Conformational change of α-synuclein fibrils in cerebrospinal fluid from different clinical phases of Parkinson's disease.

α-Synuclein (α-syn) has been shown to form various conformational fibrils associated with different synucleinopathies. But whether the conformation of α-syn fibrils changes during disease progression is unclear. Here, we amplified α-syn aggregates from the cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD) staged in preclinical PD (pre-PD), middle- to late-stage PD (mid-PD), and late-stage PD (late-PD). Our results show that α-syn fibrils derived from the late-PD patient are most potent in inducing endogenous α-syn aggregation in primary neurons, followed by the mid-PD and pre-PD fibrils. By using cryo-electron microscopy, we further determined the high-resolution structures of the CSF-amplified fibrils. The structures exhibit remarkable differences in a minor but significant population of conformational species in different staged samples. Our work demonstrates structural and pathological differences between α-syn fibrils derived from PD patients at a spectrum of clinical stages, which suggests potential conformational transition of α-syn fibrils during the progression of PD.

Network dysfunction in cognitively normal APOE ε4 carriers is related to subclinical tau.

INTRODUCTION: Apolipoprotein E (APOE) ε4 allele status is associated with amyloid and tau-related pathological changes related to Alzheimer's disease (AD). However, it is unknown whether brain network changes are related to amyloid beta (Aß) and/or tau-related pathology in cognitively normal APOE ε4 carriers with subthreshold Aß accumulation. METHODS: Resting state functional connectivity measures of network integrity were evaluated in cognitively normal individuals (n = 121, mean age 76.6 ± 7.8 years, 15% APOE ε4 carriers, 65% female) with minimal Aß per cerebrospinal fluid (CSF) or amyloid positron emission tomography. RESULTS: APOE ε4 carriers had increased lateralized connections relative to callosal connections within the default-mode, memory, and salience networks (P = .02), with significant weighting on linear regression toward CSF total tau (P = .03) and CSF phosphorylated tau at codon 181 (P = .03), but not CSF Aß42 . DISCUSSION: Cognitively normal APOE ε4 carriers with subthreshold amyloid accumulation may have network reorganization associated with tau.

Interaction of amyloid and tau on cortical microstructure in cognitively unimpaired adults.

INTRODUCTION: Neurite orientation dispersion and density imaging (NODDI), a multi-compartment diffusion-weighted imaging (DWI) model, may be useful for detecting early cortical microstructural alterations in Alzheimer's disease prior to cognitive impairment. METHODS: Using neuroimaging (NODDI and T1-weighted magnetic resonance imaging [MRI]) and cerebrospinal fluid (CSF) biomarker data (measured using Elecsys® CSF immunoassays) from 219 cognitively unimpaired participants, we tested the main and interactive effects of CSF amyloid beta (Aß)42 /Aß40 and phosphorylated tau (p-tau) on cortical NODDI metrics and cortical thickness, controlling for age, sex, and apolipoprotein E ε4. RESULTS: We observed a significant CSF Aß42 /Aß40 × p-tau interaction on cortical neurite density index (NDI), but not orientation dispersion index or cortical thickness. The directionality of these interactive effects indicated: (1) among individuals with lower CSF p-tau, greater amyloid burden was associated with higher cortical NDI; and (2) individuals with greater amyloid and p-tau burden had lower cortical NDI, consistent with cortical neurodegenerative changes. DISCUSSION: NDI is a particularly sensitive marker for early cortical changes that occur prior to gross atrophy or development of cognitive impairment.

The Diagnostic Value of a Short Memory Test: The TNI-93.

BACKGROUND: The TNI-93 is a quick memory test designed for all patients regardless of their education level. A significant proportion of patients with Alzheimer's disease (AD) are illiterate or poorly educated, and only a few memory tests are adapted for these patients. OBJECTIVE: In this study we aimed at assessing the diagnostic value of the TNI-93 for diagnosis of patients with biologically confirmed amyloid status. METHODS: We included all patients who had an analysis of AD cerebrospinal fluid biomarkers, a neuropsychological assessment including a TNI-93 and an anatomical brain imaging at Avicenne Hospital between January 2009 and November 2019. We compared the TNI-93 scores in patients with amyloid abnormalities (A+) and patients without amyloid abnormalities (A-) according to the AT(N) diagnostic criteria. RESULTS: 108 patients were included (mean age: 66.9±8.5 years old, mean education level: 8.9±5.2 years). Patients from the A + group (N= 80) were significantly more impaired than patients from the A- group (N= 28) on immediate recall (A+: 5.9±2.8; A-: 7.4±2.6; p = 0.001), free recall (A+: 3.5±2.7; A-: 5.9±2.8; p ≤ 0.001), total recall (A+: 5.7±3.5; A-:7.8±2.8; p ≤ 0.001), and on number of intrusions during the recall phase (A+: 1±1.8; A-: 0.1±0.3; p = 0.002). ROC curves revealed that the best scores to discriminate A + from A- patients were immediate recall (Area under curve (AUC): 0.70), number of encoding trials (AUC: 0.73), free recall (AUC: 0.74), and total recall (AUC: 0.74). CONCLUSION: The TNI-93's immediate, free, and total recalls are valuable tools for the 39 diagnosis of AD.

Association of Amyotrophic Lateral Sclerosis and Alzheimer's Disease: New Entity or Coincidence? A Case Series.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia have a strong clinical, genetic, and pathological connection but association of ALS with Alzheimer's disease (AD) is seldom reported. We report a series of 5 cases of AD associated with ALS. Our patients presented with cognitive deterioration with episodic memory impairment meeting criteria for AD. ALS occurred subsequently in all cases and its phenotype was not homogenous. Amyloid process was confirmed in four cases with cerebrospinal fluid biomarkers. One case underwent postmortem exam, demonstrating hallmarks lesions of both diseases. This series highlights that ALS-AD phenotype could be a specific underexplored entity.

Personalized prediction of progression in pre-dementia patients based on individual biomarker profile: A development and validation study.

INTRODUCTION: The prognosis of patients at the pre-dementia stage is difficult to define. The aim of this study is to develop and validate a biomarker-based continuous model for predicting the individual cognitive level at any future moment. In addition to personalized prognosis, such a model could reduce trial sample size requirements by allowing inclusion of a homogenous patient population. METHODS: Disease-progression modeling of longitudinal cognitive scores of pre-dementia patients (baseline Clinical Dementia Rating ≤ 0.5) was used to derive a biomarker profile that was predictive of patient's cognitive progression along the dementia continuum. The biomarker profile model was developed and validated in the MEMENTO cohort and externally validated in the Alzheimer's Disease Neuroimaging Initiative. RESULTS: Of nine candidate biomarkers in the development analysis, three cerebrospinal fluid and two magnetic resonance imaging measures were selected to form the final biomarker profile. The model-based prognosis of individual future cognitive deficit was shown to significantly improve when incorporating biomarker information on top of cognition and demographic data. In trial power calculations, adjusting the primary analysis for the baseline biomarker profile reduced sample size requirements by ≈10%. Compared to conventional cognitive cut-offs, inclusion criteria based on biomarker-profile cut-offs resulted in up to 28% reduced sample size requirements due to increased homogeneity in progression patterns. DISCUSSION: The biomarker profile allows prediction of personalized trajectories of future cognitive progression. This enables accurate personalized prognosis in clinical care and better selection of patient populations for clinical trials. A web-based application for prediction of patients' future cognitive progression is available online.

Application of the ATN classification scheme in a population without dementia: Findings from the EPAD cohort.

BACKGROUND: We classified non-demented European Prevention of Alzheimer's Dementia (EPAD) participants through the amyloid/tau/neurodegeneration (ATN) scheme and assessed their neuropsychological and imaging profiles. MATERIALS AND METHODS: From 1500 EPAD participants, 312 were excluded. Cerebrospinal fluid cut-offs of 1000 pg/mL for amyloid beta (Aß)1-42 and 27 pg/mL for p-tau181 were validated using Gaussian mixture models. Given strong correlation of p-tau and t-tau (R2  = 0.98, P < 0.001), neurodegeneration was defined by age-adjusted hippocampal volume. Multinomial regressions were used to test whether neuropsychological tests and regional brain volumes could distinguish ATN stages. RESULTS: Age was 65 ± 7 years, with 58% females and 38% apolipoprotein E (APOE) ε4 carriers; 57.1% were A-T-N-, 32.5% were in the Alzheimer's disease (AD) continuum, and 10.4% suspected non-Alzheimer's pathology. Age and cerebrovascular burden progressed with biomarker positivity (P < 0.001). Cognitive dysfunction appeared with T+. Paradoxically higher regional gray matter volumes were observed in A+T-N- compared to A-T-N- (P < 0.001). DISCUSSION: In non-demented individuals along the AD continuum, p-tau drives cognitive dysfunction. Memory and language domains are affected in the earliest stages.

Multiomics Investigation of Hypertension and White Matter Hyperintensity as a Source of Vascular Dementia or a Comorbidity to Alzheimer's Disease.

BACKGROUND: Age-related comorbidity is common and significantly increases the burden for the healthcare of the elderly. Alzheimer's disease (AD) and hypertension are the two most prevalent age-related conditions and are highly comorbid. While hypertension is a risk factor for vascular dementia (VD), hypertension with AD (ADHyp+) is often characterized as probable vascular dementia. In the absence of imaging and other diagnostic tests, differentiating the two pathological states is difficult. OBJECTIVE: Our goals are to (1) identify differences in CSF-based vascular dementia profiles, if any, between individuals who have AD only (ADHyp-), and individuals with ADHyp+ using CSF levels of amyloid ß, tau and p-tau, and (2) compare genome-wide DNA profiles of ADHyp- and ADHyp+ with an unaffected control population. METHOD: Genotype and clinical data were used to compare healthy controls to AD Hyp- vs. AD Hyp+. We compared the CSF biomarkers followed by evaluating genome wide profiles in three groups, and mapped SNPs to genes based on position and lowest p-value. The significant genes were examined for co-expression and known disease networks. RESULTS: We found no differences between Aß, tau and p-tau levels between ADHyp- and ADHyp+. We found TOMM40 to be associated with ADHyp- as expected but not with ADHyp+. Interestingly, SLC9A3R2 polymorphism was associated with ADHyp+, and significant gene expression changes were observed for neighboring genes. CONCLUSION: Through this exploratory study using a novel cohort stratification design, we highlight the genetic differences in clinically similar phenotypes, indicating the utility of genetic profiling in aiding differential diagnosis of ADHyp+ and VD.

Association between CSF Aß42 and amyloid negativity in patients with different stage mild cognitive impairment.

Whether the cerebrospinal fluid (CSF) biomarkers of amyloid-positive and amyloid-negative patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD) are significantly different is still unknown. The purpose of this study is to compare the differences in CSF total tau, P-tau and Aß42 in patients with amyloid-positive positron emission tomography (PET) and amyloid-negative PET, and to explore related risk factors in cognitive normal (CN), early MCI (EMCI), late MCI (LMCI) and AD. 558 participants (140 CN; 233 EMCI; 125 LMCI; 60 AD) were recruited in this study from the AD Neuroimaging Initiative (ADNI) database. The associations between CSF biomarkers were assessed by partial correlation analysis. The relations between significant variables were determined by multinomial logistic regression. Compared with amyloid-positive PET patients, patients with amyloid-negative PET had higher CSF Aß42 and lower P-tau in the whole samples. The concentration of Aß42 in the positive amyloid PET was significantly different in different groups, but not the negative amyloid PET (CN vs. LMCI; CN vs. AD; EMCI vs. AD, all P < 0.05). When amyloid PET was positive, a weak correlation was found between the levels of Aß42 and P-tau only in CN group. However, a moderate degree of correlation between Aß42 and P-tau was found in EMCI and LMCI when amyloid PET was negative. After covariates adjustment, CSF Aß42 was significantly associated with EMCI [adjusted odds ratio (OR) = 0.99, 95 % confidence interval (CI) = 0.99-1.00, P = 0.02) and LMCI (adjusted OR = 0.99, 95 % CI = 0.99-1.00, P = 0.007)] in patients with negative amyloid PET, not in patients with positive amyloid PET. Our findings highlight that Aß42 had strong correlations with other biomarkers and might help reduce risk of EMCI or LMCI in patients with amyloid negativity.

Amylin, Aß42, and Amyloid in Varicella Zoster Virus Vasculopathy Cerebrospinal Fluid and Infected Vascular Cells.

BACKGROUND: Varicella zoster virus (VZV) vasculopathy is characterized by persistent arterial inflammation leading to stroke. Studies show that VZV induces amyloid formation that may aggravate vasculitis. Thus, we determined if VZV central nervous system infection produces amyloid. METHODS: Aß peptides, amylin, and amyloid were measured in cerebrospinal fluid (CSF) from 16 VZV vasculopathy subjects and 36 stroke controls. To determine if infection induced amyloid deposition, mock- and VZV-infected quiescent primary human perineurial cells (qHPNCs), present in vasculature, were analyzed for intracellular amyloidogenic transcripts/proteins and amyloid. Supernatants were assayed for amyloidogenic peptides and ability to induce amyloid formation. To determine amylin's function during infection, amylin was knocked down with small interfering RNA and viral complementary DNA (cDNA) was quantitated. RESULTS: Compared to controls, VZV vasculopathy CSF had increased amyloid that positively correlated with amylin and anti-VZV antibody levels; Aß40 was reduced and Aß42 unchanged. Intracellular amylin, Aß42, and amyloid were seen only in VZV-infected qHPNCs. VZV-infected supernatant formed amyloid fibrils following addition of amyloidogenic peptides. Amylin knockdown decreased viral cDNA. CONCLUSIONS: VZV infection increased levels of amyloidogenic peptides and amyloid in CSF and qHPNCs, indicating that VZV-induced amyloid deposition may contribute to persistent arterial inflammation in VZV vasculopathy. In addition, we identified a novel proviral function of amylin.

Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns.

White matter hyperintensities (WMHs) are associated with vascular risk and Alzheimer's disease. In this study, we examined relations between WMH load and distribution, amyloid pathology and vascular risk in 339 controls and cases with either subjective (SCD) or mild cognitive impairment (MCI). Regional deep (DWMH) and periventricular (PWMH) WMH loads were determined using an automated algorithm. We stratified on Aß1-42 pathology (Aß+/-) and analyzed group differences, as well as associations with Framingham Risk Score for cardiovascular disease (FRS-CVD) and age. Occipital PWMH (p = 0.001) and occipital DWMH (p = 0.003) loads were increased in SCD-Aß+ compared with Aß- controls. In MCI-Aß+ compared with Aß- controls, there were differences in global WMH (p = 0.003), as well as occipital DWMH (p = 0.001) and temporal DWMH (p = 0.002) loads. FRS-CVD was associated with frontal PWMHs (p = 0.003) and frontal DWMHs (p = 0.005), after adjusting for age. There were associations between global and all regional WMH loads and age. In summary, posterior WMH loads were increased in SCD-Aß+ and MCI-Aß+ cases, whereas frontal WMHs were associated with vascular risk. The differences in WMH topography support the use of regional WMH load as an early-stage marker of etiology.

Amyloidogenic Nanoplaques in Cerebrospinal Fluid: Relationship to Amyloid Brain Uptake and Clinical Alzheimer's Disease in a Memory Clinic Cohort.

BACKGROUND: Aggregation of amyloid-ß (Aß) is an early pathological event in Alzheimer's disease (AD). Consequently, measures of pathogenic aggregated Aß are attractive biomarkers for AD. Here, we use a recently developed Thioflavin-T-Fluorescence Correlation Spectroscopy (ThT-FCS) assay to quantify structured ThT-responsive protein aggregates, so-called nanoplaques, in the cerebrospinal fluid (CSF). OBJECTIVE: The overall aim of this work was to assess whether ThT-FCS determined CSF nanoplaque levels could predict amyloid brain uptake as determined by 18F-Flutemetamol PET analysis. Further, we assess whether nanoplaque levels could predict clinical AD. METHODS: Nanoplaque levels in the CSF from 54 memory clinic patients were compared between sub-groups classified by 18F-Flutemetamol PET as amyloid-positive or amyloid-negative, and by clinical assessment as AD or non-AD. RESULTS: Nanoplaque levels did not differ between amyloid groups and could not predict brain amyloid uptake. However, nanoplaque levels were significantly increased in patients with clinical AD, and were significant predictors for AD when adjusting for age, sex, cognitive function, and apolipoprotein E (APOE) genotype. CONCLUSION: The concentration of nanoplaques in the CSF differentiates patients with clinical AD from non-AD patients.

Weight Loss is a Preclinical Signal of Cerebral Amyloid Deposition and Could Predict Cognitive Impairment in Elderly Adults.

BACKGROUND: Higher late-life body mass index (BMI) was associated with reduced risk of Alzheimer's disease (AD), which might be explained by a reverse causal relationship. OBJECTIVE: To investigate whether weight loss was a preclinical manifestation of AD pathologies and could be a predictor of cognitive impairment. METHODS: A total of 1,194 participants (mean age = 73.2 [range: 54 to 91] years, female = 44.5%) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were grouped according to AD biomarker profile as indicated by amyloid (A) and tau (TN) status and clinical stage by clinical dementia rating (CDR). BMI across the biomarker-defined clinical stages was compared with Bonferroni correction. Pearson correlation analysis was performed to test the relationship between the amyloid change by PET and the BMI change. Multiple regression models were used to explore the influences of amyloid pathologies on BMI change as well as the effects of weight loss on longitudinal changes of global cognitive function. RESULTS: BMI was significantly decreased in AD preclinical stage (amyloid positive [A+] and CDR = 0) and dementia stage (A+/TN+ and CDR = 0.5 or 1), compared with the healthy controls (A-/TN-and CDR = 0, p < 0.005), while no significant differences were observed between preclinical AD and AD dementia. Amyloid PET change was inversely correlated with BMI change (p = 0.023, ß= -14). Individuals in amyloid positive group exhibited faster weight loss (time×group interaction p = 0.019, ß= -0.20) compared to the amyloid negative group. Greater weight loss predicted higher risk of developing cognitive disorders. CONCLUSION: Elders who experienced greater weight loss might belong to preclinical stage of AD and could be targeted for primary prevention of the disease.

Race modifies default mode connectivity in Alzheimer's disease.

Background: Older African Americans are more likely to develop Alzheimer's disease (AD) than older Caucasians, and this difference cannot be readily explained by cerebrovascular and socioeconomic factors alone. We previously showed that mild cognitive impairment and AD dementia were associated with attenuated increases in the cerebrospinal fluid (CSF) levels of total and phosphorylated tau in African Americans compared to Caucasians, even though there was no difference in beta-amyloid 1-42 level between the two races. Methods: We extended our work by analyzing early functional magnetic resonance imaging (fMRI) biomarkers of the default mode network in older African Americans and Caucasians. We calculated connectivity between nodes of the regions belonging to the various default mode network subsystems and correlated these imaging biomarkers with non-imaging biomarkers implicated in AD (CSF amyloid, total tau, and cognitive performance). Results: We found that race modifies the relationship between functional connectivity of default mode network subsystems and cognitive performance, tau, and amyloid levels. Conclusion: These findings provide further support that race modifies the AD phenotypes downstream from cerebral amyloid deposition, and identifies key inter-subsystem connections for deep imaging and neuropathologic characterization.

Real-space navigation testing differentiates between amyloid-positive and -negative aMCI.

OBJECTIVE: To distinguish between patients with amyloid-positive (A+) and -negative (A-) amnestic mild cognitive impairment (aMCI) by simultaneously investigating navigation performance, visual exploration behavior, and brain activations during a real-space navigation paradigm. METHODS: Twenty-one patients with aMCI were grouped into A+ (n = 11) and A- cases by amyloid-PET imaging and amyloid CSF levels and compared to 15 healthy controls. Neuropsychological deficits were quantified by use of the Consortium to Establish a Registry for Alzheimer's Disease-plus cognitive battery. All participants performed a navigation task in which they had to find items in a realistic spatial environment and had to apply egocentric and allocentric route planning strategies. 18F-fluorodeoxyglucose was injected at the start to detect navigation-induced brain activations. Subjects wore a gaze-controlled, head-fixed camera that recorded their visual exploration behavior. RESULTS: A+ patients performed worse during egocentric and allocentric navigation compared to A- patients and controls (p < 0.001). Both aMCI subgroups used fewer shortcuts, moved more slowly, and stayed longer at crossings. Word-list learning, figural learning, and Trail-Making tests did not differ in the A+ and A- subgroups. A+ patients showed a reduced activation of the right hippocampus, retrosplenial, and parietal cortex during navigation compared to A- patients (p < 0.005). CONCLUSIONS: A+ patients with aMCI perform worse than A- patients with aMCI in egocentric and allocentric route planning because of a more widespread impairment of their cerebral navigation network. Navigation testing in real space is a promising approach to identify patients with aMCI with underlying Alzheimer pathology.

Multicenter Alzheimer's and Parkinson's disease immune biomarker verification study.

INTRODUCTION: Multiple immunity biomarkers have been suggested as tracers of neuroinflammation in neurodegeneration. This study aimed to verify findings in cerebrospinal fluid (CSF) samples of Alzheimer's disease (AD) and Parkinson's disease (PD) subjects from the network of the European, Innovative Medicines Initiative-funded project AETIONOMY. METHODS: A total of 227 samples from the studies/centres AETIONOMY, ICEBERG, and IDIBAPS were used to analyse 21 selected immunity biomarkers in CSF. Results were compared to data of an independent cohort of 399 subjects previously published. RESULTS: Immunity markers were predominantly and reproducibly associated with pathological levels of tau isoforms, but also with amyloid levels, aging, sex, APOE genotype, and center-specific factors. DISCUSSION: Immunity biomarker levels in CSF reflect molecular and cellular pathology rather than diagnosis in neurodegenerative disorders. Assay standardization and stratification for age and other covariates could improve the power of such markers in clinical applications or intervention studies targeting immune responses in neurodegeneration.

In pursuit of a sensitive EEG functional connectivity outcome measure for clinical trials in Alzheimer's disease.

OBJECTIVE: In clinical trials in Alzheimer's Disease (AD), an improvement of impaired functional connectivity (FC) could provide biological support for the potential efficacy of the drug. Electroencephalography (EEG) analysis of the SAPHIR-trial showed a treatment induced improvement of global relative theta power but not of FC measured by the phase lag index (PLI). We compared the PLI with the amplitude envelope correlation with leakage correction (AEC-c), a presumably more sensitive FC measure. METHODS: Patients with early AD underwent 12 weeks of placebo or treatment with PQ912, a glutaminylcyclase inhibitor. Eyes-closed task free EEG was measured at baseline and follow-up (PQ912 n = 47, placebo n = 56). AEC-c and PLI were measured in multiple frequency bands. Change in FC was compared between treatment groups by using two models of covariates. RESULTS: A significant increase in global AEC-c in the alpha frequency band was found with PQ912 treatment compared to placebo (p = 0.004, Cohen's d = 0.58). The effect remained significant when corrected for sex, country, ApoE ε4 carriage, age, baseline value (model 1; p = 0.006) and change in relative alpha power (model 2; p = 0.004). CONCLUSIONS: Functional connectivity in early AD, measured with AEC-c in the alpha frequency band, improved after PQ912 treatment. SIGNIFICANCE: AEC-c may be a robust and sensitive FC measure for detecting treatment effects.

Surface tension and intrinsic amyloid fluorescence of serum and cerebrospinal fluid samples in Alzheimer´s disease.

AIM: Surface tension of biological fluids can be influenced by changes in oligomerization or aggregation of surfactant peptides or proteins. Amphiphilic peptides of amyloid-ß or other amyloidogenic peptides/proteins display properties of surfactants, oligomerization and aggregation increase also their fluorescence intensity compared with native structures. Results/methodology: We estimated surface tension and native/ThioflavinT-based/intrinsic amyloid fluorescence intensity in serum and cerebrospinal fluid samples for their evalution as diagnostic biomarkers for Alzheimer´s disease (AD). DISCUSSION/CONCLUSION: Our results indicate that values of surface tension are not a suitable biomarker for AD. However, the ratio of ThioflavinT-based fluorescence to intrinsic amyloid fluorescence in cerebrospinal fluid appears to be an acceptable supportive diagnostic biomarker for AD (its sensitivity was 61.1%, and the specificity 70.8% when compared with aged controls).

Protofibrillar and Fibrillar Amyloid-ß Binding Proteins in Cerebrospinal Fluid.

Aggregation and deposition of misfolded amyloid-ß (Aß) peptide in the brain is central to Alzheimer's disease (AD). Oligomeric, protofibrillar, and fibrillar forms of Aß are believed to be neurotoxic and cause neurodegeneration in AD, but the toxicity mechanisms are not well understood and may involve Aß-interacting molecular partners. In a previous study, we identified potential Aß42 protofibrillar-binding proteins in serum and cerebrospinal fluid (CSF) using an engineered version of Aß42 (Aß42CC) that forms protofibrils, but not fibrils. Here we studied binding of proteins to Aß42 fibrils in AD and non-AD CSF and compared these with protofibrillar Aß42CC-binding partners. Aß42 fibrils sequestered 2.4-fold more proteins than Aß42CC protofibrils. Proteins with selective binding to fibrillar aggregates with low nanomolar affinity were identified. We also found that protofibrillar and fibrillar Aß-binding proteins represent distinct functional categories. Aß42CC protofibrils triggered interactions with proteins involved in catalytic activities, like transferases and oxidoreductases, while Aß42 fibrils were more likely involved in binding to proteoglycans, growth factors and neuron-associated proteins, e.g., neurexin-1, -2, and -3. Interestingly, 10 brain-enriched proteins were identified among the fibril-binding proteins, while protofibril-extracted proteins had more general expression patterns. Both types of Aß aggregates bound several extracellular proteins. Additionally, we list a set of CSF proteins that might have potential to discriminate between AD and non-AD CSF samples. The results may be of relevance both for biomarker studies and for studies of Aß-related toxicity mechanisms.