Association of Klotho protein levels and KL-VS heterozygosity with Alzheimer disease and amyloid and tau burden

Importance Identification of proteins and genetic factors that reduce Alzheimer disease (AD) pathology is of importance when searching for novel AD treatments. Heterozygosity of the KL-VS haplotype has been associated with reduced amyloid and tau burden. Whether this association is mediated by the Klotho protein remains unclear. Objectives To assess concentrations of Klotho in cerebrospinal fluid (CSF) and plasma among cognitively healthy controls and patients with AD and to correlate these findings with KL-VS heterozygosity status and amyloid and tau burden. Design, Setting, and Participants This case-control study combined 2 independent case-control AD cohorts consisting of 243 referred patients with AD and volunteer controls recruited from January 1, 2009, to December 31, 2018. Klotho levels were measured in CSF and plasma and correlated with KL-VS heterozygosity status and levels of CSF amyloid-β 42 (Aβ42), total tau, and phosphorylated tau. Statistical analysis was performed from January 1, 2021, to March 1, 2022. Main Outcomes and Measures Associations of Klotho levels in CSF and plasma with levels of CSF biomarkers were analyzed using linear regression. Association analyses were stratified separately by clinical groups, APOE4 status, and KL-VS heterozygosity. Pearson correlation was used to assess the correlation between CSF and plasma Klotho levels. Results A total of 243 participants were included: 117 controls (45 men [38.5%]; median age, 65 years [range, 41-84 years]), 102 patients with mild cognitive impairment due to AD (AD-MCI; 59 men [57.8%]; median age, 66 years [range, 46-80 years]), and 24 patients with dementia due to AD (AD-dementia; 12 men [50.0%]; median age, 64.5 years [range, 54-75 years]). Median CSF Klotho levels were higher in controls (1236.4 pg/mL [range, 20.4-1726.3 pg/mL]; β = 0.103; 95% CI, 0.023-0.183; P = .01) and patients with AD-MCI (1188.1 pg/mL [range, 756.3-1810.3 pg/mL]; β = 0.095; 95% CI, 0.018-0.172; P = .02) compared with patients with AD-dementia (1073.3 pg/mL [range, 698.2-1661.4 pg/mL]). Higher levels of CSF Klotho were associated with lower CSF Aβ42 burden (β = 0.519; 95% CI, 0.201-0.836; P < .001) and tau burden (CSF total tau levels: β = −0.884; 95% CI, 0.223 to −0.395; P < .001; CSF phosphorylated tau levels: β = −0.672; 95% CI, −1.022 to −0.321; P < .001) independent of clinical, KL-VS heterozygosity, or APOE4 status. There was a weak correlation between Klotho CSF and plasma levels among the entire cohort (Pearson correlation r = 0.377; P < .001). Conclusions and Relevance The findings of this case-control study suggest that Klotho protein levels were associated with clinical stages of AD, cognitive decline, and amyloid and tau burden and that these outcomes were more clearly mediated by the protein directly rather than the KL-VS heterozygosity variant. When selecting individuals at risk for clinical trials, the Klotho protein level and not only the genetic profile should be considered

Beyond the Global Brain Differences:Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers

BACKGROUND: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and globalbrain differences compared with noncarriers. However, interpreting regional differences is challenging if a globaldifference drives the regional brain differences. Intraindividual variability measures can be used to test for regionaldifferences beyond global differences in brain structure.METHODS: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n =30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matchednoncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual’sregional difference and global difference, were used to test for regional differences that diverge from the globaldifference.RESULTS: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differedmore than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thicknessin regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal andsomatosensory cortex differed more than the global difference in cortical thickness.CONCLUSIONS: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distaland 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distaland 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanismsinvolved in altered neurodevelopment

Cerebrospinal fluid levels of amyloid beta 1-43 in patients with amnestic mild cognitive impairment or early Alzheimer’s disease: a 2-year follow-up study

Abstract IntroductionBiomarkers that will reliably predict the onset of Alzheimer’s disease (AD) are urgently needed. Although cerebrospinal fluid (CSF) amyloid beta 1-42 (Aβ42), total tau and phosphorylated tau can be used to complement the clinical diagnosis of AD, amnestic mild cognitive impairment (aMCI), the prodromal phase of AD, is heterogeneous. Biomarkers should be able to determine which patients with aMCI are at greatest risk of AD. Histological studies and animal models indicate that amyloid beta 1-43 (Aβ43) aggregates early, and may play a role in the pathological process of AD. We have examined levels of CSF Aβ43 in a two-year longitudinal study of aMCI and early AD. Materials and methodsCSF was collected at baseline, and after one and two years from patients with AD (n=19), and patients with aMCI (n=42). Of these, 21 progressed to AD during the two years of study, whereas 21 did not. Controls (n=32) were lumbar punctured at baseline only. CSF analyses of Aβ43, Aβ42 and total tau were carried out with ELISA.ResultsAt baseline, CSF Aβ43, CSF Aβ42 and ratios with total tau could be used to separate controls from all three patient groups. CSF Aβ43, but not Aβ42, could separate patients with aMCI who progressed to AD during the two years of follow-up, from those that did not. The CSF total tau/Aβ43 ratio had a slightly but significantly larger area under the receiver operating characteristic curve when compared to the CSF total tau/Aβ42 ratio. CSF Aβ43 levels, but not Aβ42 levels, decreased from baseline to two years in the AD group.Discussion and conclusionCSF Aβ43 was demonstrated to be significantly reduced in patients already by the time that aMCI or AD was diagnosed, compared to controls, and this change must have occurred during the preclinical period. Since our results suggested that CSF Aβ43 distinguishes between subgroups of patients with aMCI better than CSF Aβ42, it may prove to be a useful additional biomarker for identifying aMCI patients at greatest risk of AD

The Amyloid, Tau, and Neurodegeneration (A/T/N) Classification Applied to a Clinical Research Cohort with Long-Term Follow-Up

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 (A42, 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 (AT + N+), and those with triple negative status. A-T-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

Alpha-synuclein measured in cerebrospinal fluid from patients with Alzheimer's disease, mild cognitive impairment, or healthy controls: a two year follow-up study

Background α-Synuclein has been proposed as a potential biomarker for Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI). However, results from α-synuclein measurements in cerebrospinal fluid (CSF) have been inconclusive, and to our knowledge, longitudinal studies of changes prior to the AD diagnosis have not been investigated. Methods Levels of α-synuclein at baseline and after one and two years were measured in CSF, by enzyme-linked immunosorbent assay. Twenty-six patients with early AD (AD-AD), 48 patients with aMCI, subdivided as 23 that developed AD during follow-up (MCI-AD), and 25 that did not (MCI-MCI), and 25 healthy control individuals, were included. One-way ANOVA was applied to compare mean α-synuclein baseline values between all four study groups, and a linear mixed model was used to compare mean change over time between the three patient groups. Linear associations between α-synuclein and amyloid-β 1–42 (Aβ42), amyloid-β 1–40 (Aβ40), total tau and phosphorylated tau were also examined. Results A large variation in individual α-synuclein CSF levels was observed, particularly in the MCI-AD group. No significant differences were found in mean α-synuclein levels between all the study groups at baseline. When using a linear mixed model, no significant differences were found at follow-up for estimated mean changes between the patient groups. MCI-AD patients with short duration of symptoms prior to inclusion in the study (≤2 years) had considerably higher mean CSF α-synuclein levels compared to patients with a longer symptom duration (802.2 vs. 442.8 pg/mL, p = 0.01). No such difference was seen in the MCI-MCI or AD-AD groups. Significant linear associations (p < 0.0005) between α-synuclein and Aβ40, total tau and phosphorylated tau were found. Conclusion The observed difference in mean CSF α-synuclein level according to duration of symptoms in the MCI-AD group, may be an indication of changes related to disease progression. However, the lack of significant differences between groups, as well as the large individual variation in CSF levels of α-synuclein in the present study, suggest that α-synuclein is not a useful biomarker for AD.© 2016 The Author(s).Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated

Alpha-synuclein measured in cerebrospinal fluid from patients with Alzheimer's disease, mild cognitive impairment, or healthy controls: a two year follow-up study

Background α-Synuclein has been proposed as a potential biomarker for Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI). However, results from α-synuclein measurements in cerebrospinal fluid (CSF) have been inconclusive, and to our knowledge, longitudinal studies of changes prior to the AD diagnosis have not been investigated. Methods Levels of α-synuclein at baseline and after one and two years were measured in CSF, by enzyme-linked immunosorbent assay. Twenty-six patients with early AD (AD-AD), 48 patients with aMCI, subdivided as 23 that developed AD during follow-up (MCI-AD), and 25 that did not (MCI-MCI), and 25 healthy control individuals, were included. One-way ANOVA was applied to compare mean α-synuclein baseline values between all four study groups, and a linear mixed model was used to compare mean change over time between the three patient groups. Linear associations between α-synuclein and amyloid-β 1–42 (Aβ42), amyloid-β 1–40 (Aβ40), total tau and phosphorylated tau were also examined. Results A large variation in individual α-synuclein CSF levels was observed, particularly in the MCI-AD group. No significant differences were found in mean α-synuclein levels between all the study groups at baseline. When using a linear mixed model, no significant differences were found at follow-up for estimated mean changes between the patient groups. MCI-AD patients with short duration of symptoms prior to inclusion in the study (≤2 years) had considerably higher mean CSF α-synuclein levels compared to patients with a longer symptom duration (802.2 vs. 442.8 pg/mL, p = 0.01). No such difference was seen in the MCI-MCI or AD-AD groups. Significant linear associations (p < 0.0005) between α-synuclein and Aβ40, total tau and phosphorylated tau were found. Conclusion The observed difference in mean CSF α-synuclein level according to duration of symptoms in the MCI-AD group, may be an indication of changes related to disease progression. However, the lack of significant differences between groups, as well as the large individual variation in CSF levels of α-synuclein in the present study, suggest that α-synuclein is not a useful biomarker for AD

Cerebrospinal fluid A?43 is reduced in early-onset compared to late-onset Alzheimer's disease, but has similar diagnostic accuracy to A?42

Background: Amyloid beta 1–43 (Aβ43) may be a useful additional biomarker for diagnosing Alzheimer’s disease (AD). We have investigated cerebrospinal fluid (CSF) levels of Aβ43 in patients with early-onset AD in contrast to levels in late-onset AD. For comparison, in addition to the ‘core’ biomarkers, several other analytes were also determined [YKL-40, neurofilament light (NF-L), glial fibrillary acidic protein (GFAP), and progranulin]. Material and Methods: Cerebrospinal fluid samples were obtained from patients with early-onset AD (age ≤ 62, n = 66), late-onset AD (age ≥ 68, n = 25), and groups of cognitively intact individuals (age ≤ 62, n = 41, age ≥ 68, n = 39). Core CSF AD biomarkers [amyloid beta 1–42 (Aβ42), total tau, phosphorylated tau] were analyzed, as well as levels of Aβ43 and other analytes, using commercially available enzyme-linked immunosorbent assays. Results: Cerebrospinal fluid Aβ43 was significantly reduced in early-onset AD compared to late-onset AD (14.8 ± 7.3 vs. 21.8 ± 9.4 pg/ml, respectively), whereas the levels of Aβ42 in the two AD groups were not significantly different (474.9 ± 142.0 vs. 539.6 ± 159.9 pg/ml, respectively). Aβ43 and all core biomarkers were significantly altered in patients with AD compared to corresponding controls. NF-L was significantly increased in early-onset AD compared to younger controls, an effect not found between the older groups. Relationships between the Aβ peptides and tau proteins, YKL-40, NF-L, GFAP and progranulin were also investigated without finding marked associations. However, age-associated increases in levels of tau proteins, YKL-40, NF-L and GFAP were found with respect to age in healthy controls. Results for these other analytes were similar to previously published data. Aβ43 did not improve diagnostic accuracy in either AD group compared to Aβ42. Discussion: Cerebrospinal fluid Aβ43, but not Aβ42 levels, varied significantly with age in patients with AD. If CSF levels of Aβ peptides reflect amyloid deposition in brain, the possibility arises that there is a difference between Aβ43 and Aβ42 deposition in younger compared to older brain. However, the level of Aβ43 in CSF shows no improvement over Aβ42 regarding diagnostic accuracy

Cerebrospinal Fluid Levels of Amyloid Beta 1-43 in Patients with Amnestic Mild Cognitive Impairment or Early Alzheimer's Disease: A 2-Year Follow-Up Study

Introduction: Biomarkers that will reliably predict the onset of Alzheimer’s disease (AD) are urgently needed. Although cerebrospinal fluid (CSF) amyloid beta 1–42 (Aβ42), total tau, and phosphorylated tau can be used to complement the clinical diagnosis of AD, amnestic mild cognitive impairment (aMCI), the prodromal phase of AD, is heterogeneous. Biomarkers should be able to determine which patients with aMCI are at greatest risk of AD. Histological studies and animal models indicate that amyloid beta 1–43 (Aβ43) aggregates early, and may play a role in the pathological process of AD. We have examined levels of CSF Aβ43 in a 2-year longitudinal study of aMCI and early AD. Materials and Methods: Cerebrospinal fluid was collected at baseline, and after one and 2 years from patients with AD (n = 19), and patients with aMCI (n = 42). Of these, 21 progressed to AD during the 2 years of study, whereas 21 did not. Controls (n = 32) were lumbar punctured at baseline only. CSF analyses of Aβ43, Aβ42, and total tau were carried out with ELISA. Results: At baseline, CSF Aβ43, CSF Aβ42 and ratios with total tau could be used to separate controls from all three patient groups. CSF Aβ43, but not Aβ42, could separate patients with aMCI who progressed to AD during the 2 years of follow-up, from those that did not. The CSF total tau/Aβ43 ratio had a slightly but significantly larger area under the receiver operating characteristic curve when compared to the CSF total tau/Aβ42 ratio. CSF Aβ43 levels, but not Aβ42 levels, decreased from baseline to 2 years in the AD group. Discussion and Conclusion: CSF Aβ43 was demonstrated to be significantly reduced in patients already by the time that aMCI or AD was diagnosed, compared to controls, and this change must have occurred during the preclinical period. Since our results suggested that CSF Aβ43 distinguishes between subgroups of patients with aMCI better than CSF Aβ42, it may prove to be a useful additional biomarker for identifying aMCI patients at greatest risk of AD

CSF neurofilament light may predict progression from amnestic mild cognitive impairment to Alzheimer's disease dementia

Neurofilament light (NfL) is a promising biomarker of neurodegeneration in Alzheimer's disease (AD). In this study, cerebrospinal fluid (CSF) NfL was measured in a 24-month longitudinal cohort consisting of control (n = 52), amnestic mild cognitive impairment (aMCI) (n = 55), and probable AD dementia (n = 28) individuals. The cohort was reevaluated after 6-10 years. Baseline CSF NfL was significantly elevated in aMCI and probable AD dementia groups compared to controls (p < 0.0001). CSF NfL was significantly lower in stable aMCI patients compared to aMCI patients who converted to probable AD dementia within the 24-month period (p = 0.004). Substituting T-tau for NfL in the core AD biomarkers model (Aβ42/P-tau/T-tau) did not improve ability to separate control and AD, or stable and converter aMCI patients. Our results support that elevated CSF NfL could predict progression in aMCI patients, but its utility cannot improve the core AD biomarkers

Demographically adjusted CERAD wordlist test norms in a Norwegian sample from 40 to 80 years

Background/Objective: In recent years, several slightly younger cohorts have been established in order to study the preclinical and prodromal phases of dementia. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) wordlist memory test (WLT) is widely used in dementia research. However, culturally adapted and demographically adjusted test norms for younger ages are lacking. Method: This paper investigates effects of age, gender and years of education on test performance and offers demographically adjusted norms for the CERAD WLT using a regression-based norming procedure for the age span 40–80 years based on healthy controls (n = 227) from the Norwegian “Dementia Disease Initiation” (DDI) (n = 168) and “Trønderbrain” (n = 59) cohorts. In order to evaluate normative performance, we apply the norms to an independent sample of persons diagnosed with mild cognitive impairment (MCI = 168) and perform multiple regression analyses to evaluate adjustment of pertinent demographics. Results: CERAD WLT norms adjusted for effects of age, gender and educational level are proposed. The norms successfully adjusted for effects of age, gender and education in an independent sample of Norwegians with MCI. Conclusion: Demographically adjusted norms for the CERAD WLT for ages 40–80 years based on a Norwegian sample are proposed. To our knowledge, this is the first normative study of this test to offer demographically adjusted norms for this age span.<p