Accumulating evidence demonstrating higher cerebrospinal fluid (CSF) α-synuclein (αSyn) levels and αSyn pathology in the brains of Alzheimer’s disease (AD) patients suggests that αSyn is involved in the pathophysiology of AD. To investigate whether αSyn could be related to specific aspects of the pathophysiology present in both sporadic and familial disease, we quantified CSF levels of αSyn and assessed links to various disease parameters in a longitudinally followed cohort (n = 136) including patients with sporadic mild cognitive impairment (MCI) and AD, and in a cross-sectional sample from the Dominantly Inherited Alzheimer’s Network (n = 142) including participants carrying autosomal dominant AD (ADAD) gene mutations and their non-mutation carrying family members.Our results show that sporadic MCI patients that developed AD over a period of two years exhibited higher baseline αSyn levels (p = 0.03), which inversely correlated to their Mini-Mental State Examination scores, compared to cognitively normal controls (p = 0.02). In the same patients, there was a dose-dependent positive association between CSF αSyn and the APOEε4 allele. Further, CSF αSyn levels were higher in symptomatic ADAD mutation carriers versus non-mutation carriers (p = 0.03), and positively correlated to the estimated years from symptom onset (p = 0.05) across all mutation carriers. In asymptomatic (Clinical Dementia Rating < 0.5) PET amyloid-positive ADAD mutation carriers CSF αSyn was positively correlated to 11C-Pittsburgh Compound-B (PiB) retention in several brain regions including the posterior cingulate, superior temporal and frontal cortical areas. Importantly, APOEε4-positive ADAD mutation carriers exhibited an association between CSF αSyn levels and mean cortical PiB retention (p = 0.032). In both the sporadic AD and ADAD cohorts we found several associations predominantly between CSF levels of αSyn, tau and amyloid-β1–40.Our results suggest that higher CSF αSyn levels are linked to AD pathophysiology at the early stages of disease development and to the onset of cognitive symptoms in both sporadic and autosomal dominant AD. We conclude that APOEε4 may promote the processes driven by αSyn, which in turn may reflect on molecular mechanisms linked to the asymptomatic build-up of amyloid plaque burden in brain regions involved in the early stages of AD development.

Background: The unbiased amyloid, tau, and neurodegeneration (A/T/N) classification is designed to characterize individuals in the Alzheimer continuum and is currently little explored in clinical cohorts. Objective: A retrospective comparison of the A/T/N classification system with the results of a two-year clinical study, with extended follow-up up to 10 years after inclusion. Methods: Patients (n = 102) clinically diagnosed as Alzheimer's disease (AD) with dementia or amnestic mild cognitive impairment (MCI), and 61 cognitively healthy control individuals were included. Baseline cerebrospinal fluid core biomarkers for AD (A␤ 42 , phosphorylated tau, and total tau) were applied to the A/T/N classification using the final clinical diagnosis at extended follow-up as the gold standard. Results: A + T + N+ was a strong predictor for AD dementia, even among cognitively healthy individuals. Amnestic MCI was heterogenous, considering both clinical outcome and distribution within A/T/N. Some individuals with amnestic MCI progressed to clinical AD dementia within all four major A/T/N groups. The highest proportion of progression was among triple positive cases, but progression was also common in individuals with suspected non-Alzheimer pathophysiology (A-T + N+), and those with triple negative status. AT -N-individuals who were cognitively healthy overwhelmingly remained cognitively intact over time, but in amnestic MCI the clinical outcome was heterogenous, including AD dementia, other dementias, and recovery. Conclusion: The A/T/N framework accentuates biomarkers over clinical status. However, when selecting individuals for research, a combination of the two may be necessary since the prognostic value of the A/T/N framework depends on clinical status.

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Background: Kallikrein 6 (KLK6) is known to be an age-related protease expressed at high levels in the central nervous system. It was previously shown to be involved in proteolysis of extracellular proteins implicated in neurodegenerative diseases such as Alzheimer's disease (AD), prompting validation of KLK6 as a potential biomarker of disease. However, analyses of both plasma and cerebrospinal fluid (CSF) levels of KLK6 in patients with AD have been inconclusive. We present a detailed analysis of KLK6 in plasma and CSF in two separate cohorts in a cross-sectional and a longitudinal clinical setting. Methods: The cross-sectional cohort included control subjects without dementia and patients with AD, and the longitudinal cohort included patients with MCI and patients with AD followed over a 2-year period. Plasma and CSF levels of KLK6 were quantified by use of a previously developed and validated enzyme-linked immunosorbent assay. Statistical analyses were performed to compare KLK6 levels between diagnostic groups and to identify potential associations between KLK6 level, age, apolipoprotein E (APOE) genotype, total apoE level and the classical CSF AD biomarkers. Results: In the cross-sectional setting, KLK6 levels in plasma but not in CSF were significantly higher in the AD group than in control subjects. CSF but not plasma KLK6 levels were positively correlated with age in both the cross-sectional and longitudinal settings. In both cohorts, the CSF KLK6 levels were significantly and positively correlated with the CSF levels of core AD biomarkers. Total plasma and CSF apoE levels were positively associated with KLK6 in the crosssectional study. Finally, during the 2-year monitoring period of the longitudinal cohort, CSF KLK6 levels increased with disease progression over time in the investigated patient groups. Conclusions: In two separate cohorts we have confirmed the previously reported correlation between age and CSF levels of KLK6. Increased plasma KLK6 levels in patients with AD with a more advanced disease stage suggest KLK6 as a potential biomarker in patients with AD with more severe dementia. Significant correlations between KLK6 levels and core CSF AD biomarkers suggest molecular links between KLK6 and AD-related pathological processes.

Introduction: Amyloid beta 1-43 (Aβ43), with its additional C-terminal threonine residue, is hypothesized to play a role in early Alzheimer’s disease pathology possibly different from that of amyloid beta 1-42 (Aβ42). Cerebrospinal fluid (CSF) Aβ43 has been suggested as a potential novel biomarker for predicting conversion from mild cognitive impairment (MCI) to dementia in Alzheimer’s disease. However, the relationship between CSF Aβ43 and established imaging biomarkers of Alzheimer’s disease has never been assessed.Materials and Methods: In this observational study, CSF Aβ43 was measured with ELISA in 89 subjects; 34 with subjective cognitive decline (SCD), 51 with MCI, and four with resolution of previous cognitive complaints. All subjects underwent structural MRI; 40 subjects on a 3T and 50 on a 1.5T scanner. Forty subjects, including 24 with SCD and 12 with MCI, underwent 18F-Flutemetamol PET. Seventy-eight subjects were assessed with 18F-fluorodeoxyglucose PET (21 SCD/7 MCI and 11 SCD/39 MCI on two different scanners). Ten subjects with SCD and 39 with MCI also underwent diffusion tensor imaging.Results: Cerebrospinal fluid Aβ43 was both alone and together with p-tau a significant predictor of the distinction between SCD and MCI. There was a marked difference in CSF Aβ43 between subjects with 18F-Flutemetamol PET scans visually interpreted as negative (37 pg/ml, n = 27) and positive (15 pg/ml, n = 9), p < 0.001. Both CSF Aβ43 and Aβ42 were negatively correlated with standardized uptake value ratios for all analyzed regions; CSF Aβ43 average rho -0.73, Aβ42 -0.74. Both CSF Aβ peptides correlated significantly with hippocampal volume, inferior parietal and frontal cortical thickness and axial diffusivity in the corticospinal tract. There was a trend toward CSF Aβ42 being better correlated with cortical glucose metabolism. None of the studied correlations between CSF Aβ43/42 and imaging biomarkers were significantly different for the two Aβ peptides when controlling for multiple testing.Conclusion: Cerebrospinal fluid Aβ43 appears to be strongly correlated with cerebral amyloid deposits in the same way as Aβ42, even in non-demented patients with only subjective cognitive complaints. Regarding imaging biomarkers, there is no evidence from the present study that CSF Aβ43 performs better than the classical CSF biomarker Aβ42 for distinguishing SCD and MCI.