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INTRODUCTION: We examined the relations of misfolded alpha synuclein (α‐synuclein) with Alzheimer's disease (AD) biomarkers in two large independent cohorts. METHODS: We included Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably Two (BioFINDER‐2) and Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (n = 2315, cognitively unimpaired, mild cognitive impairment, AD dementia) who had cross‐sectional cerebrospinal fluid (CSF) α‐synuclein measurement from seed‐amplification assay as well as cross‐sectional and longitudinal amyloid beta (Aβ) and tau levels (measured in CSF and/or by positron emission tomography). All analyses were adjusted for age, sex, and cognitive status. RESULTS: Across cohorts, the main biomarker associated with α‐synuclein positivity at baseline was higher levels of Aβ pathology (all p values ≤ 0.02), but not tau. Looking at longitudinal measures of AD biomarkers, α‐synuclein –positive participants had a statistically significant faster increase of Aβ load, although of modest magnitude (1.11 Centiloid/year, p = 0.02), compared to α‐synuclein –negative participants in BioFINDER‐2 but not in ADNI. DISCUSSION: We showed associations between concurrent misfolded α‐synuclein and Aβ levels, providing in vivo evidence of links between these two molecular disease pathways in humans. Highlights: Amyloid beta (Aβ), but not tau, was associated with alpha‐synuclein (α‐synuclein) positivity.Such association was consistent across two cohorts, beyond the effect of age, sex, and cognitive status.α‐synuclein–positive participants had a small, statistically significant faster increase in Aβ positron emission tomography levels in one of the two cohorts. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. METHODS: Using an α‐synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. RESULTS: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α‐synuclein seeding activity in CSF in vivo. DISCUSSION: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala‐ or olfactory‐predominant LBP, for which CSF α‐synuclein SAA has low sensitivity. Highlights: Cerebrospinal fluid (CSF) real‐time quaking‐induced conversion (RT‐QuIC) detects misfolded α‐synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients.CSF RT‐QuIC does not detect α‐synuclein seeding activity in asymptomatic mutation carriers.Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala‐predominant variants.LBP develops late in the disease course in ADAD.CSF α‐synuclein RT‐QuIC has low sensitivity for focal, low‐burden LBP. [ABSTRACT FROM AUTHOR]

INTRODUCTION: 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. METHODS: 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). RESULTS: 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). DISCUSSION: 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. [ABSTRACT FROM AUTHOR]

Background: Beta‐synuclein (beta‐syn) is an emerging biofluid marker for synaptic damage in several neurological diseases. In particular, patients with prion disease showed significantly higher cerebrospinal fluid (CSF) and blood beta‐syn levels compared to controls and subjects with other neurodegenerative disorders. However, to date, no study explored the biomarker distribution and prognostic value across the heterogeneous spectrum of sporadic Creutzfeldt‐Jakob disease (sCJD) as well as its diagnostic performance in the real‐life setting of patients with rapidly progressive dementia (RPD). Method: Using in house established immunoassays we measured CSF and/or plasma beta‐syn concentrations in 150 patients with sCJD, belonging to the most prevalent molecular subtypes [MM(V)1, VV2 and MV2K], and in 106 subjects with non‐prion RPD. In the same cohort, we assessed CSF levels of total tau (t‐tau) and protein 14‐3‐3. We compared the diagnostic performance of CSF/plasma beta‐syn with that of classic CSF markers and we tested the possible associations of CSF/plasma beta‐syn with survival in patients with sCJD. Result: sCJD patients showed higher CSF and plasma beta‐syn levels compared to non‐prion RPD subjects (p<0.001 for both) (Figure 1A, B). Different CSF and blood profiles of beta‐syn were observed for the most prevalent sCJD molecular subtypes (Figure 1C, D). Concerning the diagnostic value, CSF beta‐syn outperformed 14‐3‐3 (AUC 0.95 vs. 0.89, p = 0.028) but not t‐tau (AUC 0.92, p = 0.212). Further, the discriminative accuracy of plasma beta‐syn (AUC 0.91) was not inferior to that of classic CSF markers (t‐tau, p = 0.765 and 14‐3‐3, p = 0.447) and CSF beta‐syn (p = 0.135). In the whole sCJD cohort, CSF and plasma beta‐syn were significantly associated with survival at univariate analyses but not after accounting for codon 129 genotype or molecular subtype. Conclusion: CSF beta‐syn performed similar or better compared to t‐tau and 14‐3‐3, respectively, thus, the marker might represent an alternative first‐level test in patients with suspected sCJD. Most interestingly, the high diagnostic value of beta‐syn in plasma, which was comparable to that of classic CSF surrogate markers, suggests that beta‐syn might be used as highly accurate blood surrogate marker in sCJD for patient screening and monitoring. [ABSTRACT FROM AUTHOR]