Kentucky Alzheimer's Disease Research Articles

Alzheimer's disease and inflammatory biomarkers positively correlate in plasma in the UK-ADRC cohort.

Protein-based plasma assays provide hope for improving accessibility and specificity of molecular diagnostics to diagnose dementia. Plasma was obtained from participants (N=837) in our community-based University of Kentucky Alzheimer's Disease Research Center cohort. We evaluated six Alzheimer's disease (AD)- and neurodegeneration-related (Aβ40, Aβ42, Aβ42/40, p-tau181, total tau, and NfLight) and five inflammatory biomarkers (TNF𝛼, IL6, IL8, IL10, and GFAP) using the SIMOA-based protein assay platform. Statistics were performed to assess correlations. Our large cohort reflects previous plasma biomarker findings. Relationships between biomarkers to understand AD-inflammatory biomarker correlations showed significant associations between AD and inflammatory biomarkers suggesting peripheral inflammatory interactions with increasing AD pathology. Biomarker associations parsed out by clinical diagnosis (normal, MCI, and dementia) reveal changes in strength of the correlations across the cognitive continuum. Unique AD-inflammatory biomarker correlations in a community-based cohort reveal a new avenue for utilizing plasma-based biomarkers in the assessment of AD and related dementias. Large community cohorts studying sex, age, and APOE genotype effects on biomarkers are few. It is unknown how biomarker-biomarker associations vary through aging and dementia. Six AD (Aβ40, Aβ42, Aβ42/40, p-tau181, total tau, and NfLight) and five inflammatory biomarkers (TNFα, IL6, IL8, IL10, and GFAP) were used to examine associations between biomarkers. Plasma biomarkers suggesting increasing cerebral AD pathology corresponded to increases in peripheral inflammatory markers, both pro-inflammatory and anti-inflammatory. Strength of correlations, between pairs of classic AD and inflammatory plasma biomarker, changes throughout cognitive progression to dementia.

In severe ADNC, hippocampi with comorbid LATE-NC and hippocampal sclerosis have substantially more astrocytosis than those with LATE-NC or hippocampal sclerosis alone.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and hippocampal sclerosis of aging (HS-A) pathologies are found together at autopsy in ∼20% of elderly demented persons. Although astrocytosis is known to occur in neurodegenerative diseases, it is currently unknown how the severity of astrocytosis is correlated with the common combinations of pathologies in aging brains. To address this knowledge gap, we analyzed a convenience sample of autopsied subjects from the University of Kentucky Alzheimer's Disease Research Center community-based autopsy cohort. The subjects were stratified into 5 groups (n = 51 total): pure ADNC, ADNC + LATE-NC, ADNC + HS-A, ADNC + LATE-NC + HS-A, and low-pathology controls. Following GFAP immunostaining and digital slide scanning with a ScanScope, we measured GFAP-immunoreactive astrocytosis. The severities of GFAP-immunoreactive astrocytosis in hippocampal subfield CA1 and subiculum were compared between groups. The group with ADNC + LATE-NC + HS-A had the most astrocytosis as operationalized by either any GFAP+ or strong GFAP+ immunoreactivity in both CA1 and subiculum. In comparison to that pathologic combination, ADNC + HS or ADNC + LATE-NC alone showed lower astrocytosis. Pure ADNC had only marginally increased astrocytosis in CA1 and subiculum, in comparison to low-pathology controls. We conclude that there appeared to be pathogenetic synergy such that ADNC + LATE-NC + HS-A cases had relatively high levels of astrocytosis in the hippocampal formation.

Urinary Incontinence in a Community-Based Autopsy Cohort Is Associated with Limbic Predominant Age-Related TDP-43 Encephalopathy Neuropathologic Changes.

Dementia and urinary incontinence (UI) are etiologically complex clinical syndromes. Dementia and UI often occur in the same individuals, but underlying factors connecting them are incompletely understood. Query data from a community-based autopsy series to assess pathologies that underlie UI. Included research subjects came to autopsy from the University of Kentucky Alzheimer's Disease Research Center longitudinal cohort. A total of 368 research volunteers met inclusion criteria for this cross-sectional study. The average age at death was 85.3 years and the average number of annual clinic visits was 5.2 visits. Statistical models were run to evaluate which pathologies were associated with UI. Data included pathologies scored according to conventional stage-based systems, and these studies were complemented by quantitative digital neuropathology. Dementia was diagnosed at the final clinical visit in 208 (56.7% of the sample) and UI was documented in 156 (42.7%). UI was associated with depression and dementia (both p < 0.001). More women than men had a history of UI (p < 0.04), and women with UI had had more biological children than those without UI (p < 0.005). Participants with limbic predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) were more likely to have UI than those without LATE-NC (p < 0.001). The presence of LATE-NC (Stage > 1) was associated with UI with or without severe Alzheimer's disease neuropathologic changes and/or Lewy body pathology. In this community-based autopsy cohort, multiple factors were associated with UI, but the neuropathologic change most robustly associated with UI was LATE-NC.

Plasma TDP-43 levels are associated with neuroimaging measures of brain structure in limbic regions.

We evaluated the relationship between plasma levels of transactive response DNA binding protein of 43kDa (TDP-43) and neuroimaging (magnetic resonance imaging [MRI]) measures of brain structure in aging. Plasma samples were collected from 72 non-demented older adults (age range 60-94 years) in the University of Kentucky Alzheimer's Disease Research Center cohort. Multivariate linear regression models were run with plasma TDP-43 level as the predictor variable and brain structure (volumetric or cortical thickness) measurements as the dependent variable. Covariates included age, sex, intracranial volume, and plasma markers of Alzheimer's disease neuropathological change (ADNC). Negative associations were observed between plasma TDP-43 level and both the volume of the entorhinal cortex, and cortical thickness in the cingulate/parahippocampal gyrus, after controlling for ADNC plasma markers. Plasma TDP-43 levels may be directly associated with structural MRI measures. Plasma TDP-43 assays may prove useful in clinical trial stratification. Plasma transactive response DNA binding protein of 43kDa (TDP-43) levels were associated with entorhinal cortex volume.Biomarkers of TDP-43 and Alzheimer's disease neuropathologic change (ADNC) may help distinguish limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) from ADNC.A comprehensive biomarker kit could aid enrollment in LATE-NC clinical trials.

The Association Between Cancer and Alzheimer's-Type Neuropathology: A Community-Based Cohort Study

Background: Cancer and Alzheimer's disease are common diseases in aging populations. Intriguingly, prior research has reported a lower incidence of Alzheimer's disease dementia among individuals with a history of cancer. Both are prevalent and lethal conditions. The current study was conducted to investigate the association of cancer history with neuropathological and cognitive features. Methods: Data were drawn from elderly, longitudinally evaluated participants in a community-based cohort study of aging and dementia who came to autopsy at the University of Kentucky Alzheimer's Disease Research Center. The data were linked to the Kentucky Cancer Registry, which is a population-based state cancer surveillance system, to obtain cancer-related data. We examined the relationship between cancer history, clinical dementia diagnoses, Mini-Mental State examination test scores, and neuropathological features using inverse probability weighting to address confounding and selection bias. Results: Included participants (n = 785) had a mean ±SD age of death of 83.8 ±8.6 years; 60.1% were female. Positive cancer history was determined in 190 (24.2%) participants. The prevalence of at least one APOE ε4 allele was lower among participants with cancer history compared to cancer-free participants (32.6% vs 42.0%, P = 0.0063). Participants with cancer history had lower odds of MCI/Dementia, and higher cognitive test scores (e.g., comparing MMSE scores evaluated at six and &amp;lt; two years prior to death., P &amp;lt; 0.001). Cancer history was also associated with reduced odds of intermediate (III/IV) or severe (V/VI) Braak Neurofibrillary tangle stages, moderate/frequent neuritic plaques, moderate/frequent diffuse plaques, and moderate/severe cerebral amyloid angiopathy (all P&amp;lt;0.05). By contrast, TDP-43, √é±-synuclein, and cerebrovascular pathologies were not associated with cancer history. Conclusion: In this study, we showed that cancer history was associated with a lower burden of Alzheimer's disease pathology and clinical dementia. These findings provide an additional basis of support for prior epidemiological research reporting a protective association between cancer and Alzheimer's disease-type dementia.

Examining the association between blood-based biomarkers and human post mortem neuropathology in the University of Kentucky Alzheimer's Disease Research Center autopsy cohort.

Clinically, detection of disease-causing pathology associated with Alzheimer's disease (AD) and vascular contributions to cognitive impairment and dementia (VCID) is limited to magnetic resonance imaging and positron emission tomography scans, which are expensive and not widely accessible. Here, we assess angiogenic, inflammatory, and AD-related plasma biomarkers to determine their relationships with human post mortem neuropathology. Plasma samples were analyzed using a digital immunoassay and pathological evaluation was performed by University of Kentucky Alzheimer's Disease Research Center neuropathologists. The association of plasma markers with neuropathology was estimated via proportional odds and logistic regressions adjusted for age. Included cases (N=90) showed increased tau/amyloid beta (Aβ)42 ratio, glial fibrillary acidic protein (GFAP), vascular endothelial growth factor A (VEGF-A), and placental growth factor (PlGF) were positively associated with higher level of AD neuropathological change, while higher Aβ42/Aβ40 ratio was inversely associated. Higher PlGF, VEGF-A, and interleukin 6 were inversely associated with chronic cerebrovascular disease, while Aβ42/Aβ40 ratio was positively associated. Our results provide support for the continued study of plasma biomarkers as a clinical screening tool for AD and VCID pathology.

Genetic expression changes and pathologic findings associated with hyperhomocysteinemia in human autopsy brain tissue.

Vascular contributions to cognitive impairment and dementia (VCID) are a leading cause of dementia. An underappreciated, modifiable risk factor for VCID is hyperhomocysteinemia (HHcy), defined by elevated levels of plasma homocysteine, most often due to impaired B vitamin absorption in aged persons. Studies aimed at identifying neuropathologic features and gene expression profiles associated with HHcy have been lacking. A subset of research volunteers from the University of Kentucky Alzheimer's Disease Research Center longitudinal cohort came to autopsy and had ante mortem plasma homocysteine levels available. Brain tissue and blood plasma drawn closest to death were used to measure homocysteine and related metabolites in the current pilot study. Genetic expression profiles of inflammatory markers were evaluated using the Human Neuroinflammation NanoString panel. Further analyses included an evaluation of plasma homocysteine effects on amyloid beta, tau, ionized calcium-binding adaptor molecule 1, and glial fibrillary acidic protein immunohistochemistry in the frontal and occipital cortices. Analytes and other study outcomes were evaluated in relation to ante mortem HHcy status: We identified 13 persons with normal ante mortem plasma homocysteine levels (<14µmol/L) and 18 who had high plasma homocysteine levels (≥14µmol/L). Participants with HHcy demonstrated increased levels of several plasma homocysteine cycle metabolites such as total cysteine, S-adenosyl-homocysteine, cystathionine, and choline. Inflammatory gene expression profiles showed a general downregulation in the setting of elevated plasma homocysteine. HHcy was associated with more and longer microglial processes, but smaller and fewer astrocytes, especially in participants of older age at death. HHcy in older participants was also associated with occipital cortex microhemorrhages and increased severity of atherosclerosis throughout the cerebral vasculature. Increased plasma homocysteine and older age were associated with the downregulation of inflammatory gene expression markers in association with significant glial and vascular pathology changes. Impaired immune function is a plausible mechanism by which HHcy increases cerebrovascular damage leading to impaired cognitive function.

Apolipoprotein E Proteinopathy Is a Major Dementia-Associated Pathologic Biomarker in Individuals with or without the APOE Epsilon 4 Allele

The amygdala is vulnerable to multiple or "mixed" mis-aggregated proteins associated with neurodegenerative conditions that can manifest clinically with amnestic dementia; the amygdala region is often affected even at earliest disease stages. With the original intent of identifying novel dementia-associated proteins, the detergent-insoluble proteome was characterized from the amygdalae of 40 participants from the University of Kentucky Alzheimer's Disease Center autopsy cohort. These individuals encompassed a spectrum of clinical conditions (cognitively normal to severe amnestic dementia). Polypeptides from the detergent-insoluble fraction were interrogated using liquid chromatography-electrospray ionization-tandem mass spectrometry. As anticipated, portions of peptides previously associated with neurologic diseases were enriched from subjects with dementia. Among all detected peptides, Apolipoprotein E (ApoE) stood out: even more than the expected Tau, APP/Aβ, and α-Synuclein peptides, ApoE peptides were strongly enriched in dementia cases, including from individuals lacking the APOE ε4 genotype. The amount of ApoE protein detected in detergent-insoluble fractions was robustly associated with levels of complement proteins C3 and C4. Immunohistochemical staining of APOE ε3/ε3 subjects' amygdalae confirmed ApoE co-localization with C4 in amyloid plaques. Thus, analyses of human amygdala proteomics indicate that rather than being only an "upstream" genetic risk factor, ApoE is an aberrantly aggregated protein in its own right, and show that the ApoE protein may play active disease-driving mechanistic roles in persons lacking the APOE ε4 allele.

Exploring older adults' experiences using technology during a viral pandemic

BackgroundOlder adults are at greater risk for morbidity and mortality associated with COVID‐19. Spatial distancing and sequestering practices are recommended to limit viral exposure. Older adults adopting these practices are at increased risk of social isolation and adverse health outcomes. Remote technologies offer various platforms for satisfying socialization and healthcare needs while sequestering. Understanding how older adults are using technology has implications for wellbeing during a pandemic.MethodResearchers attempted to contact all participants enrolled in the University of Kentucky Alzheimer's Disease Research Center longitudinal study via telephone to survey technology use (n = 706). Participants were contacted directly, except for demented participants, whose primary caregivers were contacted to respond on their behalf, when possible. Participants and caregivers gave their assent verbally to complete the voluntary survey, the procedures of which were approved by the IRB. The surveys consisted of validated instruments to gauge the extent of use of and comfort with technology. Spearman correlations, chi‐square tests, and t‐tests were used to explore data.ResultUltimately, 384 participants were reached and 332 consented to participate. Most reported reliable home internet access (91.5%) and some internet use (90.6%). Recent feelings of loneliness were not related to any technology‐related variables (all ps > 0.29) other than decreasing with greater willingness to use telehealth (Rho = ‐0.11, p = 0.06). Those who reported a lack of comfort with technology (n = 76) were less likely to text messaging (67% vs 78%) and social media (56% vs 69%), ps ≤ 0.06, but felt socially connected using technology at similar levels (82% vs 75%), p = 0.22. Nearly 70% of this group reported they would use technology more with training. Across all participants, willingness to use telehealth was not related to frequency of frustration with tech (Rho = 0, p = 0.99).ConclusionThe results suggest that some older adults’ use of technology is limited by familiarity. Lack of familiarity does not appear to create a barrier to using telehealth nor does frustration with technology appear to limit telehealth use. The findings have implications for supporting older adults sequestered during a pandemic but potentially more broadly.

Cancer history associates with a lower burden of dementia and Alzheimer’s‐type neuropathology in autopsied research volunteers

Cancer and Alzheimer's disease (AD) are common diseases in aging populations. Intriguingly, prior research has reported a lower incidence of AD among individuals with a history of cancer. The current study was conducted to investigate the association of cancer history with neuropathological and cognitive features.Data were drawn from elderly, longitudinally evaluated participants in a community-based cohort study of aging and dementia who came to autopsy at the University of Kentucky Alzheimer's Disease Research Center (UK-ADRC). The UK-ADRC data were linked to the Kentucky Cancer Registry (KCR), which is a population-based cancer state surveillance system, to obtain cancer-related data. We examined the causal relationship between cancer history and neuropathological features and clinical diagnoses using inverse probability weighting to address confounding and selection bias. Linear mixed-effects models with random intercepts and slopes were used to compare cognitive trajectories in participants with or without cancer history.Included participants (n=785) had a mean [SD] age of death of 83.8 [8.6] years; 60.1% were female (Table 1). History of cancer was reported in 190 (24.2%) participants. The prevalence of ≥1 APOE ε4 allele was lower among the participants with cancer history compared to cancer-free participants (32.6% vs 42%). Participants with cancer history had significantly lower odds of MCI/dementia at the last UK-ADRC visit (odds ratio [OR], 0.45; 95% confidence interval [CI], 0.31-0.65). Participants with cancer history had lower odds of Braak neurofibrillary tangle stages III/IV (OR=0.52 [0.34-0.79]) and V/VI (OR=0.38 [0.26-0.55]) vs. 0/I/II. Cancer history was also associated with reduced odds of moderate/frequent neuritic plaques, OR=0.53 (0.37-0.76); moderate/frequent diffuse plaques, OR=0.53 (0.36-0.78); and moderate/frequent cerebral amyloid angiopathy, OR=0.58 (0.37-0.91). TDP-43, α-synuclein, and cerebrovascular pathologies were not associated with cancer history. The cancer-free participants had lower significantly more rapid decline in longitudinally assessed MMSE scores (β= -0.47 per year increase in age) than the participants with cancer history (Figure 1).In this study, we showed that cancer history was associated with lower burden of AD pathology and less risk of dementia. These findings provide an additional basis of support for prior epidemiological research reporting a protective association between cancer and AD-type dementia.

A Comparison of Methods for Predicting Future Cognitive Status: Mixture Modeling, Latent Class Analysis, and Competitors.

The present work compares various methods for using baseline cognitive performance data to predict eventual cognitive status of longitudinal study participants at the University of Kentucky's Alzheimer's Disease Center. Cox proportional hazards models examined time to cognitive transition as predicted by risk strata derived from normal mixture modeling, latent class analysis, and a 1-SD thresholding approach. An additional comparator involved prediction directly from a numeric value for baseline cognitive performance. A normal mixture model suggested 3 risk strata based on Consortium to Establish a Registry for Alzheimer's Disease (CERAD) T scores: high, intermediate, and low risk. Cox modeling of time to cognitive decline based on posterior probabilities for risk stratum membership yielded an estimated hazard ratio of 4.00 with 95% confidence interval 1.53-10.44 in comparing high risk membership to low risk; for intermediate risk membership versus low risk, the modeling yielded hazard ratio=2.29 and 95% confidence interval=0.98-5.33. Latent class analysis produced 3 groups, which did not have a clear ordering in terms of risk; however, one group exhibited appreciably greater hazard of cognitive decline. All methods for generating predictors of cognitive transition yielded statistically significant likelihood ratio statistics but modest concordance statistics. Posterior probabilities from mixture modeling allow for risk stratification that is data-driven and, in the case of CERAD T scores, modestly predictive of later cognitive decline. Incorporating other covariates may enhance predictions.

Reduced rank multinomial logistic regression in Markov chains with application to cognitive data.

Finite Markov chains are useful tools for studying transitions among health states; these chains can be complex consisting of a mix of transient and absorbing states. The transition probabilities, which are often affected by covariates, can be difficult to estimate due to the presence of many covariates and/or a subset of transitions that are rarely observed. The purpose of this article is to show how to estimate the effect of a subset of covariates of interest after adjusting for the presence of multiple other covariates by applying multidimensional dimension reduction to the latter. The case in which transitions within each row of the one-step transition probability matrix are estimated by multinomial logistic regression is discussed in detail. Dimension reduction for the adjustment covariates involves estimating the effect of the covariates by a product of matrices iteratively; at each iteration one matrix in the product is fixed while the second is estimated using either standard software or nonlinear estimation, depending on which of the matrices in the product is fixed. The algorithm is illustrated by an application where the effect of at least one Apolipoprotein-E (APOE) gene allele on transition probability is estimated in a Markov Chain that includes adjustment for eight covariates and focuses on transitions from normal cognition to several forms of mild cognitive impairment, with possible absorption into dementia. Data were drawn from annual cognitive assessments of 649 participants enrolled in the BRAiNS cohort at the University of Kentucky's Alzheimer's Disease Research Center.

Embedding Brain Tissue for Routine Histopathology: A Processing Step Worthy of Consideration in the Digital Pathology Era.

The importance of technical quality for histopathologic examination has only increased in recent years with the expanding use of digital pathology. The University of Kentucky Alzheimer's Disease Center (UK-ADC) Neuropathology Core has decades of experience with brain histopathology and has emphasized the importance of quantitative assessments of histopathologic hallmarks. Technical artifacts and nonuniform samples are challenging for high-throughput digital analyses after the slides have been scanned, so that methodological optimization may be helpful. We do not know of published literature that systematically reviews how different procedures at the various stages of tissue processing can impact the quality of the histopathologic preparations in human brain samples. We wanted to pass along our experience in the hope that it will help others to improve their results. Here we describe the UK-ADC method of embedding for neuropathologic evaluation and provide specific examples (with a comparison to another processing workflow) that help support the idea that the methods and tools used in the embedding process can alter the quality of the formalin-fixed paraffin-embedded histopathologic results. The process used at the UK-ADC has been successful for us, but results may vary in relation to each embedding machine and with other factors.

One-Year Evaluation of a Targeted Medication Therapy Management Intervention for Older Adults.

Older adults are especially susceptible to adverse effects of inappropriate medication therapy, and anticholinergic medications are common culprits for cognitive dysfunction due to their action on the central nervous system. Medication therapy management (MTM) interventions can aid in deprescribing and reducing inappropriate medication use in older adults. However, there is sparse literature on the long-term sustainability of these interventions. To (a) investigate whether the deprescribing of anticholinergic medications during an 8-week randomized controlled trial (RCT) of a targeted MTM intervention is sustained at 1-year postintervention follow-up and (b) compare anticholinergic utilization trends in the study population with a large sample of similar individuals not exposed to the intervention. Participants in the targeted MTM (tMTM) RCT had normal cognition or mild cognitive impairment and were recruited from enrollees in a longitudinal study at the University of Kentucky Alzheimer's Disease Center (ADC) and thus have pertinent medical information gathered approximately annually. In this posttrial observational follow-up, sustainability of the anticholinergic deprescribing intervention was assessed in participants in the RCT, and anticholinergic medication use trends were described from the RCT baseline (which occurred immediately following an ADC visit) to the next annual visit in all participants. Mean change in anticholinergic burden from RCT baseline to the next annual visit was estimated using analysis of covariance, and participants were compared with 2 external samples. Anticholinergic burden was measured using the Anticholinergic Drug Scale (ADS). The odds of decreasing baseline anticholinergic burden and number of total and strong anticholinergic medications at the follow-up study time point was assessed using logistic regression. Of the deprescribing changes made during the initial RCT, 50% were sustained after 1 year. Participants in the tMTM trial reported decreases in the use of anticholinergic antihistamines and bladder agents (-6.5 and -4.4%, respectively), but there was no change in the use of anticholinergic agents targeted at the central nervous system. While the anticholinergic burden of RCT participants decreased over 1 year (adjusted mean ADS change [95% CI] = -0.33 [-0.72, 0.07]), it was not different than the change observed in 2 external samples at the trial center (-0.20 [-0.42, 0.02]) and nationally (-0.33 [-0.39, -0.26]). There were no statistically significant differences between trial participants and external samples in the odds of decreasing anticholinergic burden nor in decreasing the number of total, or strongly anticholinergic, medications at the 1-year follow-up. This study demonstrates that the sustainability of deprescribing is limited to the period of intervention, rather than affording lasting effects even over periods as short as 1 year, which was demonstrated not only in the small group of RCT participants but also by comparison with external groups. Future work should extend the duration of intervention and follow-up periods for MTM interventions to allow further insights regarding the sustainability of deprescribing efforts in older adults. The original trial was supported by a pilot study award from the University of Kentucky Center for Clinical and Translational Sciences (UL1TR000117). Additional support for this study was provided by the National Institutes of Health/National Institute on Aging (R01 AG054130). Jicha reports contract research for Esai, Biohaven, Alltech, Suven, Novartis, and Lilly. The other authors have nothing to disclose.

Behaviors Characteristic of Autism Spectrum Disorder in a Geriatric Cohort With Mild Cognitive Impairment or Early Dementia.

Autism spectrum disorder (ASD) represents a heterogenous cluster of clinical phenotypes that are classically diagnosed by the time of adolescence. The possibility of late-life emergence of ASD has been poorly explored. To more fully characterize the possibility of late-life emergence of behaviors characteristic of ASD in mild cognitive impairment and AD, we surveyed caregivers of 142 older persons with cognitive impairment from the University of Kentucky Alzheimer's Disease Center Longitudinal Cohort using the Gilliam Autism Rating Scale-2. Participants with high autism index ratings (autism "possible/very likely," n=23) reported significantly (statistically and clinically) younger age at the onset of cognitive impairment than those who scored in the autism "unlikely" range (n=119): 71.14±10.9 vs. 76.65±8.25 (P=0.034). In addition, those in the autism "possible/very likely" group demonstrated advanced severity of cognitive impairment, indicated by the Clinical Dementia Rating Scale Sum of Boxes scores. Data demonstrate that ASD behaviors may seem de novo of degenerative dementia and such behaviors are more prevalent in those with early onset dementia. Further work elucidating a connection between ASD and dementia could shed light on subclinical forms of ASD, identify areas of shared neuroanatomic involvement between ASD and dementias, and provide valuable insights that might hasten the development of therapeutic strategies.

P1‐479: RELATIONSHIPS BETWEEN ALZHEIMER'S DISEASE BIOMARKERS ON SEMANTIC CUEING AND TOTAL RECALL IN THE FREE AND CUED SELECTIVE REMINDING TEST (FSCRT)

Semantic cueing (SC) can enhance performance on learning and recall tasks. SC may be a sensitive measure for detecting early neurocognitive changes in individuals with preclinical Alzheimer's disease (pAD). While free delayed recall is dependent on both the Papez circuit and distributed cortical networks, SC is especially sensitive to deficits in the Papez circuit that is affected early in AD. The present study examined SC in a series of cognitively normal subjects that had undergone structural MRI and CSF analyses for Aβ and tau in order to test the hypothesis that SC deficits can predict pAD. Inclusion/exclusion criteria included Mini-Mental Status Exam (MMSE) score of ≥26 (indicating intact global cognition), a Hachinski Ischemic Scale (HIS) score <4 (indicating low cerebrovascular risk), and no significant medical or neurologic disease that could cause cognitive deficits. The Free and Cued Selective Reminding Test (FCSRT), 3D-MPRAGE T1 sequences on MRI, and CSF were collected on 66 cognitively normal participants seen at the University of Kentucky Alzheimer's Disease Center. Linear regression was used to examine relationships between SC recall, cortical thickness, and CSF. Participants had a mean MMSE score of 28.7 ± 1.8, age of 73.9 ± 5.7 years, an education of 16.6 ± 2.5 years, and were 52.9% female. None of these variables were significant predictors of pAD. While higher CSF Aβ levels were significantly associated with free recall (β=0.025, p=0.01), they showed no association with SC. In contrast, increased levels of CSF tau were significantly associated with decreased SC recall performance (β=0.001, p=0.002). The association of decreased CSF Aβ with free delayed recall but not SC suggests dysfunction in cortical and other brain regions, with relative sparing of the Papez circuit. In contrast, the present data demonstrates that SC is associated with both the presence of tau abnormalities in CSF and entorhinal cortex atrophy, which is indicative of active neurofibrillary tangle pathology. While SC recall does not appear to predict amyloid positivity, it appears to be associated with neuropsychological change early in the neurofibrillary tangle cascade. These results allow for the development of more effective neuropsychological assessments for individuals with preclinical Alzheimer's disease.

Tobacco Smoking and Dementia in a Kentucky Cohort: A Competing Risk Analysis.

Tobacco smoking was examined as a risk for dementia and neuropathological burden in 531 initially cognitively normal older adults followed longitudinally at the University of Kentucky's Alzheimer's Disease Center. The cohort was followed for an average of 11.5 years; 111 (20.9%) participants were diagnosed with dementia, while 242 (45.6%) died without dementia. At baseline, 49 (9.2%) participants reported current smoking (median pack-years = 47.3) and 231 (43.5%) former smoking (median pack-years = 24.5). The hazard ratio (HR) for dementia for former smokers versus never smokers based on the Cox model was 1.64 (95% CI: 1.09, 2.46), while the HR for current smokers versus never smokers was 1.20 (0.50, 2.87). However, the Fine-Gray model, which accounts for the competing risk of death without dementia, yielded a subdistribution hazard ratio (sHR) = 1.21 (0.81, 1.80) for former and 0.70 (0.30, 1.64) for current smokers. In contrast, current smoking increased incidence of death without dementia (sHR = 2.38; 1.52, 3.72). All analyses were adjusted for baseline age, education, sex, diabetes, head injury, hypertension, overweight, APOEɛ4, family history of dementia, and use of hormone replacement therapy. Once adjusted for the competing risk of death without dementia, smoking was not associated with incident dementia. This finding was supported by neuropathology on 302 of the participants.

TDP-43 proteinopathy in aging: Associations with risk-associated gene variants and with brain parenchymal thyroid hormone levels

TDP-43 proteinopathy is very prevalent among the elderly (affecting at least 25% of individuals over 85 years of age) and is associated with substantial cognitive impairment. Risk factors implicated in age-related TDP-43 proteinopathy include commonly inherited gene variants, comorbid Alzheimer's disease pathology, and thyroid hormone dysfunction. To test parameters that are associated with aging-related TDP-43 pathology, we performed exploratory analyses of pathologic, genetic, and biochemical data derived from research volunteers in the University of Kentucky Alzheimer's Disease Center autopsy cohort (n = 136 subjects). Digital pathologic methods were used to discriminate and quantify both neuritic and intracytoplasmic TDP-43 pathology in the hippocampal formation. Overall, 46.4% of the cases were positive for TDP-43 intracellular inclusions, which is consistent with results in other prior community-based cohorts. The pathologies were correlated with hippocampal sclerosis of aging (HS-Aging) linked genotypes. We also assayed brain parenchymal thyroid hormone (triiodothyronine [T3] and thyroxine [T4]) levels. In cases with SLCO1A2/IAPP or ABCC9 risk associated genotypes, the T3/T4 ratio tended to be reduced (p = .051 using 2-tailed statistical test), and in cases with low T3/T4 ratios (bottom quintile), there was a higher likelihood of HS-Aging pathology (p = .025 using 2-tailed statistical test). This is intriguing because the SLCO1A2/IAPP and ABCC9 risk associated genotypes have been associated with altered expression of the astrocytic thyroid hormone receptor (protein product of the nearby gene SLCO1C1). These data indicate that dysregulation of thyroid hormone signaling may play a role in age-related TDP-43 proteinopathy.

Distinct White Matter Changes Associated with Cerebrospinal Fluid Amyloid-β1-42 and Hypertension.

Alzheimer's disease (AD) pathology and hypertension (HTN) are risk factors for development of white matter (WM) alterations and might be independently associated with these alterations in older adults. To evaluate the independent and synergistic effects of HTN and AD pathology on WM alterations. Clinical measures of cerebrovascular disease risk were collected from 62 participants in University of Kentucky Alzheimer's Disease Center studies who also had cerebrospinal fluid (CSF) sampling and MRI brain scans. CSF Aβ1-42 levels were measured as a marker of AD, and fluid-attenuated inversion recovery imaging and diffusion tensor imaging were obtained to assess WM macro- and microstructural properties. Linear regression analyses were used to assess the relationships among WM alterations, cerebrovascular disease risk, and AD pathology. Voxelwise analyses were performed to examine spatial patterns of WM alteration associated with each pathology. HTN and CSF Aβ1-42 levels were each associated with white matter hyperintensities (WMH). Also, CSF Aβ1-42 levels were associated with alterations in normal appearing white matter fractional anisotropy (NAWM-FA), whereas HTN was marginally associated with alterations in NAWM-FA. Linear regression analyses demonstrated significant main effects of HTN and CSF Aβ1-42 on WMH volume, but no significant HTN×CSF Aβ1-42 interaction. Furthermore, voxelwise analyses showed unique patterns of WM alteration associated with hypertension and CSF Aβ1-42. Associations of HTN and lower CSF Aβ1-42 with WM alteration were statistically and spatially distinct, suggesting independent rather than synergistic effects. Considering such spatial distributions may improve diagnostic accuracy to address each underlying pathology.

Diffuse Amyloid-β Plaques, Neurofibrillary Tangles, and the Impact of APOE in Elderly Persons' Brains Lacking Neuritic Amyloid Plaques.

Data from a large autopsy series were analyzed to address questions pertinent to primary age-related tauopathy (PART) and Alzheimer's disease (AD): what factors are associated with increased severity of neurofibrillary degeneration in brains that lack neuritic amyloid plaques?; is there an association between Apolipoprotein E (APOE) alleles and PART pathologic severity independent of amyloid-β (Aβ) deposits?; and, how do the stains used to detect plaques and tangles impact the experimental results? Neuropathologic data were evaluated from elderly research volunteers whose brain autopsies were performed at University of Kentucky Alzheimer's Disease Center (UK-ADC; N = 145 subjects). All of the included subjects' brains lacked neuritic amyloid plaques according to the CERAD diagnostic criteria and the average final MMSE score before death was 26.8±4.6 stdev. The study incorporated evaluation of tissue with both silver histochemical stains and immunohistochemical stains to compare results; the immunohistochemical stains (Aβ and phospho-tau) were scanned and quantified using digital pathologic methods. Immunohistochemical stains provided important advantages over histochemical stains due to sensitivity and detectability via digital methods. When AD-type pathology was in its presumed earliest phases, neocortical parenchymal Aβ deposits were associated with increased medial temporal lobe neurofibrillary tangles. The observation supports the NIA-AA consensus recommendation for neuropathologic diagnoses, because even these "diffuse" Aβ deposits signal that AD pathobiologic mechanisms are occurring. Further, the data were most compatible with the hypothesis that the APOEɛ4 allele exerts its effect(s) via driving Aβ deposition, i.e., an "upstream" influence, rather than being associated directly with Aβ- independent PART pathology.