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We have employed structural equation models to explicitly distinguish dementia-relevant variance in cognitive task performance (i.e., δ) from the variance that is unrelated to a dementing process (i.e., g'). Together g' and d comprise Spearman's "g". Although d represents only a minor fraction of the total variance in cognitive task performance, it is more strongly associated with dementia severity than is g'. In this analysis, we replicate δ in a new dataspace, the University of Kansas Brain Aging Project, and associate it specifically with regional grey matter atrophy by voxel-based morphometry of magnetic resonance imaging data. The latent variable d localizes to elements of the default mode network and related structures in the R hemisphere. [ABSTRACT FROM AUTHOR]

The temporal growth of Alzheimer's disease (AD) neuropathology cannot be easily determined because autopsy data are available only after death. We combined autopsy data from 471 participants in the Honolulu-Asia Aging Study (HAAS) into latent factor measures of neurofibrillary tangle and neuritic plaque counts. These were associated with intercept and slope parameters from a latent growth curve (LGC) model of 9-year change in cognitive test performance in 3244 autopsied and non-autopsied HAAS participants. Change in cognition fully mediated the association between baseline cognitive performance and AD lesions counts. The mediation effect of cognitive change on both AD lesion models effectively dates them within the period of cognitive surveillance. Additional analyses could lead to an improved understanding of lesion propagation in AD. [ABSTRACT FROM AUTHOR]

Patients with parkinsonism pose a diagnostic challenge. Parkinson's disease may be difficult to distinguish from multiple system atrophy and progressive supranuclear palsy, whereas Parkinson's disease and dementia with Lewy bodies can be difficult to distinguish from Alzheimer's disease and other dementias. A number of studies have found diminished cardiac (123) I-metaiodobenzylguanidine uptake in Lewy body-related conditions (Parkinson's disease and Lewy body dementia). In 2005, the Dementia With Lewy Bodies Consortium considered (123) I-metaiodobenzylguanidine cardiac scintigraphy a "supportive" diagnostic feature, based on limited evidence. We report a meta-analysis of the literature and an assessment of the utility of (123) I-metaiodobenzylguanidine for the diagnosis of dementia with Lewy bodies and Parkinson's disease. A search was conducted of articles published between 1950 and June 2010. Forty-six studies involving neuropsychiatric and movement disorders, comprising 2680 subjects, were included in the analysis. A mixed-effects regression model was used to analyze the delayed mean heart-to-mediastinum ratio of (123) I-metaiodobenzylguanidine uptake. (123) I-metaiodobenzylguanidine cardiac scintigraphy sensitively detected and specifically distinguished 2 diagnostic clusters: (1) Parkinson's disease, dementia with Lewy bodies, and rapid eye movement sleep behavior disorder; and (2) normal controls and patients with Alzheimer's disease, multiple system atrophy, progressive supranuclear palsy, vascular dementia, and frontotemporal dementia. The area under the receiver operating characteristic curve was 0.987 at a cluster discriminatory heart-to-mediastinum ratio threshold of 1.77. This threshold yielded 94% sensitivity and 91% specificity for the discrimination of these diagnostic clusters. (123) I-metaiodobenzylguanidine cardiac scintigraphy can accurately distinguish between 2 movement disorders, Parkinson's disease and multiple system atrophy, and between 2 common causes of dementia, Alzheimer's disease and dementia with Lewy bodies. © 2011 Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: We assessed the effects of impaired Executive Control Function (ECF) on Instrumental Activities of Daily Living (IADL) and level of care among noninstitutionalized elderly retirees with "subclinical" cognitive impairment.Methods: Subjects (N = 561; age 78.2 +/- 5.0 years) were residents of a single, 1,500 bed, continuing care retirement community. Subjects were examined for cognitive impairment using the Executive Interview (EXIT25), Mini-Mental State Examination (MMSE), and an executive clock-drawing task (CLOX). The CLOX is divided into executively sensitive (CLOX 1) and simple constructional (CLOX2) subtests.Results: Residents in congregate high-rises (n = 301) differed significantly from those in independent-living apartments (n = 260) with respect to age, gender, percent living alone, EXIT25, CLOX1, MMSE, and CLOX2 scores (all p < .03). Only differences in ECF measures persisted after adjusting for age and living alone (p < .004). The EXIT25 (p < .006) and CLOX2 (p = .02) were associated with the use of prostheses. The differences in EXIT25 scores persisted after adjusting for level and living alone (p = .01). All instruments distinguished residents with impairment in IADLs. However, only CLOX2 (p < .001), EXIT25 (p < .001), and age (p < .001) made significant independent contributions.Conclusions: ECF has statistically significant effects on level of care and IADL impairment, even among noninstitutionalized retirees. This emergent disability is not well detected by traditional global cognitive measures. Evaluation and treatment may be delayed unless ECF measures are employed. [ABSTRACT FROM AUTHOR]

We examined six clock-drawing task (CDT) scoring systems relative to the Executive Interview (EXIT25, a measure of Executive Control Function [ECF]) and the Mini-Mental State Exam (MMSE). Subjects included n = 33 National Institute of Neurological, Communicative Disorders, and Stroke 'probable' Alzheimer's disease (AD) cases and n = 52 independent living controls. AD cases and controls differed on the EXIT25, MMSE, and all CDTs. All CDTs were significantly correlated with the EXIT25 (ranging from r = .56 to r = .78). These associations generally persisted after adjusting for Age, Education, and MMSE scores. In backwards stepwise linear multivariate regression models, only CLOX: An Executive Clock-Drawing Task scores contribute significantly to EXIT25 scores (R2 = .68) and MMSE scores (R2 = .72). Clock drawing draws upon both executive and general cognitive resources. CLOX explains incrementally more variance in ECF than other CDTs. [ABSTRACT FROM AUTHOR]

Objective: Biomarker-specific interventions (e.g., for dementia) will necessitate an individualized approach to treatment. We have constructed a psychometric classifier to identify persons adversely impacted by plasma adipokines., Method: The subjects ( N = 1,737) of the Alzheimer's Disease Neuroimaging Initiative were assigned to groups "afflicted" by versus "resilient" against the unique effect of plasma adipokines using a classifier derived by confirmatory factor analysis in a structural equation model framework. The impact of affliction class above and beyond observed biomarker levels and covariates was tested by multivariate regression using CDR "Sum of Boxes" as the dependent variable. The affliction class' moderation of adipokines' effect was tested by chi-square difference. The effect of affliction class on prospective conversion risk was tested by Cox's proportional hazards models., Results: Seven hundred four out of the 1,737 subjects (40.53%) were assigned to the afflicted class. The afflicted subjects had greater dementia severity, lower (adverse) Adipokines factor composite scores (by analysis of variance, F (1, 1,735) 2619.68, p < .001) and higher observed levels of plasma adipokines (by Tukey's honestly significant difference test, all p < .001). Adipokines ' association with dementia severity was moderated by affliction class. The effect persisted at 48 months. Afflicted cases were more likely to convert to Alzheimer's disease in that timeframe, by Cox's F : F (234, 286) = 3.89, p < .001., Conclusions: Our approach could guide precision interventions against specific biomarkers. This classifier could be administered by telephone, making class assignment feasible without direct patient contact or biomarker assessment. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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.

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., Competing Interests: The authors have disclosed their co-invention of δ, its homologs and orthologs, and of their INFLAMMATION construct to the University of Texas Health Science Center at San Antonio, which in turn holds a patent relating to the use of a partially overlapping set of δ-related blood-based biomarkers as predictors of Mild Cognitive Impairment (MCI) in non-Hispanic whites (U.S. Patent 13/943,654: “A Serum Biomarker Screen for the Diagnosis of Clinical and Pre-clinical Alzheimer’s Disease in Non-Hispanic Populations”). There are no other patents, products in development or marketed products to declare. This does not alter our adherence to all the PLoS ONE policies on sharing data and materials., (Copyright: © 2024 Royall, Palmer. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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., Competing Interests: The authors have no competing interests to declare., (© 2023 The Authors. Published by Elsevier B.V.)

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.

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).

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., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

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)., (© 2020 John Wiley & Sons Ltd.)

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., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

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., (© 2019 The Authors.)

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., Competing Interests: We have the following potential interests: The authors have disclosed the results of these analyses to the University of Texas Health Science Center at San Antonio (UTHSCSA), which has filed patent applications 61/603,226: "A Latent Variable Approach to the Identification and/or Diagnosis of Cognitive Disorders", 61/671,858: “A Serum Biomarker Screen for the Diagnosis of Clinical and Pre-clinical Alzheimer’s Disease in Non-Hispanic Populations”, and 62/112,703: “Methods and Approach for Detection and Prediction of Change in Dementia Severity or Clinical Diagnosis over Time” relating to the latent variable δ’s construction and biomarkers. There are no further patents, products in development or marketed products to declare. This does not alter our adherence to all the PLoS ONE policies on sharing data and materials.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10 -7 ), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

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.

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.

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.

In this cross-sectional study, we examined the neuropsychiatric profile of mild cognitive impairment (MCI) and Alzheimer's disease (AD) using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Data were available on 875 controls, 339 MCI cases, and 975 AD participants. Surprisingly, differences in neuropsychiatric symptom (NPS) severity by ethnicity in subjects with AD, but not with MCI, were found. More so, in Hispanics with AD, a higher frequency in most of the individual NPI-Q symptom items of the scale was observed, except for apathy. After adjustment for clinical features, some individual NPI-Q symptoms also showed an association with Hispanic ethnicity in the control group that nearly reached statistical significance. There may be cross-ethnic differences in the neuropsychiatric presentation of AD in Hispanics versus non-Hispanic whites. Future studies are needed to clarify the etiology of these differences, and to assess the need for ethnicity-specific treatment and care-giving interventions.

Background: The latent variable "δ" has been validated as a dementia phenotype. δ can be extracted from Spearman's general intelligence factor "g" in any data set that contains measures of cognition and instrumental activities of daily living (IADL). We used δ composites ("d-scores") to estimate the prevalence of dementia in the Hispanic Established Population for Epidemiological Studies in the Elderly (H-EPESE)., Method: δ was constructed from Mini-Mental State Examination, a clock-drawing task (CLOX), and IADL. δ's H-EPESE factor weights were validated in the well-characterized Texas Alzheimer's Research and Care Consortium (TARCC). Optimal thresholds for the discrimination between "Alzheimer's disease" (AD) versus normal controls (NCs) were determined by receiver operating characteristic curve. Those thresholds were used to estimate the prevalence of dementia in H-EPESE., Results: Each δ homolog fits its source's data well. d-scores were strongly associated with Clinical Dementia Rating scale Sum of Boxes (r = .74-.85, all p < .001], and accurately distinguished AD cases from NCs, in both Mexican Americans (MAs) and non-Hispanic Whites (NHWs) [c = 0.94-0.96]. The TARCC MA threshold estimated the prevalence of dementia at 21.4% in H-EPESE. The NHW threshold estimated the prevalence of dementia at 21.0%., Conclusions: It is possible to export δ composites from populations to well-characterized cohorts for validation., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10 -4 ) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10 -8 ) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10 -10 , odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 -10 , OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 -14 , OR = 1.67, MAF cases = 0.0143, MAF controls = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Objective: The objective of this study was to determine if a clock copying task predicts 18-month mortality in an Adult Protective Services (APS) sample referred for a decision-making capacity assessment., Methods: The authors performed a retrospective medical record review of clients (N = 233) referred by APS for a decision-making capacity assessment during a 3-year time period. Information extracted included demographic data and neuropsychological performance on a battery sensitive to executive function, visuospatial ability, depression, memory, and general cognition. A Cox proportional hazards models was constructed to determine the relationship between Executive Clock Drawing Task Part 2 (CLOX2) performance and survival., Results: Poor clock copying, as measured by CLOX2, predicted 18-month mortality when covaried for age, education, sex, rural dwelling status, depression, and general cognition., Conclusions: Clock copying is an easily administered visuospatial task that may inform survival in this vulnerable population., (Copyright © 2017 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

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.

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.

Introduction: We tested the latent variable "δ" (for "dementia")'s ability to predict conversion to "mild cognitive impairment" (MCI) and Alzheimer's disease (AD)., Methods: An ethnicity equivalent d homolog ("dEQ") was constructed in n = 1113 Mexican- American (MA) and n = 1958 non-Hispanic white (NHW) participants in the Texas Alzheimer's Research and Care Consortium. "Normal Controls" (NC) (n = 1276) and MCI cases (n = 611) were followed annually for up to 6 years [m = 4.7(0.6)]., Results: 22.0% (n = 281) of NC converted to "MCI" or "AD". 17.3%( n = 106) of MCI converted to "AD." Independently of covariates, each quintile increase in the dEQ scores of NC increased the odds of conversion by 52%. Each quintile increase in the dEQ scores of MCI cases increased the odds of conversion to AD almost three-fold., Discussion: Baseline δ scores predict MCI and AD conversions from nondemented states in MA and NHW.

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., Competing Interests: DRR and RFP have disclosed the results of these analyses to the University of Texas Health Science Center at San Antonio (UTHSCSA), which has filed patent application 2012.039.US1.HSCS and provisional patents 61/603,226 and 61/671,858 relating to the latent variable δ's construction and biomarkers.

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.

Introduction: Serum 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)., Methods: We 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., Results: dEQ 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., Discussion: We 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.

"δ", a latent variable constructed from cognitive performance and functional status measures, can accurately diagnose dementia. The minimal assessment needed is unknown. We have constructed a δ homolog, "dTEXAS", from Telephone Executive Assessment Scale (TEXAS) items, and validated it in a convenience sample of Japanese persons (n = 176). dTEXAS scores correlated strongly with both Instrumental Activities of Daily Living (IADL) (r = -0.86, p <  0.001) and Clinical Dementia Rating Scale (CDR) (r = 0.71, p <  0.001). Constructed independently of their diagnoses, dTEXAS scores accurately distinguished dementia versus controls (area under the receiver operating curve [(AUC; ROC) = 0.92], dementia versus mild cognitive impairment (MCI) (AUC = 0.80) and controls versus MCI (AUC = 0.74). These AUCs are higher than those of multiple observed executive measures, as reported recently by Matsuoka et al., 2014. A dTEXAS score of -0.58 best discriminated between dementia versus controls with 90.1% sensitivity and 80.0% specificity.