Dataset Information

Associations between baseline amyloid, sex, and APOE on subsequent tau accumulation in cerebrospinal fluid.

ABSTRACT: We investigated the effect of baseline A?, sex, and APOE on longitudinal tau accumulation in cerebrospinal fluid (CSF) in clinically normal older adults. Two hundred thirty-nine participants (aged 56-89 years, clinical dementia rating = 0) underwent serial CSF collection for A?1-42, total-tau (t-tau) and phospho-tau181P (p-tau). We used preprocessed data from fully automated Roche Elecsys immunoassays. A series of linear regressions were used to examine cross-sectional effects of A?1-42, sex, and APOE?4 on baseline CSF tau and linear mixed models for longitudinal changes in CSF tau. Cross-sectionally, CSF t-tau and p-tau were associated with abnormal A?1-42 and APOE?4 but not with sex. Longitudinally, low baseline CSF A?1-42 levels, but not APOE?4 or sex, predicted faster p-tau accumulation. The relationship between baseline CSF A?1-42 and tau accumulation was strongest in APOE?4 carriers, and particularly female carriers, relative to other groups. The current findings support an association between baseline CSF A?1-42 and changes in CSF tau. Elevated risk in females, apparent only in carriers, reinforces findings of sex-related vulnerability in those with genetic predisposition for Alzheimer's disease.

SUBMITTER: Buckley RF

PROVIDER: S-EPMC6545139 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Associations between baseline amyloid, sex, and APOE on subsequent tau accumulation in cerebrospinal fluid.

Buckley Rachel F RF Mormino Elizabeth C EC Chhatwal Jasmeer J Schultz Aaron P AP Rabin Jennifer S JS Rentz Dorene M DM Acar Diler D Properzi Michael J MJ Dumurgier Julien J Jacobs Heidi H Gomez-Isla Teresa T Johnson Keith A KA Sperling Reisa A RA Hanseeuw Bernard J BJ

Neurobiology of aging 20190307

We investigated the effect of baseline Aβ, sex, and APOE on longitudinal tau accumulation in cerebrospinal fluid (CSF) in clinically normal older adults. Two hundred thirty-nine participants (aged 56-89 years, clinical dementia rating = 0) underwent serial CSF collection for Aβ<sub>1-42</sub>, total-tau (t-tau) and phospho-tau<sub>181P</sub> (p-tau). We used preprocessed data from fully automated Roche Elecsys immunoassays. A series of linear regressions were used to examine cross-sectional effe ...[more]

PMID: 30947113

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Project description:Importance:The strongest genetic risk factor for Alzheimer disease (AD), the apolipoprotein E (APOE) gene, has a stronger association among women compared with men. Yet limited work has evaluated the association between APOE alleles and markers of AD neuropathology in a sex-specific manner. Objective:To evaluate sex differences in the association between APOE and markers of AD neuropathology measured in cerebrospinal fluid (CSF) during life or in brain tissue at autopsy. Design, Setting, and Participants:This multicohort study selected data from 10 longitudinal cohort studies of normal aging and AD. Cohorts had variable recruitment criteria and follow-up intervals and included population-based and clinic-based samples. Inclusion in our analysis required APOE genotype data and either CSF data available for analysis. Analyses began on November 6, 2017, and were completed on December 20, 2017. Main Outcomes and Measures:Biomarker analyses included levels of ?-amyloid 42, total tau, and phosphorylated tau measured in CSF. Autopsy analyses included Consortium to Establish a Registry for Alzheimer's Disease staging for neuritic plaques and Braak staging for neurofibrillary tangles. Results:Of the 1798 patients in the CSF biomarker cohort, 862 were women, 226 had AD, 1690 were white, and the mean (SD) age was 70 [9] years. Of the 5109 patients in the autopsy cohort, 2813 were women, 4953 were white, and the mean (SD) age was 84 (9) years. After correcting for multiple comparisons using the Bonferroni procedure, we observed a statistically significant interaction between APOE-?4 and sex on CSF total tau (??=?0.41; 95% CI, 0.27-0.55; P?<?.001) and phosphorylated tau (??=?0.24; 95% CI, 0.09-0.38; P?=?.001), whereby APOE showed a stronger association among women compared with men. Post hoc analyses suggested this sex difference was present in amyloid-positive individuals (??=?0.41; 95% CI, 0.20-0.62; P?<?.001) but not among amyloid-negative individuals (??=?0.06; 95% CI, -0.18 to 0.31; P?=?.62). We did not observe sex differences in the association between APOE and ?-amyloid 42, neuritic plaque burden, or neurofibrillary tangle burden. Conclusions and Relevance:We provide robust evidence of a stronger association between APOE-?4 and CSF tau levels among women compared with men across multiple independent data sets. Interestingly, APOE-?4 is not differentially associated with autopsy measures of neurofibrillary tangles. Together, the sex difference in the association between APOE and CSF measures of tau and the lack of a sex difference in the association with neurofibrillary tangles at autopsy suggest that APOE may modulate risk for neurodegeneration in a sex-specific manner, particularly in the presence of amyloidosis.

Project description:Tau gene has been consistently associated with the risk of Parkinson disease in recent genome wide association studies. In addition, alterations of the levels of total tau, phosphorylated tau [181P], and amyloid beta 1-42 in cerebrospinal fluid have been reported in patients with sporadic Parkinson disease and asymptomatic carriers of leucine-rich repeat kinase 2 mutations, in patterns that clearly differ from those typically described for patients with Alzheimer disease. To further determine the potential roles of these molecules in Parkinson disease pathogenesis and/or in tracking the disease progression, especially at early stages, the current study assessed all three proteins in 403 Parkinson disease patients enrolled in the DATATOP (Deprenyl and tocopherol antioxidative therapy of parkinsonism) placebo-controlled clinical trial, the largest cohort to date with cerebrospinal fluid samples collected longitudinally. These initially drug-naive patients at early disease stages were clinically evaluated, and cerebrospinal fluid was collected at baseline and then at endpoint, defined as the time at which symptomatic anti-Parkinson disease medications were determined to be required. General linear models were used to test for associations between baseline cerebrospinal fluid biomarker levels or their rates of change and changes in the Unified Parkinson Disease Rating Scale (total or part III motor score) over time. Robust associations among candidate markers are readily noted. Baseline levels of amyloid beta were weakly but negatively correlated with baseline Unified Parkinson Disease Rating Scale total scores. Baseline phosphorylated tau/total tau and phosphorylated tau/amyloid beta were significantly and negatively correlated with the rates of the Unified Parkinson Disease Rating Scale change. While medications (deprenyl and/or tocopherol) did not appear to alter biomarkers appreciably, a weak but significant positive correlation between the rate of change in total tau or total tau/amyloid beta levels and the change of the Unified Parkinson Disease Rating Scale was observed. Notably, these correlations did not appear to be influenced by APOE genotype. These results are one of the very first pieces of evidence suggesting that tau and amyloid beta are critically involved in early Parkinson disease progression, potentially by a different mechanism than that in Alzheimer disease, although their applications as Parkinson disease progression markers will likely require the addition of other proteins.

Project description:Cerebral accumulation of amyloid-? is thought to be the starting mechanism in Alzheimer's disease. Amyloid-? can be detected by analysis of cerebrospinal fluid amyloid-?42 or amyloid positron emission tomography, but it is unknown if any of the methods can identify an abnormal amyloid accumulation prior to the other. Our aim was to determine whether cerebrospinal fluid amyloid-?42 change before amyloid PET during preclinical stages of Alzheimer's disease. We included 437 non-demented subjects from the prospective, longitudinal Alzheimer's Disease Neuroimaging Initiative (ADNI) study. All underwent (18)F-florbetapir positron emission tomography and cerebrospinal fluid amyloid-?42 analysis at baseline and at least one additional positron emission tomography after a mean follow-up of 2.1 years (range 1.1-4.4 years). Group classifications were based on normal and abnormal cerebrospinal fluid and positron emission tomography results at baseline. We found that cases with isolated abnormal cerebrospinal fluid amyloid-? and normal positron emission tomography at baseline accumulated amyloid with a mean rate of 1.2%/year, which was similar to the rate in cases with both abnormal cerebrospinal fluid and positron emission tomography (1.2%/year, P = 0.86). The mean accumulation rate of those with isolated abnormal cerebrospinal fluid was more than three times that of those with both normal cerebrospinal fluid and positron emission tomography (0.35%/year, P = 0.018). The group differences were similar when analysing yearly change in standardized uptake value ratio of florbetapir instead of percentage change. Those with both abnormal cerebrospinal fluid and positron emission tomography deteriorated more in memory and hippocampal volume compared with the other groups (P < 0.001), indicating that they were closer to Alzheimer's disease dementia. The results were replicated after adjustments of different factors and when using different cut-offs for amyloid-? abnormality including a positron emission tomography classification based on the florbetapir uptake in regions where the initial amyloid-? accumulation occurs in Alzheimer's disease. This is the first study to show that individuals who have abnormal cerebrospinal amyloid-?42 but normal amyloid-? positron emission tomography have an increased cortical amyloid-? accumulation rate similar to those with both abnormal cerebrospinal fluid and positron emission tomography and higher rate than subjects where both modalities are normal. The results indicate that cerebrospinal fluid amyloid-?42 becomes abnormal in the earliest stages of Alzheimer's disease, before amyloid positron emission tomography and before neurodegeneration starts.

Dataset Information

Associations between baseline amyloid, sex, and APOE on subsequent tau accumulation in cerebrospinal fluid.

Publications

Associations between baseline amyloid, sex, and APOE on subsequent tau accumulation in cerebrospinal fluid.

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