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

IMPORTANCE: 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. OBJECTIVE: We aim to validate a psychometric classifier to identify persons adversely impacted by inflammation and replicate it in a second cohort. DESIGN: 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). SETTING: Two large, well-characterized multi-center convenience samples. PARTICIPANTS: Volunteers with normal cognition (NC), Mild Cognitive Impairment (MCI) or clinical "Alzheimer's Disease (AD)". EXPOSURE: Participants were assigned to "Afflicted" or "Resilient" classes on the basis of a psychometric classifier derived by confirmatory factor analysis. MAIN OUTCOME(S) AND MEASURE(S): 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. RESULTS: 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). CONCLUSIONS AND RELEVANCE: 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.

Toward a cross-cultural understanding of intraindividual variability metrics.

OBJECTIVE: Compare the construct validity and predictive utility of cognitive intraindividual variability (IIV) in a sample of community-dwelling Hispanic and non-Hispanic white (NHW) older adults. METHODS: The present study included annual data from 651 older adult control participants (Hispanic = 293; NHW = 358) enrolled in the Texas Alzheimer's Research and Care Consortium for at least 5 years. Mean composite z-scores were calculated for attention, language, memory, and executive domains. IIV was calculated as was the standard deviation both within (IIV-Within) and between (IIV-Between) these domains. RESULTS: At baseline, NHW individuals obtained significantly higher mean scores in each domain than their Hispanic counterparts. They also showed significantly greater variability within and between domains, except for IIV-Within the language domain which was significantly larger in the Hispanic group. IIV-Between domains was driven primarily by IIV-Within the executive function domain in the NHW cohort and by IIV-Within the language domain in the Hispanic cohort. In both groups, the addition of IIV-Within and IIV-Between cognitive domains at baseline significantly improved prediction of global cognitive status after 5 years above and beyond demographic characteristics, genetic and cardiovascular risk. However, IIV-Between domains was the strongest predictor in the NHW group, while IIV-Within the attention domain was the strongest predictor in the Hispanic group. CONCLUSIONS: Findings suggest that, while IIV-Between domains is a promising adjunctive method for predicting future cognitive decline, its construct validity and predictive utility varies based on ethnic group.

Statin use moderates APOE's and CRP's associations with dementia and is associated with lesser dementia severity in ε4 carriers.

INTRODUCTION: We tested the effect of statins on C-reactive protein (CRP) and apolipoprotein E (APOE)'s associations with dementia severity. METHODS: A total of 1725 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI) were assigned from 12-month follow-up data into the following groups: (1) ε4 (-)/statin (-), (2) ε4 (-)/statin (+), (3) ε4 (+)/statin (-), and (4) ε4 (+)/statin (+). Dementia severity was assessed by a δ homolog: "dHABS." A mediation model was stratified on statin use and moderation effects tested by a chi-square difference. RESULTS: Plasma CRP level decreased with ε4 allelic dose. Statins had no effect on the dHABS d-score in non-carriers but were associated with better scores in carriers. Treated carriers did not have more severe dementia than non-carriers. Statin use moderated the mutual adjusted effects of APOE and CRP. CRP was not a mediator of APOE's effect. DISCUSSION: Statins may provide a protective effect on the dementia severity of ε4 carriers. HIGHLIGHTS: δ is a dementia-specific phenotype related to general intelligence "g" and is assessed via a "d-score." Apolipoprotein E (APOE) and plasma C-reactive protein (CRP) are independently associated with δ. Plasma CRP decreases with ε4 allelic dose. Statins were associated with better (less demented) d-scores in ε4 carriers but had no effect in non-ε4 carriers. Treated ε4 carriers did not have more severe dementia than non-carriers. Statin use moderated the effects of APOE and CRP on δ. CRP was not a mediator of APOE's effect on δ.

The effects of CNS atrophy and ICVD on tests of executive function and functional status are mediated by intelligence.

Background: Impairments in executive function (EF) are often attributed to ischemic cerebrovascular disease (ICVD) and frontal circuit pathology. However, EF can be distinguished from general intelligence and the latter is likely to manifest in "executive" measures. We aimed to distinguish the effects of imaging biomarkers on these constructs. Methods: We tested neuroimaging biomarkers as independent predictors of observed 12 month-prospective cognitive performance by a Multiple Indicators Multiple Causes (MIMIC) model in the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N ≅ 1750). Results: ICVD was associated with ''Organization" (ORG) and "Planning" (PLAN) domain scores from the test of Every Day Cognition. Left anterior cingulate (LAC) atrophy was independently associated with Trail-Making part B and Animal Naming. The MIMIC model had excellent fit and tests additional latent variables i.e., EF and dEF (a latent δ homolog derived from Spearman's general intelligence factor, g). Only dEF was associated with instrumental activities of daily living (IADL). ICVD and LAC were both associated with observed executive measures through dEF. ICVD was independently associated with those same measures through EF. Conclusions: Observed EF is independently determined by multiple factors. The effects of EF-associated MRI biomarkers can be related to disability and dementia only via their effects on g. Because g /δ are unlikely to be located within the frontal lobes, the dementia-specific variance in executive measures may have little to do with either frontal structure or function. Conversely, domain-specific variance in EF may have little to do with either IADL-impairment or dementia.

Multiple Adipokines Predict Dementia Severity as Measured by δ: Replication Across Biofluids and Cohorts.

BACKGROUND: We have explored dementia's blood-based protein biomarkers in the Texas Alzheimer's Research and Care Consortium (TARCC) study. Among them are adipokines, i.e., proteins secreted by adipose tissue some of which have been associated with cognitive impairment. OBJECTIVE: To associate adipokines with dementia severity and replicate their association across cohorts and biofluids (serum /plasma). METHODS: We used eight rationally chosen blood-based protein biomarkers as indicators of a latent variable, i.e., "Adipokines". We then associated that construct with dementia severity as measured by the latent dementia-specific phenotype "δ" in structural equation models (SEM). Significant factor loadings and Adipokines' association with δ were replicated across biofluids in the Alzheimer's Disease Neuroimaging Initiative (ADNI). RESULTS: Eight adipokine proteins loaded significantly on the Adipokines construct. Adipokines measured in plasma (ADNI) or serum (TARCC) explained 24 and 70% of δ's variance, respectively. An Adipokine composite score, derived from the latent variables, rose significantly across clinical diagnoses and achieved high areas under the receiver operating characteristic curve (ROC/AUC) for discrimination of Alzheimer's disease from normal controls (NC) or cases of mild cognitive impairment (MCI) and between NC and MCI. CONCLUSION: These results again suggest that SEM can be used to create latent biomarker classifiers that replicate across samples and biofluids, and that a substantial fraction of dementia's variance is attributable to peripheral blood-based protein levels via the patterns codified in those latent constructs.

Cognitive intraindividual variability as a potential biomarker for early detection of cognitive and functional decline.

OBJECTIVE: Intraindividual variability (IIV) in cognitive performance has been associated with cognitive decline and reductions in white matter integrity, but the predictive utility of IIV-between versus IIV-within domains is unknown. The present study aimed to determine if IIV-within a "frontal-subcortical" domain may be a more robust predictor of changes in general cognitive status and functional independence over time than IIV-between cognitive domains. METHOD: Mixed linear modeling was used to analyze the relationship between cognitive IIV and cognitive and functional status in 651 controls, 211 people with mild cognitive impairment, and 218 people with Alzheimer's disease over a 5-year period. RESULTS: Both IIV-between and IIV-within a frontal-subcortical domain improved prediction of cognitive and functional declines beyond demographic characteristics, genetic risk, and vascular integrity. IIV-between showed the greatest effect over time and was driven primarily by increases in IIV-within. CONCLUSIONS: Cognitive IIV, especially between cognitive domains, may be useful for identifying individuals at risk for cognitive and functional decline. Findings may facilitate investigations into mechanisms underlying declines in global cerebral integrity and aid clinical trials aimed at early detection and treatment. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Blood biomarkers for cognitive decline and clinical progression in a Mexican American cohort.

Introduction: The clinical translation of biofluid markers for dementia requires validation in diverse cohorts. The study goal was to evaluate if blood biomarkers reflecting diverse pathophysiological processes predict disease progression in Mexican American adults. Methods: Mexican American adults (n = 745), 50 years of age and older, completed annual assessments over a mean of 4 years. Serum collected at baseline was assayed for total tau, neurofilament light (NFL), ubiquitin carboxyl-terminal hydrolase LI, glial fibrillary acidic protein (GFAP), soluble cluster of differentiation 14 (sCD14), and chitinase-3-like protein 1 (YKL-40). Results: Higher GFAP and NFL were associated with global cognitive decline. Only GFAP was associated with increased incident dementia risk (hazard ratio: 1.611 (95% confidence interval: 1.204-2.155)) and inclusion of additional biomarkers did not improve model fit. Discussion: Among a panel of six blood biomarkers previously associated with neurodegenerative disease, only GFAP predicted incident dementia in our cohort. The findings suggest that blood GFAP levels may aid dementia-risk prediction among Mexican American adults.

Blood-based protein mediators of senility with replications across biofluids and cohorts.

Dementia severity can be quantitatively described by the latent dementia phenotype 'δ' and its various composite 'homologues'. We have explored δ's blood-based protein biomarkers in the Texas Alzheimer's Research and Care Consortium. However, it would be convenient to replicate them in the Alzheimer's Disease Neuroimaging Initiative. To that end, we have engineered a δ homologue from the observed cognitive performance measures common to both projects [i.e. 'd:Texas Alzheimer's Research and Care Consortium to Alzheimer's Disease Neuroimaging Initiative' (dT2A)]. In this analysis, we confirm 13/22 serum proteins as partial mediators of age's effect on dementia severity as measured by dT2A in the Texas Alzheimer's Research and Care Consortium and then replicate 4/13 in the Alzheimer's Disease Neuroimaging Initiative's plasma data. The replicated mediators of age-specific effects on dementia severity are adiponectin, follicle-stimulating hormone, pancreatic polypeptide and resistin. In their aggregate, the 13 confirmed age-specific mediators suggest that 'cognitive frailty' pays a role in dementia severity as measured by δ. We provide both discriminant and concordant support for that hypothesis. Weight, calculated low-density lipoprotein and body mass index are partial mediators of age's effect in the Texas Alzheimer's Research and Care Consortium. Biomarkers related to other disease processes (e.g. cerebrospinal fluid Alzheimer's disease-specific biomarkers in the Alzheimer's Disease Neuroimaging Initiative) are not. It now appears that dementia severity is the sum of multiple independent processes impacting δ. Each may have a unique set of mediating biomarkers. Age's unique effect appears to be at least partially mediated through proteins related to frailty. Age-specific mediation effects can be replicated across cohorts and biofluids. These proteins may offer targets for the remediation of age-specific cognitive decline (aka 'senility'), help distinguish it from other determinants of dementia severity and/or provide clues to the biology of Aging Proper.

δ scores predict multiple neuropsychiatric symptoms.

OBJECTIVES: 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. METHODS: 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. RESULTS: "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. CONCLUSION: 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).

δ-Related Biomarkers Attenuate Multiple Alzheimer's Disease Conversion Risks and Offer Targets for Intervention.

BACKGROUND: We tested certain serum proteins' ability to mediate the effects of demographic variables on prospective 5-year conversion to clinical "Alzheimer's disease" from non-demented states (i.e. normal control and mild cognitive impairment). The proteins were rationally selected from previously published mediators of those same variables' (plural posessive) association with the latent variable "δ," a novel omnibus dementia severity metric. METHODS: Each protein's attenuation of its risk factor's independent association with conversion was performed using logistic regression, adjusted for education, ethnicity, self-reported diabetes mellitus, and hypertension, among initially non-demented Mexican American and non-Hispanic white (N = 772) participants in the Texas Alzheimer's Research and Care Consortium. RESULTS: A total of 70 (9.1%) non-demented participants at baseline converted to "Alzheimer's disease", with a mean follow-up of 5.4 years. Age >80 years (odds ratio = 3.1), 30-item Geriatric Depression Scale >10/30 (odds ratio = 2.3), female gender (odds ratio = 2.2), and the presence of an apolipoprotein E ε4 allele (odds ratio = 2.4) were independently associated with prospective conversion. These effects were fully attenuated by five serum proteins: age: insulin-like growth factor-binding protein 2 and epidermal growth factor receptor 1; depression: resistin; gender: thrombopoietin; and apolipoprotein E: C-reactive protein. CONCLUSION: Clinical dementia arises from the sum of independent δ-related processes. This analysis provides proof of concept for the rational selection of antidementia targets and offers a foundation for precision antidementia therapy.

Serum Adiponectin is Related to Dementia.

BACKGROUND: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Selection for depression-specific dementia cases with replication in two cohorts.

The latent variable "δ" (for "dementia") provides an etiologically "agnostic" omnibus dementia severity metric capable of recognizing the dementing potential of any condition. Depressive symptoms are independent predictors of δ and are thereby implicated as "dementing". Serum resistin levels partially mediate the association between depressive symptoms and δ. We use a novel "off-diagonal" CHI SQ algorithm to demonstrate our ability to select individuals demented solely by depression's effect in both the Texas Alzheimer's Research and Care Consortium (TARCC) (N ≌ 3,500), and the Alzheimer's Disease Neuroimaging Initiative (ADNI (N ≌ 1,750), and demonstrate the higher resistin levels of such cases in TARCC. This approach can be adapted to any δ-related dementia risk factor or biomarker and used identify individuals who might revert back to non-demented states after its successful treatment.

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

BACKGROUND: 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. OBJECTIVES: To assess δ's impact on MCI conversion risk. METHODS: 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. RESULTS: 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. CONCLUSION: A sizable minority of MCI cases may be misdiagnosed and they account disproportionately for AD conversions.

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.

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

INTRODUCTION: Dementia 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"). METHODS: We 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. RESULTS: Nine 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. DISCUSSION: These 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.

Construction of a Potential Telephone Assessment of Dementia Prevalence and Severity.

The "δ" (for "dementia") is a latent dementia phenotype that can be constructed by a unique confirmatory bifactor model in a structural equation model framework. Because it is derived from Spearman's general intelligence factor, "g," δ can be constructed from any cognitive battery. This may allow for accurate dementia case-finding by telephone and in the absence of expert clinical evaluation or review. The authors constructed a new δ homolog in a large ethnically diverse convenience sample: the Texas Alzheimer's Research and Care Consortium, comprising 2,016 participants (Alzheimer's disease [AD], N=920; mild cognitive impairment, N=277; normal controls, N=819). A δ composite ("dTEL") was extracted from informant-rated Instrumental Activities of Daily Living and a brief battery of verbal cognitive measures. The entire battery was engineered to be administered over the telephone. dTEL's model had excellent fit. dTEL correlated strongly with dementia severity, as measured by the Clinical Dementia Rating "sum of boxes" scale (r=0.78, p<0.001). The dTEL composite's area under the receiver operating characteristic curve for the discrimination between control subjects and AD patients was 0.97 (95% CI=0.964-0.975). This was superior to all dTEL indicators. Therefore, the authors have demonstrated that a δ homolog composite constructed entirely from verbal measures is strongly associated with dementia severity, can accurately diagnose dementia, and outperforms all observed measures from which it is constructed. Future studies are required to assess dTEL's performance relative to evaluation by expert clinicians when obtained by lay psychometricians over the telephone.

Serum proteins mediate depression's association with dementia.

The latent variable "δ" (for "dementia") uniquely explains dementia severity. Depressive symptoms are independent predictors of δ. We explored 115 serum proteins as potential causal mediators of the effect of depressive symptoms on δ in a large, ethnically diverse, longitudinal cohort. All models were adjusted for age, apolipoprotein E, education, ethnicity, gender, hemoglobin A1c, and homocysteine, and replicated in randomly selected 50% subsets. Alpha1-antitrypsin (A1AT), FAS, Heparin-binding EGF-like Growth Factor (HB-EGF), Insulin-like Growth Factor-1 (IGF-1), Luteinizing Hormone (LH), Macrophage Inflammatory Protein type 1 alpha (MIP-1α), Resitin, S100b, Tissue Inhibitor of Metalloproteinase type 1 (TIMP-1), and Vascular Cell Adhesion Molecule type 1 (VCAM-1) each were partial mediators of depression's association with δ. These proteins may offer targets for the treatment of depression's specific effect on dementia severity and Alzheimer's Disease (AD) conversion risk.