Texas Alzheimer's Research And Care Consortium Research Articles

INFLAMMATION's cognitive impact revealed by a novel "Line of Identity" approach.

Dementia is an "overdetermined" syndrome. Few individuals are demented by any single biomarker, while several may independently explain small fractions of dementia severity. It may be advantageous to identify individuals afflicted by a specific biomarker to guide individualized treatment. We aim to validate a psychometric classifier to identify persons adversely impacted by inflammation and replicate it in a second cohort. Secondary analyses of data collected by the Texas Alzheimer's Research and Care Consortium (TARCC) (N = 3497) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 1737). Two large, well-characterized multi-center convenience samples. Volunteers with normal cognition (NC), Mild Cognitive Impairment (MCI) or clinical "Alzheimer's Disease (AD)". Participants were assigned to "Afflicted" or "Resilient" classes on the basis of a psychometric classifier derived by confirmatory factor analysis. The groups were contrasted on multiple assessments and biomarkers. The groups were also contrasted regarding 4-year prospective conversions to "AD" from non-demented baseline diagnoses (controls and MCI). The Afflicted groups were predicted to have adverse levels of inflammation-related blood-based biomarkers, greater dementia severity and greater risk of prospective conversion. In ADNI /plasma, 47.1% of subjects were assigned to the Afflicted class. 44.6% of TARCC's subjects were afflicted, 49.5% of non-Hispanic Whites (NHW) and 37.2% of Mexican Americans (MA). There was greater dementia severity in the Afflicted class [by ANOVA: ADNI /F(1) = 686.99, p <0.001; TARCC /F(1) = 1544.01, p <0.001]. "INFLAMMATION" factor composite scores were significantly higher (adverse) in Afflicted subjects [by ANOVA in ADNI /plasma F(1) = 1642.64, p <0.001 and in TARCC /serum F(1) = 3059.96, p <0.001]. Afflicted cases were more likely to convert to AD in the next four years [by Cox's F, ADNI /plasma: F (252, 268) = 3.74 p < 0.001; TARCC /serum: F (160, 134) = 3.03, p < 0.001 (in TARCC's entire sample), F (110, 90) = 4.92, p <0.001 in NHW, and F(50, 44) = 2.13, p = 0.006 in MA]. The proportions converting were similar among afflicted NHW in both cohorts /biofluids but MA exhibited a lower risk (7% in TARCC /serum at 48 months). Our inflammation-specific psychometric classifier selects individuals with pre-specified biomarker profiles and predicts conversion to "AD" across cohorts, biofluids, and ethnicities. This algorithm might be applied to any dementia-related biomarker making the psychometric estimation of individual biomarker effects feasible without biomarker assessment. Our approach also distinguishes individuals resilient to individual biomarker effects allowing for more accurate prediction and precision intervention.

Factors Associated with Apathy in Alzheimer's Disease: A Cross-Sectional Analysis of the Texas Alzheimer's Research and Care Consortium (TARCC) Study.

Apathy is among the most frequent neuropsychiatric syndromes in Alzheimer's disease (AD). To determine the prevalence of apathy and the associated clinical and laboratorial parameters (focus on inflammatory biomarkers) in patients with dementia enrolled at the Texas Alzheimer's Research and Care Consortium (TARCC) study. This is a cross-sectional analysis of TARCC baseline. Participants were evaluated through different clinical tools, including the Mini-Mental State Examination (MMSE) and the Lawton-Brody Instrumental Activities of Daily Life (IADL)/Physical Self-Maintenance Scale (PSMS). Apathy was defined by a positive response to the respective item in the Neuropsychiatric Inventory-Questionnaire applied to caregivers. Serum levels of 16 biomarkers were determined by HumanMap multiplex immunoassay. Comparisons between apathy versus non-apathy groups were carried out with non-parametric tests. Logistic regression and the least absolute shrinkage and selection operator (LASSO) were used to separately model apathy as a function of each biomarker, adjusted for the potential confounders. From 1,319 patients with AD (M/F: 579/740, mean age ± SD: 75.3 ± 8.4), 373 (28.3%) exhibited apathy. When categorized according to the presence of apathy, the groups had significant differences in sex, diabetes diagnosis, and tobacco use. The apathy group also had worse cognitive performance and daily functioning than the non-apathy group as assessed, respectively, by MMSE and IADL/PSMS. Higher levels of interleukin-6, interleukin-10, and leptin were associated with higher odds of apathy. Apathy is associated with cognitive and functional status in AD. The association between apathy and peripheral inflammatory mediators deserves further investigation.

δ scores predict multiple neuropsychiatric symptoms.

Dementia severity is strongly related to Spearman's general intelligence factor "g", via the latent dementia phenotype "δ" and is distinct from domain-specific cognitive impairments arising from disease-specific regional pathologies. It is an empiric question whether behavioral and psychological symptoms of dementia (BPSD) are associated with δ or with domain-specific constructs. A recently developed δ homolog ("dDx") was tested as a predictor of 1 year prospective BPSD in n = 723 Mexican-American and non-Hispanic White participants in the Texas Alzheimer's Research and Care Consortium (TARCC). The informant-rated frequencies of 12 BPSD were rated by the neuropsychiatric inventory (NPI-Q). Baseline BPSD, demographic features, selected biomarkers, and treatment exposure to acetylcholinesterase inhibitors were used as covariates. Composite scores derived from orthogonal latent measures of domain-specific memory (MEM) and executive function (EF) were also tested as predictors. "Functionally salient cognitive impairment (FSCI)" that is, categorical "dementia" as diagnosed by dDx was associated with increased prospective frequency of 11/12 BPSD, independently of baseline behavior and covariates. Age, depressive symptoms, and EF were associated with individual BPSD. MEM was not associated with any. Dementia severity, as measured by dDx, was also associated with a prospective increase in total NPI-Q scores. δ is associated non-specifically with multiple BPSD. This suggests the existence of a dementia-specific behavioral profile, arising from insults to general intelligence, and unrelated to disease-specific regional pathology(ies).

Blood-based protein predictors of dementia severity as measured by δ: Replication across biofluids and cohorts

IntroductionDementia severity can be empirically described by the latent dementia phenotype “δ” and its various composite “homologs”. We have explored δ's blood-based protein biomarkers in the Texas Alzheimer's Research and Care Consortium (TARCC) study. However, it would be convenient to replicate those associations in the Alzheimer's Disease Neuroimaging Initiative (ADNI). To this end, we recently engineered a δ homolog from observed cognitive performance measures common to both projects (i.e., “dT2A”). MethodsWe used nine rationally chosen peripheral blood-based protein biomarkers as indicators of a latent variable “INFLAMMATION”. We then associated that construct with dT2A in structural equation models adjusted for age, gender, depressive symptoms, and apolipoprotein E (APOE) ε4 allelic burden. Significant factor loadings and INFLAMMATION's association with dT2A were confirmed in random splits of TARCC's relatively large sample, and across biofluids in the ADNI. ResultsNine proteins measured in serum (TARCC) or plasma (ADNI) explained ≅10% of dT2A's variance in both samples, independently of age, APOE, education, and gender. All loaded significantly on INFLAMMATION, and positively or negatively, depending on their known roles are PRO- or ANTI-inflammatory proteins, respectively. The parameters of interest were confirmed across random 50% splits of the TARCC's sample, and replicated across biofluids in the ADNI. DiscussionThese results suggest that SEM can be used to replicate biomarker findings across samples and biofluids, and that a substantial fraction of dementia's variance is attributable to peripheral blood-based protein levels.

δ Scores Identify Subsets of "Mild Cognitive Impairment" with Variable Conversion Risks.

The latent variable "δ" (for "dementia) is a transdiagnostic measure of dementia severity. δ can be reified and applied to individuals as a composite "d-score". Like Spearman's general intelligence factor "g", δ can be constructed from almost any cognitive battery. So many are available that we must further distinguish each composite as a δ "homolog". Fourteen have been validated. All are strongly associated with dementia severity and potentially with mild cognitive impairment (MCI) conversion. To assess δ's impact on MCI conversion risk. A new δ homolog (dDx) was constructed in 1,230 Mexican-American (MA) and 2,215 non-Hispanic White (NHW) participants in the Texas Alzheimer's Research and Care Consortium (TARCC). 1,445 normal controls (NC) and 723 MCI were followed annually for up to 6 years. Each SD decrease in the dDx score increased the risk of conversion sixteen-fold [OR = 16.39 (CI: 5.0-52.6)]. Cases below the optimal diagnostic threshold for Alzheimer's disease (AD) versus NC were labeled as having a functionally salient cognitive impairment (FSCI). Such cases were at a 73-fold increase risk of a diagnosis of AD [OR = 73.19 (95% CI: 58.3-92.0)]. However, 25.6% of MCI cases were also FSCI(+). They accounted disproportionately for prospective conversions. Age <80 years, the absence of an ɛ4 allele, <12 years of education, and MA ethnicity independently increased the risk of diagnosing FSCI as MCI. A sizable minority of MCI cases may be misdiagnosed and they account disproportionately for AD conversions.

Serum Adiponectin is Related to Dementia.

The adipokine adiponectin (APN)'s role in Alzheimer's disease (AD) is controversial. Some studies suggest APN is neuroprotective while others propose it has harmful effects. We have used Multiple Indicators Multiple Causes (MIMIC) models to evaluate the effects of serum protein biomarkers on cognitive performance in the Texas Alzheimer's Research and Care Consortium (TARCC) (Royall DR, Bishnoi RJ, Palmer RF. Serum IGF-BP2 strongly moderates age's effect on cognition: a MIMIC analysis. Neurobiol Aging. 2015;36:2232-2240; Bishnoi RJ, Palmer RF, Royall DR. Vitamin D binding protein as a serum biomarker of Alzheimer's disease. J Alzheimers Dis. 2015;43:37-45; Bishnoi RJ, Palmer RF, Royall DR. Serum interleukin (IL)-15 as a biomarker of Alzheimer's disease. PLoS One. 2015;10:e0117282). MIMIC models were constructed and replicated in randomly selected 50% splits of TARCC's data (Group 1 N = 1,691; Group 2 N = 1,690) and used to evaluate the relationship between serum APN levels and cognition. Our approach has been to divide general intelligence (Spearman's g) (Spearman C. The Abilities of Man: Their Nature and Measurement. 1932) into two latent variables, δ (ie, a dementia-specific phenotype representing the disabling fraction of cognitive variance) and g prime (g') (ie, the residual non-disabling fraction). Only effects on δ are likely to be dementing. Serum APN was significantly related to δ scores (r = .10, p = .015). APN had no significant effect on g' (r = -.25, p = .66), nor did it have any independent direct effects on cognitive performance. These results were replicated across random subsets (ΔCHISQ = 2.8(7), p > .90). APN's effect on cognition is mediated through intelligence (ie, δ), likely to be disabling, and therefore to mediate one or more dementing processes. We have previously shown APN to partially mediate age's-specific effect on δ (Royall DR, Al-Rubaye S, Bishnoi R, Palmer RF. Serum protein mediators of dementia and aging proper. Aging (Albany NY). 2016;8:3241-3254). However, because the current model is age adjusted, APN must mediate one or more additional age-independent dementing process(es), possibly AD.

A δ Homolog for Dementia Case Finding with Replication in the Alzheimer's Disease Neuroimaging Initiative.

Dementia can be empirically described by the latent dementia phenotype "δ" and its various composite "homologs". We have explored δ's blood-based protein biomarkers in the Texas Alzheimer's Research and Care Consortium (TARCC) study. However, it would be convenient to replicate those associations in the Alzheimer's Disease Neuroimaging Initiative (ADNI). To this end, we have engineered a δ homolog from observed cognitive performance measures common to both projects. Our findings were replicated in randomly selected 50% splits of TARCC data (Group 1, N = 1,747; Group 2, N = 1,755), and then independently in ADNI (N = 1,737). The new δ homolog, i.e., "dT2A" (d-TARCC to ADNI), fit the data of both studies well, and was strongly correlated with dementia severity, as rated by the Clinical Dementia Rating Scale "sum of boxes" (TARCC: r = 0.99, p < 0.001; ADNI: r = 0.96, p < 0.001). dT2A achieved an area under the receiver operating characteristic curve of 0.981 (0.976-0.985) for the discrimination of Alzheimer's disease from normal controls in TARCC, and 0.988 (0.983-0.993) in ADNI. dT2A is the 12th δ homolog published to date, and opens the door to independent replications across these and similar studies.

SERUM S100B MEDIATES DEPRESSION’S EFFECT ON COGNITION

The latent variable “δ” (for “dementia”) appears to be uniquely responsible for the dementing aspects of cognitive impairment. Age, depression, and the apolipoprotein E (APOE) e4 allele are independently associated with δ. S100b is a calcium- binding protein that is secreted mainly by astrocytes. S100b has been identified as a biomarker for mood/ depressive disorders. In addition, Brain level of S100b is altered in response to chronic use of anti-depressants. In this analysis, we combine SEM (Structural Equation Model) with longitudinal data from the Texas Alzheimer's Research and Care Consortium (TARCC) to explore whether S100b is a mediator of depression's specific effect on δ. We employed structural equation models (SEM) to examine the mediation effect of S100b on depression's association with δ in a well characterized cohort (TARCC). Subjects included n= 3385 TARCC participants [1240 cases of Alzheimer's Disease (AD), 688 “Mild Cognitive Impairment “(MCI) cases, and 1384 normal controls (NC)]. Serum S100b levels were determined at baseline by Luminex assay (Rules Based Medicine /Austin, TX). All observed measures were adjusted for education, ethnicity, gender, Geriatric Depression Scale (GDS) scores, Hb1Ac, apoE4 and HCY. S100b was additionally adjusted for batch effects. We used an ethnicity equivalent δ homolog (i.e., “dEQ”). Wave 2 dEQ scores were used. Thus, the model is longitudinal and arguable causal. Furthermore, we randomly divided the cohort into 2 groups. Group A (n = 1691) was used to construct the model, while Group B (n=1694) was used to replicate and verify the parameters of interest. Analyses were conducted in Analysis of Moment Structures (AMOS). Model fit was excellent [c2 = 519.912(49), p =0.0; CFI = 0.89; RMSEA = 0.053]. Serum S100b was found to mediate 18.3% of depression's association with Wave 2 dEQ scores (p<0.001). The effect generalized across random subsets of TARCC's sample. S100B plays a role in mediating depression's independent effects on dementia severity. High levels of serum S100B are dementing. S100B is a possible serum biomarker of depression in the elderly. S100B is a target for rational anti-dementia intervention, and may be amenable to modulation by SSRI.

Few serum proteins mediate APOE's association with dementia.

The latent variable “δ” (for “dementia”) appears to be uniquely responsible for the dementing aspects of cognitive impairment. Age, depression, gender and the apolipoprotein E (APOE) e4 allele are independently associated with δ. In this analysis, we explore serum proteins as potential mediators of APOE’s specific association with δ in a large, ethnically diverse longitudinal cohort, the Texas Alzheimer’s Research and Care Consortium (TARCC). APOE was associated only with C-Reactive Protein (CRP), Adiponectin (APN) and Amphiregulin (AREG), although the latter two’s associations did not survive Bonferroni correction for multiple comparisons. All three proteins were associated with δ and had weak potential mediation effects on APOE’s association with that construct. Our findings suggest that APOE’s association with cognitive performance is specific to δ and partially mediated by serum inflammatory proteins. The majority of APOE’s significant unadjusted effect on δ is unexplained. It may instead arise from direct central nervous system effects, possibly on native intelligence. If so, then APOE may exert a life-long influence over δ and therefore all-cause dementia risk.

Serum protein mediators of dementia and aging proper.

The latent variable “δ” (for “dementia”) appears to be uniquely responsible for the dementing aspects of cognitive impairment. Age, depressive symptoms, gender and the apolipoprotein E (APOE) ε4 allele are independently associated with δ. In this analysis, we explore serum proteins as potential mediators of age's specific association with δ in a large, ethnically diverse longitudinal cohort, the Texas Alzheimer's Research and Care Consortium (TARCC). 22 serum proteins were recognized as partial mediators of age's association with δ. These include Insulin-like Growth Factor-Binding Protein 2 (IGF-BP2), which we had previously associated with age-specific cognitive change, and both Pancreatic Polypeptide (PP) and von Willebrand Factor (vWF), previously associated with δ. Nine other δ-related proteins were not confirmed by this ethnicity adjusted analysis. Our findings suggest that age's association with the disabling fraction of cognitive performance is partially mediated by serum proteins, somatomedins and hormones. Those proteins may offer targets for the specific treatment of age-related effects on dementia severity and conversion risk.

Aging is a weak but relentless determinant of dementia severity.

Structural Equation Models (SEM) can explicitly distinguish “dementia-relevant” variance in cognitive task performance (i.e., “δ” for dementia). In prior work, δ appears to uniquely account for dementia severity regardless of the cognitive measures used to construct it. In this study, we test δ as a mediator of age's prospective association with future cognitive performance and dementia severity in a large, ethnically diverse longitudinal cohort, the Texas Alzheimer's Research and Care Consortium (TARCC). Age had adverse effects on future cognition, and these were largely mediated through δ, independently of education, ethnicity, gender, depression ratings, serum homo-cysteine levels, hemoglobin A1c, and apolipoprotein e4 status. Age explained 4% of variance in δ, and through it, 11-18% of variance in future cognitive performance. Our findings suggest that normative aging is a dementing condition (i.e., a “senility”). While the majority of variance in dementia severity must be independent of age, age's specific effect is likely to accumulate over the lifespan. Our findings also constrain age's dementing effects on cognition to the age-related fraction of “general intelligence” (Spearman's “g”). That has broad biological and pathophysiological implications.

Thrombopoietin is associated with δ's intercept, and only in Non-Hispanic Whites

IntroductionSerum thrombopoietin (THPO) is a biomarker of Alzheimer's disease (AD) and the latent dementia phenotype, “δ”. Both associations may be specific to non-Hispanic whites (NHW), not Mexican-Americans (MA). In this analysis, we examine ethnicity's effect on THPO's association with change in δ scores, in the Texas Alzheimer's Research and Care Consortium (TARCC). MethodsWe constructed an ethnicity equivalent δ homolog (“dEQ”) among n = 1113 MA and n = 1958 NHW. dEQ was output as a composite “dEQ-score” for each of five annual TARCC waves. Those composites were used as indicators of a latent growth curve (LGC). The mean dEQ intercept (idEQ) and slope (ΔdEQ) were estimated in a random subset of N = 1528 participants and replicated in the remainder (n = 1544). THPO was regressed onto idEQ and ΔdEQ. Those associations were tested separately in MA and NHW. ResultsdEQ correlated strongly with CDR-SB (r = 0.99, P < .001) and achieved high AUCs for AD diagnosis at each wave (range = 0.95–0.99). THPO was significantly associated with idEQ but not ΔdEQ. That effect was observed in NHW only. In MA, THPO had no associations with either idEQ or ΔdEQ. DiscussionWe confirm THPO's ethnicity-specific association with δ in NHW. It is further clarified that this association is specific to δ's intercept and not its slope. This analysis provides a model for how dementia's specific serum biomarkers can be characterized.

Serum interleukin (IL)-15 as a biomarker of Alzheimer's disease.

Interleukin (IL-15), a pro-inflammatory cytokine has been studied as a possible marker of Alzheimer’s disease (AD); however its exact role in neuro-inflammation or the pathogenesis AD is not well understood yet. A Multiple Indicators Multiple Causes (MIMIC) approach was used to examine the relationship between serum IL-15 levels and AD in a well characterized AD cohort, the Texas Alzheimer's Research and Care Consortium (TARCC). Instead of categorical diagnoses, we used two latent construct d (for dementia) and g’ (for cognitive impairments not contributing to functional impairments) in our analysis. The results showed that the serum IL-15 level has significant effects on cognition, exclusively mediated by latent construct d and g’. Contrasting directions of association lead us to speculate that IL-15’s effects in AD are mediated through functional networks as d scores have been previously found to be specifically related to default mode network (DMN). Our finding warrants the need for further research to determine the changes in structural and functional networks corresponding to serum based biomarkers levels.

Combining select neuropsychological assessment with blood-based biomarkers to detect mild Alzheimer's disease: a molecular neuropsychology approach.

Current work has sought to establish a rapid and cost effective means of screening for Alzheimer's disease (AD) with the most recent findings showing utility of integrating blood-based biomarkers with cognitive measures. The current project sought to create a combined biomarker-cognitive profile to detect mild AD. Data was analyzed from 266 participants (129 AD cases [Early AD n = 93; Very Early AD n = 36]; 137 controls) enrolled in the Texas Alzheimer's Research and Care Consortium (TARCC). Non-fasting serum samples were collected from each participant and assayed via a multi-plex biomarker assay platform using electrochemiluminescence. Logistic Regression was utilized to detect early AD using two serum biomarkers (TNFα and IL7), demographic information (age), and one neuropsychological measure (Clock 4-point) as predictor variable. Disease severity was determined via Clinical Dementia Rating (CDR) scale global scores. In the total sample (all levels of CDR scores), the combination of biomarkers, cognitive test score, and demographics yielded the obtained sensitivity (SN) of 0.94, specificity (SP) of 0.90, and an overall accuracy of 0.92. When examining early AD cases (i.e.m CDR = 0.5-1), the biomarker-cognitive profile yielded SN of 0.94, SP of 0.85, and an overall accuracy of 0.91. When restricted to very early AD cases (i.e., CDR = 0.5), the biomarker-cognitive profile yielded SN of 0.97 and SP of 0.72, with an overall accuracy of 0.91. The combination of demographics, two biomarkers, and one cognitive test created a biomarker-cognitive profile that was highly accurate in detecting the presence of AD, even in the very early stages.

Total Cholesterol and Neuropsychiatric Symptoms in Alzheimer's Disease: The Impact of Total Cholesterol Level and Gender

Background: Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are a major factor in nursing home placement and a primary cause of stress for caregivers. Elevated cholesterol has been linked to psychiatric disorders and has been shown to be a risk factor for AD and to impact disease progression. The present study investigated the relationship between cholesterol and NPS in AD. Methods: Data on cholesterol and NPS from 220 individuals (144 females, 76 males) with mild-to-moderate AD from the Texas Alzheimer's Research and Care Consortium (TARCC) cohort were analyzed. The total number of NPS and symptoms of hyperactivity, psychosis, affect and apathy were evaluated. Groups based on total cholesterol (TC; ≥200 vs. <200 mg/dl) were compared with regard to NPS. The impact of gender was also assessed. Results: Individuals with high TC had lower MMSE scores as well as significantly more NPS and more symptoms of psychosis. When stratified by gender, males with high TC had significantly more NPS than females with high TC or than males or females with low TC. Conclusion: The role of elevated cholesterol in the occurrence of NPS in AD appears to be gender and symptom specific. A cross-validation of these findings will have implications for possible treatment interventions, especially for males with high TC.

Validation of a Latent Construct for Dementia Case-Finding in Mexican-Americans

We have constructed a latent dementia proxy, "δ", and validated it in several datasets, including well characterized subjects participating in the Texas Alzheimer's Research and Care Consortium (TARCC) study. It may be possible to construct δ homologs from almost any ad hoc combination of cognitive and functional status measures. δ homologs may also be relatively immune to measurement error, including cultural, linguistic, or educational biases. These properties make factor scores derived from latent variables a potentially attractive solution for dementia case-finding in rural or minority populations. Here we have explored an alternative and briefer assessment by which to construct a δ homolog and validate the resulting latent variable (dMA) in Mexican-American (MA) TARCC subjects. dMA, composed of simple "bedside" dementia screening instruments, achieves Areas Under the Receiver Operative Curve that rival those of δ itself. Ethnicity has a small effect on dMA's performance. These results suggest that it may be possible to validly export dMA into other MA populations, or to export δ homolog factor scores from one population to another.

The biomarkers of dementia severity vary widely by ethnicity: A latent variable approach

Structural equation models (SEM) can explicitly distinguish dementia-relevant variance in cognitive task performance (i.e., “d” for dementia). The resulting latent variable represents an “error free” continuously varying endophenotype. Here, we associate d scores with serum biomarkers among Hispanic and non-Hispanic participants of the Texas Alzheimer's Research and Care Consortium (TARCC). Data from n = 2016 TARCC participants [920 cases of Alzheimer's disease (AD), 277 “Mild Cognitive Impairment” (MCI) cases, and 819 controls] were used to construct a latent measure of baseline dementia severity (d), as previously described (Royall, Palmer & O'Bryant, 2012). A modified battery was used that employed Clinicial Dementia Rating Scale sum of boxes (CDRSUM) instead of Instrumental Activities of Daily Living (IADL), in order to improve d's sensitivity to MCI. Multivariate regression models were constructed in SEM using serum biomarkers as predictors. All observed variables were adjusted for age, gender, ethnicity, and education. Additionally, serum biomarkers were adjusted for demographic adjusted batch effects. The latent variable d achieved very high Areas Under the Receiver Operating Curve (AUC, ROC) for the discriminations between AD and Controls (AUC = 0.989) and MCI v Controls (0.830). Twelve serum proteins made significant independent contributions to d scores. Together, they explained 20% of variance d's variance. This model had excellent fit. Ten proteins can be related to platelet activation via the toll-like receptor (TLR), an innate immunological response to infectious pathogens. However, ethnicity had a strong modulating effect. Their significance was largely limited to non-Hispanic subjects. Only APOE e4, pancreatic polypeptide (PP) and von Willebrandt factor (vWF) had significant effects in Hispanics (IL-13 and thrombopoeitin (TPO) exhibited trends). We find d scores to be associated with a subset of the serum biomarkers previously associated with “AD”s categorical diagnosis in this cohort, and identify several new potential biomarkers. Moreover, our smaller panel achieves a high AUC independent of covariates, and results in an interpretable pattern that suggests platelet mediated TLR activation. However, these associations are largely limited to non-Hispanics, confirming O'Brant et al's findings (in press).

The Relation between Inflammation and Neuropsychological Test Performance.

Background. Considerable research documents an association between pro- and anti-inflammatory markers and Alzheimer's disease (AD), yet the differential relation between these markers and neuropsychological functioning in AD and nondemented controls has received less attention. The current study sought to evaluate the relationship between peripheral markers of inflammation (both pro- and anti-inflammatory) and neuropsychological functioning through the Texas Alzheimer's Research and Care Consortium (TARCC) cohort. Methods. There were 320 participants (Probable AD n = 124, Controls n = 196) in the TARCC Longitudinal Research Cohort available for analysis. Regression analyses were utilized to examine the relation between proinflammatory and anti-inflammatory markers and neuropsychological functioning. Follow-up analyses were conducted separately by case versus control status. Results. Proinflammatory and anti-inflammatory markers were found to be associated with neuropsychological testing. Third tertile proinflammatory markers were negatively associated with measures of attention and language, and anti-inflammatory markers were positively associated with measures of immediate verbal memory and delayed verbal and visual memory. Conclusions. These findings support the link between peripheral inflammatory markers and neuropsychological functioning and suggest the utility of examining profiles of inflammatory markers in the future.

Inflammatory biomarkers in the Texas Alzheimer's Research and Care Consortium (TARCC) Cohort

Inflammatory biomarkers in the Texas Alzheimer's Research and Care Consortium (TARCC) Cohort