Racial Disparity in Cerebrospinal Fluid Amyloid and Tau Biomarkers and Associated Cutoffs for Mild Cognitive Impairment.
ABSTRACT: Importance:Prior evidence suggests that racial differences exist in tau biomarkers in mild cognitive impairment (MCI) and Alzheimer disease (AD). Whether this reported disparity is associated with a differential level of neurodegeneration and disease stage or with underlying mechanisms separate from amyloid or tau is unclear. Objectives:To compare cerebrospinal fluid (CSF) biomarkers in African American and white individuals with normal cognition and MCI, to estimate race-based cutoffs for these biomarkers that maximize diagnostic discrimination between normal cognition and MCI, and to study the association of demographic characteristics, cognitive performance, and common vascular risk factors with these differences. Design, Setting, and Participants:This case-control study conducted from March 1, 2016, through January 31, 2019, included participants in the Brain Stress Hypertension and Aging Research Program cohort undergoing baseline assessment. Participants were 50 years or older and recruited from the Atlanta, Georgia, area. Exposures:Self-reported race and cognitive status categorized using modified Petersen criteria and clinical consensus diagnosis. Main Outcomes and Measures:Levels of ?-amyloid 1-42 (A?1-42), tau, and phosphorylated tau 181 (pTau181), the ratio of tau or pTau181 to A?1-42, and hippocampal volume on magnetic resonance imaging of the brain. Results:Data from 362 study participants were analyzed (mean [SD] age, 65.6 [7.9] years), of whom 152 (42.0%) were African American, 230 (63.5%) were women, and 189 (52.2%) had MCI. After adjustment for demographic characteristics and cognitive performance, lower mean (SE) levels were observed in African American vs white individuals with MCI for tau (52.40 [5.90] vs 78.98 [5.02] pg/mL; P?=?.001) and pTau181 (15.42 [2.06] vs 25.24 [1.75] pg/mL; P?=?.001) and a lower pTau181 to A?1-42 ratio (0.07 [0.02] vs 0.14 [0.01]; P?=?.003). There were no racial differences in the normal cognition group or in hippocampal volumes in the MCI group. Cutoffs for CSF biomarkers were higher for A?1-42 in African American relative to white individuals (208 [95% CI, 126-321] vs 197 [95% CI, 183-245] pg/mL) and lower for tau (51 [95% CI, 31-59] vs 59 [95% CI, 56-92] pg/mL) and pTau181 (12 [95% CI, 12-19] vs 20 [95% CI, 12-27] pg/mL) levels. Cutoffs for the pTau181 to A?1-42 ratio were 0.05 (95% CI, 0.03-0.12) for African American participants and 0.05 (95% CI, 0.05-0.13) for white participants. Conclusions and Relevance:This study found that African American individuals had lower levels of tau-based biomarkers that were not likely explained by the degree of disease stage or neurodegeneration reflected by hippocampal volumes. This study suggests that race is an important factor when interpreting CSF biomarkers, especially in the clinical diagnosis of prodromal AD. It appears that using the pTau181 to A?1-42 ratio may ameliorate these differences.
Project description:The elusive relationship between underlying pathology and clinical disease hampers diagnosis of Alzheimer's disease (AD) and preventative intervention development. We seek to understand the relationship between two classical AD biomarkers, amyloid-?<sub>1-42</sub> (A?<sub>1-42</sub>) and total-tau (t-tau), and define their trajectories across disease development, as defined by disease onset at diagnosis of mild cognitive impairment (MCI). Using longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we performed a correlation analysis of biomarkers CSF A?<sub>1-42</sub> and t-tau, and longitudinal quantile analysis. Using a mixed effects model, with MCI onset as an anchor, we develop linear trajectories to describe the rate of change across disease development. These trajectories were extended through the incorporation of data from cognitively normal, healthy adults (aged 20-62 years) from the literature, to fit sigmoid curves by means of non-linear least squares estimators, to create curves encompassing the 50 years prior to MCI onset. A strong right-angled relationship between the biomarkers A?<sub>1-42</sub> and t-tau is detected, implying a highly non-linear relationship. The rate of change of A?<sub>1-42</sub> is correlated with the baseline concentration per quantile, reflecting a reduction in the rate of loss across disease within subjects. Regression models reveal significant amyloid loss relative to MCI onset (- 2.35 pg/mL/year), compared to minimal loss relative to AD onset (- 0.97 pg/mL/year). Tau accumulates consistently relative to MCI and AD onset, (2.05 pg/mL/year) and (2.46 pg/mL/year), respectively. The fitted amyloid curve shows peak loss of amyloid 8.06 years prior to MCI diagnosis, while t-tau exhibits peak accumulation 14.17 years following MCI diagnosis, with the upper limit not yet reached 30 years post diagnosis. Biomarker trajectories aid unbiased, objective assessment of disease progression. Quantitative trajectories are likely to be of use in clinical trial design, as they allow for a more detailed insight into the effectiveness of treatments designed to delay development of biological disease.
Project description:BACKGROUND:The previously described and validated Erlangen Score (ES) algorithm enables interpretation of the cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD), ordering them on an ordinal scale: from neurochemically normal (ES?=?0) through improbable AD (ES?=?1), possible AD (ES?=?2 or 3), to probable AD (ES?=?4). Here we assess the accuracy of the ES in predicting hazards of progression from the mild cognitive impairment (MCI) stage of AD to the dementia stage of the disease (Alzheimer's disease dementia (ADD)) in a novel, single-center cohort. METHODS:Baseline CSF biomarkers (amyloid beta (A?) 1-42, A?42/40, Tau, and pTau181), interpreted according to the ES, were used to estimate time to progression from the MCI stage of AD to ADD, conditional on age, gender, APOE ?4 genotype, and Mini Mental State Examination score in 144 MCI subjects, using the Extended Cox Model; the subjects were followed-up until they developed dementia or until they had been cognitively stable for at least 2?years. In addition, ES distributions were studied in 168 ADD cases and 66 neurologic controls. Further, we stratified MCI patients into those who progressed to ADD faster (within 3 years, n?=?47) and those who progressed slower (n?=?74). RESULTS:The distributions of the ES categories across the four diagnostic groups (Controls, MCI-Stable, MCI-AD, and ADD) were highly significantly different (Kruskal-Wallis ?2(df?=?3)?=?151.4, p?<?0.001), with significant contrasts between each pair (p?<?0.005), except between the ADD and the MCI-AD groups (p?=?1.0). MCI patients with ES?=?2 or 3 had 6-8 times higher hazards to progress to ADD compared to patients with ES?=?0 or 1 in the first 3 follow-up years, and then their hazards decreased to those of the group with ES?=?0 or 1. Patients with ES?=?4 had hazards 8-12 times higher compared to the ES?=?0 or 1 group. Faster progressors with ES?=?2 or 3 had, in comparison to slower progressors, significantly lower A?1-42, A?1-40, and A?42/40, but comparable Tau and pTau181. A highly significant difference of the ES distributions between these two groups was observed (p?<?0.001). CONCLUSIONS:Our current results reconfirm and extend the conclusions of the previously published report that the Erlangen Score is a useful tool facilitating interpretation of a complex pattern of the CSF AD biomarkers.
Project description:African Americans have been reported to have a higher prevalence of Alzheimer's disease (AD) than Caucasians, but etiology-specific AD biomarkers have not been systematically analyzed in older African Americans. Coexisting cerebrovascular disease may also contribute to this increased prevalence. We hypothesized that cerebrospinal fluid (CSF) biomarkers of amyloid, neurodegeneration, and endothelial dysfunction would differ between older African Americans and Caucasians with normal cognition and cognitive impairment associated with AD.We prospectively recruited 135 older Americans to undergo detailed clinical, neuropsychological, genetic, magnetic resonance imaging (MRI), and CSF analysis from 2013 to 2015 at Emory University (Atlanta, GA, USA). We compared levels of CSF markers for ?-amyloid (A?42, A?40), total and phosphorylated tau (t-tau and p-tau181, respectively), endothelial dysfunction (soluble vascular cell adhesion molecule 1, soluble intercellular adhesion molecule 1), ?-synuclein, and neurodegeneration (neurofilament light chain [NfL]), as well as MRI markers, for hippocampal atrophy and cerebrovascular disease (white matter hyperintensity [WMH] volume).Sixty-five older African Americans (average age, 69.1 years) and 70 older Caucasians (average age, 70.8 years) were included. After adjusting for demographic variables, AD risk alleles, and cognitive function, older African Americans had lower CSF levels of p-tau181 (difference of 7.4 pg/ml; 95% CI, 3.7-11.2 pg/ml; p?<?0.001), t-tau (difference of 23.6 pg/ml; 95% CI, 9.5-37.7; p?=?0.001), and A?40 (difference of 1.35 ng/ml; 95% CI, 0.29-2.42 ng/ml; p?=?0.013) despite similar levels of A?42, NfL, WMH volume, and hippocampal volume. Cognitively impaired African Americans also had lower CSF t-tau/A?42 (difference of 0.255 per 1-SD change in composite cognition; 95% CI, 0.100-0.409; p?=?0.001) and p-tau181/A?42 (difference of 0.076 per 1-SD change in composite cognition; 95% CI, 0.031-0.122; p?=?0.001). These could not be explained by measured biomarkers of non-AD processes, but African Americans may be more susceptible than Caucasians to the cognitive effects of WMH.Despite comparable levels of CSF A?42 and A?42/A?40, cognitive impairment in African Americans is associated with smaller changes in CSF tau markers but greater impact from similar WMH burden than Caucasians. Race-associated differences in CSF tau markers and ratios may lead to underdiagnosis of AD in African Americans.ClinicalTrials.gov, NCT02089555 . Retrospectively registered on 14 March 2014.
Project description:Cerebrospinal fluid (CSF) levels of Abeta peptide 1-42 (Abeta 42), tau, and phosphorylated tau (ptau) are potential biomarkers of Alzheimer disease.To determine whether Abeta 42, tau, and ptau predict the rate of cognitive change in individuals with very mild dementia of the Alzheimer type (DAT).Retrospective analysis of CSF biomarkers and clinical data.An academic Alzheimer disease research center.Research volunteers in a longitudinal study of aging and cognition. Participants (n = 49) had a clinical diagnosis of very mild DAT with a Clinical Dementia Rating (CDR) of 0.5 at the time of lumbar puncture. All the participants had at least 1 follow-up assessment (mean [SD] follow-up, 3.5 [1.8] years).Baseline CSF levels of Abeta 42, Abeta 40, tau, and ptau at threonine 181 (ptau181) and the rate of dementia progression as measured using the CDR sum of boxes (CDR-SB) score and psychometric performance.The rate of dementia progression was significantly more rapid in individuals with lower baseline CSF Abeta 42 levels, higher tau or ptau181 levels, or high tau: Abeta 42 ratios. For example, the annual change in the CDR-SB score was 1.1 for the lowest 2 tertiles of Abeta 42 values and 0.3 for the highest tertile of Abeta 42 values.In individuals with very mild DAT, lower CSF Abeta 42 levels, high tau or ptau181 levels, or high tau:Abeta 42 ratios quantitatively predict more rapid progression of cognitive deficits and dementia. Biomarkers of CSF may be useful prognostically and to identify individuals who are more likely to progress for participation in therapeutic clinical trials.
Project description:A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-?2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and A?1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-?4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low A?1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.
Project description:Postmortem brain studies of older drivers killed in car accidents indicate that many had Alzheimer disease (AD) neuropathologic changes. We examined whether AD biomarkers are related to driving performance among cognitively normal older adults. Individuals with normal cognition, aged 65+ years, and driving at least once per week, were recruited. Participants (N=129) took part in clinical assessments, a driving test, and positron emission tomography imaging with Pittsburgh compound B (PIB) and/or cerebrospinal fluid (CSF) collection. General linear models tested whether the number of driving errors differed as a function of each of the biomarker variables (mean cortical binding potential for PIB, and CSF A?42, tau, ptau181, tau/A?42, ptau181/A?42). Higher ratios of CSF tau/A?42, ptau181/A?42, and PIB mean cortical binding potential, were associated with more driving errors (P<0.05). Preclinical AD may have subtle cognitive and functional effects, which alone may go unnoticed. However, when combined, these changes may impact complex behaviors such as driving.
Project description:Electroencephalography signatures of amyloid-?, tau and neurodegenerative pathologies would aid in screening for, tracking progression of, and critically, understanding the pathogenesis of dementia. We hypothesized that slowing of the alpha peak frequency, as a signature of hyperpolarization-activated cyclic nucleotide gated 'pacemaker' channel activity, would correlate with amyloid and tau pathology burden measured by amyloid (Pittsburgh Compound B) and tau (MK-6240) positron emission tomography or CSF biomarkers. We also hypothesized that EEG power would be associated with neurodegeneration (CSF neurofilament light and hippocampal volume). Wakeful high-density EEG data were collected from 53 subjects. Both amyloid-? and tau pathology were associated with slowing in the alpha peak frequency [Pittsburgh Compound B (+) vs. Pittsburgh Compound B (-) subjects, P?=?0.039 and MK-6240 (+) vs. MK-6240 (-) subjects, P?=?0.019]. Furthermore, slowing in the peak alpha frequency correlated with CSF A?42/40 ratio (r 2 = 0.270; P?=?0.003), phosphoTau (pTau181, r 2 = 0.290; P?=?0.001) and pTau181/A?42 (r 2 = 0.343; P?<?0.001). Alpha peak frequency was not associated with neurodegeneration. Higher CSF neurofilament light was associated with lower total EEG power (r 2 = 0.136; P?=?0.018), theta power (r 2 = 0.148; P?=?0.014) and beta power (r 2 = 0.216; P?=?0.002); the latter was also associated with normalized hippocampal volume (r 2 = 0.196; P?=?0.002). Amyloid-tau and neurodegenerative pathologies are associated with distinct electrophysiological signatures that may be useful as mechanistic tools and diagnostic/treatment effect biomarkers in clinical trials.
Project description:Defining cases and controls on the basis of biomarkers rather than clinical diagnosis may reduce sample sizes required for genetic studies. The aim of this study was to assess whether characterizing case/control status on the basis of cerebrospinal fluid (CSF) profile would increase power to replicate known genetic associations for Alzheimer's disease (AD). Independent of clinical diagnosis, Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects with 2 CSF biomarkers for AD (A?1-42 < 192 pg/mL and tau phosphorylated at threonine 181 (p-tau) > 23 pg/mL, "CSF-positive") were compared with those without CSF evidence for AD (A?1-42 > 192 pg/mL and 181-phosphorylated tau < 23 pg/mL, "CSF-negative"). Minor allele frequency (MAF) and odds ratios (ORs) between these 2 groups were calculated for 7 single-nucleotide polymorphisms (SNPs) of interest. Two hundred thirty-two individuals were CSF-positive and 94 CSF-negative. There were no differences in age (74.7 ± 7.2 vs. 75.0 ± 6.5 years, p = 0.7), but significant differences in Mini Mental State Examination (MMSE) (25.9 ± 2.6 vs. 28.2 ± 1.7, p < 0.001) between the CSF-positive and CSF-negative groups. Significant differences in MAF (p < 0.05, uncorrected) were seen for CR1 (rs1408077; OR, 1.59; 95% confidence interval [CI], 1.01-2.49), PICALM (rs541458; OR, 0.68, 95% CI, 0.47-0.98), TOMM40 (rs2075650; OR, 4.30; 95% CI, 2.61-7.06); and possession of 1 or more APOE ?4 alleles (OR, 9.84; 95% CI, 5.48-17.67). These results suggest that using biomarkers of AD pathology to define case and control status may increase power in genetic association studies.
Project description:<h4>Importance</h4>Racial differences in molecular biomarkers for Alzheimer disease may suggest race-dependent biological mechanisms.<h4>Objective</h4>To ascertain whether there are racial disparities in molecular biomarkers for Alzheimer disease.<h4>Design, setting, and participants</h4>A total of 1255 participants (173 African Americans) were enrolled from January 1, 2004, through December 31, 2015, in longitudinal studies at the Knight Alzheimer Disease Research Center at Washington University and completed a magnetic resonance imaging study of the brain and/or positron emission tomography of the brain with Pittsburgh compound B (radioligand for aggregated amyloid-β) and/or cerebrospinal fluid (CSF) assays for the concentrations of amyloid-β42, total tau, and phosphorylated tau181. Independent cross-sectional analyses were conducted from April 22, 2016, to August 27, 2018, for each biomarker modality with an analysis of variance or analysis of covariance including age, sex, educational level, race, apolipoprotein E (APOE) ε4 allele status, and clinical status (normal cognition or dementia). All biomarker assessments were conducted without knowledge of the clinical status of the participants.<h4>Main outcomes and measures</h4>The primary outcomes were hippocampal volumes adjusted for differences in intracranial volumes, global cerebral amyloid burden as transformed into standardized uptake value ratios (partial volume corrected), and CSF concentrations of amyloid-β42, total tau, and phosphorylated tau181.<h4>Results</h4>Of the 1255 participants (707 women and 548 men; mean [SD] age, 70.8 [9.9] years), 116 of 173 African American participants (67.1%) and 724 of 1082 non-Hispanic white participants (66.9%) had normal cognition. There were no racial differences in the frequency of cerebral ischemic lesions noted on results of brain magnetic resonance imaging, mean cortical standardized uptake value ratios for Pittsburgh compound B, or for amyloid-β42 concentrations in CSF. However, in individuals with a reported family history of dementia, mean (SE) total hippocampal volumes were lower for African American participants than for white participants (6418.26 [138.97] vs 6990.50 [44.10] mm3). Mean (SE) CSF concentrations of total tau were lower in African American participants than in white participants (293.65 [34.61] vs 443.28 [18.20] pg/mL; P < .001), as were mean (SE) concentrations of phosphorylated tau181 (53.18 [4.91] vs 70.73 [2.46] pg/mL; P < .001). There was a significant race by APOE ε4 interaction for both CSF total tau and phosphorylated tau181 such that only APOE ε4-positive participants showed the racial differences.<h4>Conclusions and relevance</h4>The results of this study suggest that analyses of molecular biomarkers of Alzheimer disease should adjust for race. The lower CSF concentrations of total tau and phosphorylated tau181 in African American individuals appear to reflect a significant race by APOE ε4 interaction, suggesting a differential effect of this Alzheimer risk variant in African American individuals compared with white individuals.
Project description:Intra- and inter-laboratory variability of cerebrospinal fluid (CSF) biomarker analyses remains an important issue. We investigated the clinical-diagnostic impact of CSF biomarker concentration shifts in mild cognitive impairment (MCI) and autopsy-confirmed Alzheimer's disease (AD) dementia patients. MCI patients (n?=?85), autopsy-confirmed AD dementia patients (n?=?72), and cognitively healthy controls (n?=?100) were included in this prospective, longitudinal study. AD dementia patients were followed up until death, and controls were included from 1992 until 2003. In-house validated cutoff values of biomarkers were applied: A?1-42 <638.5 pg/mL, T-tau>296.5 pg/mL, P-tau(181P) >56.5 pg/mL. Both increments and decrements (from ± 5% to ± 40% ) were added to the true (=observed) CSF biomarker values, imitating the anticipated differences in biomarker concentrations. Within certain limits, the clinical diagnostic performance of AD CSF biomarkers remains largely unchanged and clinical diagnostic accuracy deviated less than 8.2% from the reference when concentration shifts ranging between -20% and +20% were added to one of the three CSF biomarkers in MCI and autopsy-confirmed AD patients. Notwithstanding the fact that (pre- and post-)analytical parameters can affect the clinical classification, the present exploratory study provides evidence that for a specific context of use, the impact on clinical accuracy of biomarker concentration shifts might be lower than originally expected. In conclusion, induced shifts of ±20% in only one of the three biomarkers has limited impact on the clinical accuracy of AD CSF biomarkers in MCI and autopsy-confirmed AD patients when using the IWG-2 criteria.