dementia participants and faster decline in A+ T+ CN participants. Our results show that given the dynamic changes in sTREM2 and sTNFR2, the clinical impact of these distinct inflammation related biomarkers in tracking AD temporal progression across disease stages are likely to differ.

APOE differentially moderates cerebrospinal fluid and plasma phosphorylated tau181 associations with multi-domain cognition

There is an urgent need for inexpensive and minimally invasive blood biomarkers for Alzheimer disease (AD) that could be used to detect early disease changes. To assess how early in the course of AD plasma levels of tau phosphorylated at threonine 217 (P-tau217) start to change compared with levels of established cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of AD pathology. This cohort study included cognitively healthy control individuals (n = 225) and participants with subjective cognitive decline (n = 89) or mild cognitive impairment (n = 176) from the BioFINDER-2 study. Participants were enrolled at 2 different hospitals in Sweden from January 2017 to October 2019. All study participants underwent plasma P-tau217 assessments and tau- and amyloid-β (Aβ)-PET imaging. A subcohort of 111 participants had 2 or 3 tau-PET scans. Changes in plasma P-tau217 levels in preclinical and prodromal AD compared with changes in CSF P-tau217 and PET measures. Of 490 participants, 251 were women (51.2%) and the mean (SD) age was 65.9 (13.1) years. Plasma P-tau217 levels were increased in cognitively unimpaired participants with abnormal Aβ-PET but normal tau-PET in the entorhinal cortex (Aβ-PET+/ tau-PET- group vs Aβ-PET-/ tau-PET- group: median, 2.2 pg/mL [interquartile range (IQR), 1.5-2.9 pg/mL] vs 0.7 pg/mL [IQR, 0.3-1.4 pg/mL]). Most cognitively unimpaired participants who were discordant for plasma P-tau217 and tau-PET were positive for plasma P-tau217 and negative for tau-PET (P-tau217+/tau-PET-: 36 [94.7%]; P-tau217-/tau-PET+: 2 [5.3%]). Event-based modeling of cross-sectional data predicted that in cognitively unimpaired participants and in those with mild cognitive impairment, both plasma and CSF P-tau217 would change before the tau-PET signal in the entorhinal cortex, followed by more widespread cortical tau-PET changes. When testing the association with global Aβ load in nonlinear spline models, both plasma and CSF P-tau217 were increased at lower Aβ-PET values compared with tau-PET measures. Among participants with normal baseline tau-PET, the rates of longitudinal increase in tau-PET in the entorhinal cortex were higher in those with abnormal plasma P-tau217 at baseline (median standardized uptake value ratio, 0.029 [IQR, -0.006 to 0.041] vs -0.001 [IQR, -0.021 to 0.020]; Mann-Whitney U, P = .02). In this cohort study, plasma P-tau217 levels were increased during the early preclinical stages of AD when insoluble tau aggregates were not yet detectable by tau-PET. Plasma P-tau217 may hold promise as a biomarker for early AD brain pathology.

BackgroundTo assess the performance of plasma neurofilament light (NfL) and phosphorylated tau 181 (p-tau181) to inform about cerebral Alzheimer’s disease (AD) pathology and predict clinical progression in a memory clinic setting.MethodsPlasma NfL and p-tau181, along with established cerebrospinal fluid (CSF) biomarkers of AD pathology, were measured in participants with normal cognition (CN) and memory clinic patients with cognitive impairment (mild cognitive impairment and dementia, CI). Clinical and neuropsychological assessments were performed at inclusion and follow-up visits at 18 and 36 months. Multivariate analysis assessed associations of plasma NfL and p-tau181 levels with AD, single CSF biomarkers, hippocampal volume, and clinical measures of disease progression.ResultsPlasma NfL levels were higher in CN participants with an AD CSF profile (defined by a CSF p-tau181/Aβ1–42 > 0.0779) as compared with CN non-AD, while p-tau181 plasma levels were higher in CI patients with AD. Plasma NfL levels correlated with CSF tau and p-tau181 in CN, and with CSF tau in CI patients. Plasma p-tau181 correlated with CSF p-tau181 in CN and with CSF tau, p-tau181, Aβ1–42, and Aβ1–42/Aβ1–40 in CI participants. Compared with a reference model, adding plasma p-tau181 improved the prediction of AD in CI patients while adding NfL did not. Adding p-tau181, but not NfL levels, to a reference model improved prediction of cognitive decline in CI participants.ConclusionPlasma NfL indicates neurodegeneration while plasma p-tau181 levels can serve as a biomarker of cerebral AD pathology and cognitive decline. Their predictive performance depends on the presence of cognitive impairment.

<h3>Objective:</h3> To explore plasma phosphorylated tau (p-tau) 181 levels in Subjective Cognitive Decline and to investigate its role as a potential biomarker for Alzheimer’s Disease (AD) in Subjective Cognitive Decline (SCD). <h3>Background:</h3> One of the greatest challenges in AD is the discovery of new non-invasive, sensitive and specific biomarkers, which might be useful in the early stages such as SCD. Plasma p-tau181 is becoming increasingly notable in prodromal stages of AD, as a valuable marker for tauopathy, one of the core features of AD. <h3>Design/Methods:</h3> We included 27 SCD patients, who underwent clinical evaluation, neuropsychological assessment, Apolipoprotein E (APOE) genotyping, plasma p-tau181 analysis with SiMoA assay and cerebrospinal fluid (CSF) biomarkers analysis (Aβ1–42, Aβ1–42/1–40, p-tau, t-tau).Patients were rated according to A/T(N) system and classified as carrier of AD pathology (AP+) when A+ was associated with either T+ or N+, or non-carriers (AP−) when they were classified as A− (regardless of T and N classification), or A+/T−/N−. <h3>Results:</h3> Plasma p-tau181 levels were correlated with CSF p-tau (ϱ=0.819, <i>p</i>&lt;0.001) and also with age (ϱ=0.605, <i>p</i>=0.001), CSF Aβ1–42 (ϱ= −0.461, <i>p</i>=0.012), CSF Aβ1–42/1–40 (ϱ= −0.770, <i>p</i>&lt;0.001) and CSF t-tau (ϱ=0.535, <i>p</i>=0.009). A multivariate linear regression analysis showed that plasma p-tau181 were significantly associated only with CSF p-tau levels (<i>p</i>=0.027). When comparing AP+ and AP− subgroups, we found that plasma p-tau181 levels were significantly higher in the former group (2.85±0.53 vs 1.75±.66, <i>p</i>&lt;0.001). A ROC curve analysis demonstrated that plasma p-tau181 was highly accurate for discriminating between AP+ and AP− SCD patients (AUC = 0.908). <h3>Conclusions:</h3> Plasma p-tau181 levels strongly correlated with CSF p-tau. Plasma p-tau showed a high accuracy in differentiating SCD patients who were carriers from SCD patients who were non-carriers of AD pathology. Our preliminary results suggest that plasma p-tau181 might be a promising noninvasive biomarker of AD pathology which might be useful in preclinical stage of AD. <b>Disclosure:</b> Ms. Giacomucci has nothing to disclose. Mr. Mazzeo has nothing to disclose. Dr. Bagnoli has nothing to disclose. Dr. Ingannato has nothing to disclose. Sonia Padiglioni has nothing to disclose. Sandro Sorbi has nothing to disclose. Valentina Bessi has nothing to disclose. Benedetta Nacmias has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier.

IntroductionPre-analytical factors can cause substantial variability in the measurements of cerebrospinal fluid (CSF) and plasma biomarkers of Alzheimer’s disease (AD). However, their effects on the performance of one of the most promising plasma AD biomarkers, phosphorylated tau (p-tau)217, are not known.MethodsWe included 50 amyloid-β positive (Aβ+) and 50 Aβ− participants from the Swedish BioFINDER-1 study. Plasma and CSF p-tau217 were measured using an immunoassay developed by Lilly Research Laboratories. We examined the effect of four plasma handling conditions, i.e., (1) thawing at room temperature (RT) with no centrifugation, (2) thawing at RT followed by centrifugation, (3) thawing on ice with no centrifugation, and (4) thawing on ice followed by centrifugation. In addition, we also tested the effects of up to 3 freeze–thaw cycles on the associations of plasma p-tau217 with AD-related pathologies measured with CSF p-tau217 and CSF Aβ42/Aβ40.ResultsIn the whole cohort (combining Aβ+ and Aβ− participants), we found significant correlations between plasma p-tau217 and both CSF p-tau217 (Rrange, 0.614–0.717, p < 0.001) and CSF Aβ42/Aβ40 (Spearman Rrange, − 0.515 to − 0.652, p < 0.001) for each of the four tested conditions. Correlations between plasma and CSF p-tau217 were also significant for all conditions in the Aβ+ group (Rrange, 0.506–0.579, p < 0.001). However, in this Aβ+ subgroup, correlations with CSF Aβ42/Aβ40 were only significant for centrifuged samples (thawed at RT, R = − 0.394, p = 0.010; thawed on ice, R = − 0.406; p = 0.007). In Aβ− participants, correlations between plasma and CSF p-tau217 were again significant only for centrifuged samples (thawed at RT, R = 0.394, p = 0.007; thawed on ice, R = 0.334; p = 0.022), with no correlations seen between plasma p-tau217 and CSF Aβ42/Aβ40 for any of the conditions. While the accuracy of plasma p-tau217 to identify individuals with abnormal CSF Aβ42/Aβ40 or CSF p-tau217 status was high, the AUCs for samples thawed at RT and analyzed without centrifugation were numerically lower than the AUCs of other conditions (CSF Aβ42/Aβ40 = 0.845 vs 0.872–0.884; CSF p-tau217 = 0.866 vs 0.908–0.924, pdiff > 0.11). P-tau217 concentration was consistently higher in non-centrifuged samples than in centrifuged samples (p ≤ 0.021). There were no differences between samples freeze-thawed once, twice, or three times.ConclusionCentrifugation improved the performance of plasma p-tau217, but thawing temperatures and up to three freeze–thaw cycles did not have a significant impact. These results may inform the future development of standardized sample-handling protocols for AD biomarkers.

There are limitations in current diagnostic testing approaches for Alzheimer disease (AD). To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD. Three cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n = 301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n = 178), AD dementia (n = 121), and other neurodegenerative diseases (n = 99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017). Plasma P-tau217. Primary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography [PET]). Mean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve [AUC], 0.89 [95% CI, 0.81-0.97]) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72; P < .05). The discriminative accuracy of plasma P-tau217 in cohort 2 for clinical AD dementia vs other neurodegenerative diseases (AUC, 0.96 [95% CI, 0.93-0.98]) was significantly higher than plasma P-tau181, plasma NfL, and MRI measures (AUC range, 0.50-0.81; P < .001) but not significantly different compared with cerebrospinal fluid (CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P > .15). In cohort 3, plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman ρ = 0.64; P < .001), but not without (Spearman ρ = 0.15; P = .33), β-amyloid plaques in cohort 1. In cohort 2, plasma P-tau217 discriminated abnormal vs normal tau-PET scans (AUC, 0.93 [95% CI, 0.91-0.96]) with significantly higher accuracy than plasma P-tau181, plasma NfL, CSF P-tau181, CSF Aβ42:Aβ40 ratio, and MRI measures (AUC range, 0.67-0.90; P < .05), but its performance was not significantly different compared with CSF P-tau217 (AUC, 0.96; P = .22). Among 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures. Further research is needed to optimize the assay, validate the findings in unselected and diverse populations, and determine its potential role in clinical care.

Progressive medial temporal lobe atrophy during preclinical Alzheimer's disease.

Associations between cerebrospinal fluid biomarkers in individuals with normal cognitive function, mild cognitive impairment, or Alzheimer's disease by amyloid PET status: a cross-sectional survey

The aim of this study was to examine the relationship between cerebrospinal fluid (CSF) levels of biomarkers for Alzheimer's disease (AD) (Aβ1-42, t-tau, and p-tau) and 18Fluorodeoxyglucose positron emission tomography (FDG-PET) hypometabolism in subjects from the Alzheimer's Disease Neuroimaging Initiative, and specifically to determine which index of neurodegeneration was most frequently affected. The secondary objective was to determine the most frequently hypometabolic region in patients with a CSF AD signature (abnormal Aβ1-42 and abnormal p-tau). We included the 372 subjects (85 normal subjects, 212 patients with mild cognitive impairment, and 75 patients with AD) with a CSF biomarker dosage (Aβ1-42, t-tau, and p-tau) and brain FDG-PET. The relationship between FDG-PET metabolism (in five regions of interest (ROI) known to be damaged in AD) and CSF t-tau and p-tau levels was studied as a function of CSF Aβ1-42 status. FDG-PET hypometabolism and CSF t-tau and p-tau levels were correlated only in patients with an abnormal CSF Aβ1-42 level (t-tau: R2 = 0.044, p = 0.001; p-tau: R2 = 0.02, p = 0.03). In the latter patients, CSF p-tau was the most frequently (p = 0.0001) abnormal neurodegeneration marker (p-tau: 92.8%; FDG-PET: 56.5%; CSF t-tau: 59.1%). Within the five ROI of FDG PET, the angular gyrus metabolism (R2 = 0.149; p = 0.0001) was selected as the most tightly associated with CSF AD signature. The relation between CSF markers of neurodegeneration (p-tau and t-tau) and brain hypometabolism (in FDG-PET) is conditioned by presence of amyloid abnormality. This finding supports the current physiopathological model of AD. P-tau is the most frequently impaired biomarker. Using FDG PET angular gyrus hypometabolism is the most sensitive to CSF-biomarker-defined AD.

The strongest genetic risk factor for Alzheimer's disease (AD) is the Apolipoprotein E type 4 allele (ApoE ε4). The interaction between sex and ApoE ε4 carrier status on AD risk remains an area of intense investigation. We hypothesized that sex modulates the relationship between ApoE ε4 carrier status and brain tau deposition (a quantitative endophenotype in AD) in individuals with mild cognitive impairment (MCI).Methods: Preprocessed 18F-AV-1451 tau and 18F-AV-45 amyloid PET images, T1-weighted structural magnetic resonance imaging (MRI) scans, demographic information, and cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau (p-tau) measurements from 108 MCI subjects in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were included. After downloading pre-processed images from ADNI, an iterative reblurred Van Cittertiteration partial volume correction (PVC) method was applied to all PET images. MRIs were used for PET spatial normalization. Regions of interest (ROIs) were defined in standard space, and standardized uptake value ratio (SUVR) images relative to cerebellum were computed. ApoE ε4 by sex interaction analyses on 18F-AV-1451 and CSF tau (t-tau, p-tau) were assessed using generalized linear models. The association between 18F-AV-1451 SUVR and CSF tau (t-tau, p-tau) was assessed.Results: After applying PVC and controlling for age, education level and global cortical 18F-AV-45 SUVR, we found that the entorhinal cortex, amygdala, parahippocampal gyrus, posterior cingulate, and occipital ROIs exhibited a significant ApoE ε4 by sex interaction effect (false discovery rate P < 0.1) among MCI individuals. We also found a significant ApoE ε4 by sex interaction effect on CSF t-tau and p-tau. 18F-AV-1451 SUVR in the 5 ROIs with ApoE ε4 by sex interaction was significantly correlated with CSF p-tau and t-tau.Conclusions: Our findings suggest that women are more susceptible to ApoE ε4-associated accumulation of neurofibrillary tangles in MCI compared to males. Both CSF tau (p-tau, t-tau) and brain tau PET are robust quantitative biomarkers for studying ApoE ε4 by sex effects on brain tau deposition in MCI participants.

Rapidly progressive dementias (RPDs) are a group of neurological disorders characterized by a rapid cognitive decline. The diagnostic value of blood-based biomarkers for Alzheimer's disease (AD) in RPD has not been fully explored. We measured plasma brain-derived tau (BD-tau) and p-tau181 in 11 controls, 15 AD patients, and 33 with RPD, of which 19 were Creutzfeldt-Jakob disease (CJD). Plasma BD-tau differentiated AD from RPD and controls (p=0.002 and p=0.03, respectively), while plasma and cerebrospinal fluid (CSF) p-tau181 distinguished AD from RPD (p<0.001) but not controls from RPD (p>0.05). The correlation of CSF t-tau with plasma BD-tau was stronger (r=0.78, p<0.001) than the correlation of CSF and plasma p-tau181 (r=0.26, p=0.04). The ratio BD-tau/p-tau181 performed equivalently to the CSF t-tau/p-tau181 ratio, differentiating AD from CJD (p<0.0001). Plasma BD-tau and p-tau181 mimic their corresponding cerebrospinal fluid (CSF) markers. P-tau significantly increased in AD but not in RPD. Plasma BD-tau, like CSF t-tau, increases according to neurodegeneration intensity.

Our review summarizes the diagnostic accuracy of plasma and cerebrospinal fluid (CSF) phosphorylated tau 217 (p-tau217) in detecting amyloid and tau pathology on positron emission tomography (PET). We systematically reviewed studies that reported the diagnostic accuracy of plasma and CSF p-tau217, searching MEDLINE/PubMed, Scopus, and Web of Science through August 2024. The accuracy of p-tau217 in predicting amyloid and tau pathology on PET was evaluated in 30 studies. Both plasma and CSF p-tau217 effectively detect amyloid and tau PET deposition. Plasma p-tau217 showed 82% sensitivity for detecting amyloid and 83% for tau, with 86% and 83% specificity, respectively. CSF p-tau217 had 79% sensitivity for amyloid and 91% for tau, with 91% and 84% specificity. p-tau217 effectively identifies Alzheimer's disease (AD) pathology. Plasma p-tau217 was comparable to CSF p-tau217 in detecting amyloid deposition on PET. Despite being less sensitive for detecting tau deposition on PET, plasma p-tau217 can be an efficient screening tool for underlying AD pathology. HIGHLIGHTS: Plasma phosphorylated tau 217 (p-tau217) serves as a viable biomarker alternative to cerebrospinal fluid p-tau217 due to the strong concordance between their results. Plasma p-tau217 accurately identifies amyloid and tau positron emission tomography (PET) positivity, exhibiting a low rate of false negatives and positives, thereby establishing it as a reliable diagnostic tool for Alzheimer's disease (AD). Plasma p-tau217 demonstrates slightly higher accuracy in predicting amyloid PET positivity compared to tau PET positivity. Plasma p-tau217 demonstrates higher predictive accuracy in detecting AD pathology among cognitively impaired individuals, compared to cognitively unimpaired individuals, suggesting its enhanced utility as a diagnostic biomarker in clinical settings.

Although cerebrospinal fluid (CSF) amyloid-β42 peptide (Aβ42) and phosphorylated tau (p-tau) and blood p-tau are valuable for differential diagnosis of Alzheimer's disease (AD) from cognitively normal (CN) there is a lack of validated biomarkers for mild cognitive impairment (MCI). This study sought to determine how plasma and CSF protein markers compared in the characterization of MCI and AD status. This cohort study included Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who had baseline levels of 75 proteins measured commonly in plasma and CSF (257 total, 46 CN, 143 MCI, and 68 AD). Logistic regression, least absolute shrinkage and selection operator (LASSO) and Random Forest (RF) methods were used to identify the protein candidates for the disease classification. We observed that six plasma proteins panel (APOE, AMBP, C3, IL16, IGFBP2, APOD) outperformed the seven CSF proteins panel (VEGFA, HGF, PRL, FABP3, FGF4, CD40, RETN) as well as AD markers (CSF p-tau and Aβ42) to distinguish the MCI from AD [area under the curve (AUC) = 0.75 (plasma proteins), AUC = 0.60 (CSF proteins) and AUC = 0.56 (CSF p-tau and Aβ42)]. Also, these six plasma proteins performed better than the CSF proteins and were in line with CSF p-tau and Aβ42 in differentiating CN versus MCI subjects [AUC = 0.89 (plasma proteins), AUC = 0.85 (CSF proteins) and AUC = 0.89 (CSF p-tau and Aβ42)]. These results were adjusted for age, sex, education, and APOEϵ4 genotype. This study suggests that the combination of 6 plasma proteins can serve as an effective marker for differentiating MCI from AD and CN.

BackgroundIt has been proposed that amyloid-β (Aβ) deposition may trigger neurodegeneration and cognitive decline. The elevated levels of presynaptic growth-associated protein 43 (GAP-43) in cerebrospinal fluid (CSF) were significantly associated with Alzheimer’s disease (AD). To examine whether GAP-43 was associated with faster amyloid-associated neurodegeneration or cognitive decline, it was necessary to further explore whether Aβ deposition affected CSF GAP-43 through inflammation.MethodsA total of 671 participants from Alzheimer’s Disease Neuroimaging Initiative (ADNI) were enrolled with available baseline CSF GAP-43, microglia activation [measured by CSF soluble triggering receptor expressed on myeloid cells (sTREM2) and progranulin (PGRN)], neurodegeneration (measured by CSF t-tau), and Aβ pathology (measured by amyloid-PET). To compare CSF GAP-43 levels across different Aβ and clinical stages, the analysis of variance (ANOVA) and Bonferroni post hoc tests were conducted. Multiple linear regression models were used to explore the association of CSF GAP-43 with sTREM2, PGRN, amyloid-PET, p-tau, t-tau and cognitive measures at baseline. Moreover, mediation models with 10,000 bootstrapped iterations were performed to investigate whether CSF GAP-43 was related to accelerated amyloid-associated neurodegeneration, then further contribute to cognitive decline, and how Aβ deposition affected CSF GAP-43 leading to neurodegeneration.ResultsCompared with the amyloid− (A−) group, CSF GAP-43 was significantly higher at baseline in the amyloid+ (A+) group. When stratified by diagnosis, similar results were observed in A+ cognitively normal (CN) and A+ mild cognitive impairment (MCI), compared with A−CN or A−MCI participants. We found that baseline of CSF GAP-43 was positively related to CSF sTREM2, PGRN, amyloid-PET and t-tau, whereas it was negatively associated with cognition. Besides, CSF GAP-43 mediated the faster progression of amyloid-associated neurodegeneration and cognitive decline. Furthermore, the mediation analysis revealed that CSF sTREM2/PGRN was related to CSF t-tau mediated by CSF GAP-43 in the A+ group.ConclusionOur findings provided evidence that CSF GAP-43 was related to the accelerated amyloid-associated neurodegeneration, and further contributed to cognitive decline. We also demonstrated that Aβ deposition may act as a trigger for synaptic dysfunction by promoting inflammation.