Longitudinal normative standards for cognitive tests and composites using harmonized data from two Wisconsin AD-risk-enriched cohorts.

INTRODUCTION: Published norms are typically cross-sectional and often are not sensitive to preclinical cognitive changes due to dementia. We developed and validated demographically adjusted cross-sectional and longitudinal normative standards using harmonized outcomes from two Alzheimer's disease (AD) risk-enriched cohorts. METHODS: Data from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were combined. Quantile regression was used to develop unconditional (cross-sectional) and conditional (longitudinal) normative standards for 18 outcomes using data from cognitively unimpaired participants (N = 1390; mean follow-up = 9.25 years). Validity analyses (N = 2456) examined relationships between percentile scores (centiles), consensus-based cognitive statuses, and AD biomarker levels. RESULTS: Unconditional and conditional centiles were lower in those with consensus-based impairment or biomarker positivity. Similarly, quantitative biomarker levels were higher in those whose centiles suggested decline. DISCUSSION: This study presents normative standards for cognitive measures sensitive to pre-clinical changes. Future directions will investigate potential clinical applications of longitudinal normative standards. HIGHLIGHTS: Quantile regression was used to construct longitudinal norms for cognitive tests. Poorer percentile scores were related to concurrent diagnosis and Alzheimer's disease biomarkers. A ShinyApp was built to display test scores and norms and flag low performance.

Delayed primacy recall performance predicts post mortem Alzheimer's disease pathology from unimpaired ante mortem cognitive baseline.

We propose a novel method to assess delayed primacy in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) memory test. We then examine whether this measure predicts post mortem Alzheimer's disease (AD) neuropathology in individuals who were clinically unimpaired at baseline. A total of 1096 individuals were selected from the Rush Alzheimer's Disease Center database registry. All participants were clinically unimpaired at baseline, and had subsequently undergone brain autopsy. Average age at baseline was 78.8 (6.92). A Bayesian regression analysis was carried out with global pathology as an outcome; demographic, clinical, and apolipoprotein E (APOE) data as covariates; and cognitive predictors, including delayed primacy. Global AD pathology was best predicted by delayed primacy. Secondary analyses showed that delayed primacy was mostly associated with neuritic plaques, whereas total delayed recall was associated with neurofibrillary tangles. Sex differential associations were observed. We conclude that CERAD-derived delayed primacy is a useful metric for early detection and diagnosis of AD in unimpaired individuals. Highlights: We propose a novel method to analyse serial position in the CERAD memory test.We analyse data from 1096 individuals who were cognitively unimpaired at baseline.Delayed primacy predicts post mortem pathology better than traditional metrics.

A comparison of story-recall metrics to predict hippocampal volume in older adults with and without cognitive impairment.

Objective: Process-based scores of episodic memory tests, such as the recency ratio (Rr), have been found to compare favourably to, or to be better than, most conventional or "traditional" scores employed to estimate memory ability in older individuals (Bock et al., 2021; Bruno et al., 2019). We explored the relationship between process-based scores and hippocampal volume in older adults, while comparing process-based to traditional story recall-derived scores, to examine potential differences in their predictive abilities. Methods: We analysed data from 355 participants extracted from the WRAP and WADRC databases, who were classified as cognitively unimpaired, or exhibited mild cognitive impairment (MCI) or dementia. Story Recall was measured with the Logical Memory Test (LMT) from the Weschler Memory Scale Revised, collected within twelve months of the magnetic resonance imaging scan. Linear regression analyses were conducted with left or right hippocampal volume (HV) as outcomes separately, and with Rr, Total ratio, Immediate LMT, or Delayed LMT scores as predictors, along with covariates. Results: Higher Rr and Tr scores significantly predicted lower left and right HV, while Tr showed the best model fit of all, as indicated by AIC. Traditional scores, Immediate LMT and Delayed LMT, were significantly associated with left and right HV, but were outperformed by both process-based scores for left HV, and by Tr for right HV. Conclusions: Current findings show the direct relationship between hippocampal volume and all the LMT scores examined here, and that process-based scores outperform traditional scores as markers of hippocampal volume.

Associations between recall of proper names in story recall and CSF amyloid and tau in adults without cognitive impairment.

Neuropsychological measures sensitive to decline in the preclinical phase of Alzheimer's disease are needed. We previously demonstrated that higher amyloid-beta (Aß) assessed by positron emission tomography in adults without cognitive impairment was associated with recall of fewer proper names in Logical Memory story recall. The current study investigated the association between proper names and cerebrospinal fluid biomarkers (Aß42/40, phosphorylated tau181 [pTau181], neurofilament light) in 223 participants from the Wisconsin Registry for Alzheimer's Prevention. We assessed associations between biomarkers and delayed Logical Memory total score and proper names using binary logistic regressions. Sensitivity analyses used multinomial logistic regression and stratified biomarker groups. Lower Logical Memory total score and proper names scores from the most recent visit were associated with biomarker positivity. Relatedly, there was a 27% decreased risk of being classified Aß42/40+/pTau181+ for each additional proper name recalled. A linear mixed effects model found that longitudinal change in proper names recall was predicted by biomarker status. These results demonstrate a novel relationship between proper names and Alzheimer's disease-cerebrospinal fluid pathology.

Comparison of the 10-, 14- and 20-Item CES-D Scores as Predictors of Cognitive Decline.

The association between depressive symptomatology and cognitive decline has been examined using the Centre for Epidemiologic Studies-Depression Scale (CES-D); however, concerns have been raised about this self-report measure. Here, we examined how the CES-D total score from the 14- and 10-item versions compared to the 20-item version in predicting progression to cognitive decline from a cognitively unimpaired baseline. Data from 1054 participants were analysed using ordinal logistic regression, alongside moderator and receiver-operating characteristics curve analyses. All baseline total scores significantly predicted progression to cognitive decline. The 14-item version was better than the 20-item version in predicting consensus diagnosis, as shown by their AICs, while also showing the highest accuracy when discriminating between participants by diagnosis at last visit. We did not find sex to moderate the relationship between CES-D score and cognitive decline. Current findings suggest the 10- and 14-item versions of the CES-D are comparable to the 20-item version, and that the 14-item version may be better at predicting longitudinal consensus diagnosis compared to the 20-item version.

A comparison of diagnostic performance of word-list and story recall tests for biomarker-determined Alzheimer's disease.

BACKGROUND: Wordlist and story recall tests are routinely employed in clinical practice for dementia diagnosis. In this study, our aim was to establish how well-standard clinical metrics compared to process scores derived from wordlist and story recall tests in predicting biomarker determined Alzheimer's disease, as defined by CSF ptau/Aß42 ratio. METHODS: Data from 295 participants (mean age = 65 ± 9.) were drawn from the University of Wisconsin - Madison Alzheimer's Disease Research Center (ADRC) and Wisconsin Registry for Alzheimer's Prevention (WRAP). Rey's Auditory Verbal Learning Test (AVLT; wordlist) and Logical Memory Test (LMT; story) data were used. Bayesian linear regression analyses were carried out with CSF ptau/Aß42 ratio as outcome. Sensitivity analyses were carried out with logistic regressions to assess diagnosticity. RESULTS: LMT generally outperformed AVLT. Notably, the best predictors were primacy ratio, a process score indexing loss of information learned early during test administration, and recency ratio, which tracks loss of recently learned information. Sensitivity analyses confirmed this conclusion. CONCLUSIONS: Our study shows that story recall tests may be better than wordlist tests for detection of dementia, especially when employing process scores alongside conventional clinical scores.

Delayed primacy recall performance predicts post mortem Alzheimer's disease pathology from unimpaired ante mortem cognitive baseline.

INTRODUCTION: We propose a novel method to assess delayed primacy in the CERAD memory test. We then examine whether this measure predicts post mortem Alzheimer's disease (AD) neuropathology in individuals who were clinically unimpaired at baseline. METHODS: A total of 1096 individuals were selected from the Rush Alzheimer's Disease Center database registry. All participants were clinically unimpaired at baseline, and had subsequently undergone brain autopsy. Average age at baseline was 78.8 (6.92). A Bayesian regression analysis was carried out with global pathology as outcome; demographic, clinical and APOE data as covariates; and cognitive predictors, including delayed primacy. RESULTS: Global AD pathology was best predicted by delayed primacy. Secondary analyses showed that delayed primacy was mostly associated with neuritic plaques, whereas total delayed recall was associated with neurofibrillary tangles. DISCUSSION: We conclude that CERAD-derived delayed primacy is a useful metric for early detection and diagnosis of AD in unimpaired individuals.

The recency ratio assessed by story recall is associated with cerebrospinal fluid levels of neurodegeneration biomarkers.

Recency refers to the information learned at the end of a study list or task. Recency forgetting, as tracked by the ratio between recency recall in immediate and delayed conditions, i.e., the recency ratio (Rr), has been applied to list-learning tasks, demonstrating its efficacy in predicting cognitive decline, conversion to mild cognitive impairment (MCI), and cerebrospinal fluid (CSF) biomarkers of neurodegeneration. However, little is known as to whether Rr can be effectively applied to story recall tasks. To address this question, data were extracted from the database of the Alzheimer's Disease Research Center at the University of Wisconsin - Madison. A total of 212 participants were included in the study. CSF biomarkers were amyloid-beta (Aß) 40 and 42, phosphorylated (p) and total (t) tau, neurofilament light (NFL), neurogranin (Ng), and α-synuclein (a-syn). Story Recall was measured with the Logical Memory Test (LMT). We carried out Bayesian regression analyses with Rr, and other LMT scores as predictors; and CSF biomarkers (including the Aß42/40 and p-tau/Aß42 ratios) as outcomes. Results showed that models including Rr consistently provided best fits with the data, with few exceptions. These findings demonstrate the applicability of Rr to story recall and its sensitivity to CSF biomarkers of neurodegeneration, and encourage its inclusion when evaluating risk of neurodegeneration with story recall.

Associations of Hearing Loss and Hearing Aid Use With Cognition, Health-Related Quality of Life, and Depressive Symptoms.

ObjectivesDetermine associations of hearing loss (HL) and hearing aid (HA) use with cognition, health-related quality of life (HRQoL), and depressive symptoms. Methods: Participants were from the Epidemiology of Hearing Loss Study or Beaver Dam Offspring Study. HL was defined as pure-tone average (.5-4.0 kHz) > 25 dB. A principal component analysis of 5 cognitive tasks measured cognition. The SF-12 measured mental and physical HRQoL. The Centers for Epidemiological Studies Depression Scale measured depressive symptoms (score ≥ 16). Regression models returned beta (B) coefficients or odds ratios (OR) with 95% confidence intervals. Results: This study included 3574 participants. HL (vs. none) was associated with poorer cognition (B-.12 [-.18, -.06]), mental (B-.99 [-1.65, -.33]) and physical (B-.76 [-1.50, -.03]) HRQoL, and increased odds of depressive symptoms (OR 1.49 [1.16, 1.91]). HA users had better cognition than non-users. Discussion: HL likely impacts cognition and well-being. HA use may have cognitive benefits.

Toward harmonization of strategies for investigating lucidity in AD/ADRD: A preliminary research framework.

Episodes of lucidity (ELs) in Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD), have garnered increasing attention as an important area of research. Efforts to study lucidity suffer from a lack of clear definitional criteria, inconsistent conceptualization, and diverse approaches to operationalizing features of these events. To advance systematic investigation of ELs in AD/ADRD, there is a need for clarity and precision in labeling event attributes, markers, and specific measurement strategies that enable operational harmonization across distinct approaches to investigating the relatively broad and nascent phenomenon. To that end, we propose a preliminary research framework to guide harmonization of approaches to investigating ELs in AD/ADRD. Our goal is to provide an initial schematic that encourages uniform labeling of operational decisions about ELs.

"It's You": Caregiver and Clinician Perspectives on Lucidity in People Living With Dementia.

BACKGROUND AND OBJECTIVES: Episodes of lucidity (ELs), or a transient return of abilities believed to be lost in people living with dementia, are a growing area of interest. These events hold important implications for care, caregiving, and our understanding of underlying etiologies. Research on ELs is largely limited to retrospective reports. The perspectives of professional and family caregivers on ELs and research approaches can inform efforts to define and study lucidity. The present study examined family caregiver and hospice clinician experiences with and perspectives on ELs in people living with dementia and observational approaches to studying these events. RESEARCH DESIGN AND METHODS: This exploratory, descriptive qualitative study employed semistructured interviews (N = 20 caregivers, N = 6 clinicians). Data were analyzed using Rapid Identification of Themes and subsequent duplicate review of interview data to enhance trustworthiness. RESULTS: Most participants readily recalled events they perceived as ELs, describing a transient return of abilities they felt was significant and/or meaningful. Defining features, interpretations, and the perceived impact of ELs varied, although ELs were commonly conceptualized as a manifestation of self. Caregivers described extensive efforts to detect patterns and supportive social conditions for ELs. Participants supported use of audiovisual observation to study ELs and provided recommendations for privacy, workflow, and caregiver engagement. DISCUSSION AND IMPLICATIONS: Interpretations of ELs are heterogeneous, and recognition of these events may necessitate close familiarity with the person living with dementia. Participants endorse observational approaches and integration of caregivers in this research.

Cross-sectional associations of CSF tau levels with Rey's AVLT: A recency ratio study.

OBJECTIVE: The preeminent in vivo cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) are amyloid ß 1-42 (Aß42), phosphorylated Tau (p-tau), and total Tau (t-tau). The goal of this study was to examine how well traditional (total and delayed recall) and process-based (recency ratio [Rr]) measures derived from Rey's Auditory Verbal Learning test (AVLT) were associated with these biomarkers. METHOD: Data from 235 participants (Mage = 65.5, SD = 6.9), who ranged from cognitively unimpaired to mild cognitive impairment, and for whom CSF values were available, were extracted from the Wisconsin Registry for Alzheimer's Prevention. Bayesian regression analyses were carried out using CSF scores as outcomes, AVLT scores as predictors, and controlling for demographic data and diagnosis. RESULTS: We found moderate evidence that Rr was associated with both CSF p-tau (Bayesian factor [BFM] = 5.55) and t-tau (BFM = 7.28), above and beyond the control variables, while it did not correlate with CSF Aß42 levels. In contrast, total and delayed recall scores were not linked with any of the AD biomarkers, in separate analyses. When comparing all memory predictors in a single regression, Rr remained the strongest predictor of CSF t-tau levels (BFM = 3.57). CONCLUSIONS: Our findings suggest that Rr may be a better cognitive measure than commonly used AVLT scores to assess CSF levels of p-tau and t-tau in nondemented individuals. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Early ultrasonic vocalization deficits and related thyroarytenoid muscle pathology in the transgenic TgF344-AD rat model of Alzheimer's disease.

Background: Alzheimer's disease (AD) is a progressive neurologic disease and the most common cause of dementia. Classic pathology in AD is characterized by inflammation, abnormal presence of tau protein, and aggregation of ß-amyloid that disrupt normal neuronal function and lead to cell death. Deficits in communication also occur during disease progression and significantly reduce health, well-being, and quality of life. Because clinical diagnosis occurs in the mid-stage of the disease, characterizing the prodrome and early stages in humans is currently challenging. To overcome these challenges, we use the validated TgF344-AD (F344-Tg(Prp-APP, Prp-PS1)19/Rrrc) transgenic rat model that manifests cognitive, behavioral, and neuropathological dysfunction akin to AD in humans. Objectives: The overarching goal of our work is to test the central hypothesis that pathology and related behavioral deficits such as communication dysfunction in part manifest in the peripheral nervous system and corresponding target tissues already in the early stages. The primary aims of this study are to test the hypotheses that: (1) changes in ultrasonic vocalizations (USV) occur in the prodromal stage at 6 months of age and worsen at 9 months of age, (2) inflammation as well as AD-related pathology can be found in the thyroarytenoid muscle (TA) at 12 months of age (experimental endpoint tissue harvest), and to (3) demonstrate that the TgF344-AD rat model is an appropriate model for preclinical investigations of early AD-related vocal deficits. Methods: USVs were collected from male TgF344-AD (N = 19) and wildtype (WT) Fischer-344 rats (N = 19) at 6 months (N = 38; WT: n = 19; TgF344-AD: n = 19) and 9 months of age (N = 18; WT: n = 10; TgF344-AD: n = 8) and acoustically analyzed for duration, mean power, principal frequency, low frequency, high frequency, peak frequency, and call type. RT-qPCR was used to assay peripheral inflammation and AD-related pathology via gene expressions in the TA muscle of male TgF344-AD rats (n = 6) and WT rats (n = 6) at 12 months of age. Results: This study revealed a significant reduction in mean power of ultrasonic calls from 6 to 9 months of age and increased peak frequency levels over time in TgF344-AD rats compared to WT controls. Additionally, significant downregulation of AD-related genes Uqcrc2, Bace2, Serpina3n, and Igf2, as well as downregulation of pro-inflammatory gene Myd88 was found in the TA muscle of TgF344-AD rats at 12 months of age. Discussion: Our findings demonstrate early and progressive vocal deficits in the TgF344-AD rat model. We further provide evidence of dysregulation of AD-pathology-related genes as well as inflammatory genes in the TA muscles of TgF344-AD rats in the early stage of the disease, confirming this rat model for early-stage investigations of voice deficits and related pathology.

Associations of the Lifestyle for Brain Health index with longitudinal cognition and brain amyloid beta in clinically unimpaired older adults: Findings from the Wisconsin Registry for Alzheimer's Prevention.

Introduction: Modifiable health and lifestyle factors increase risk of dementia, but whether modifiable factors, when measured in late-midlife, impact the emergence or progression of Alzheimer's disease (AD) pathophysiologic or cognitive changes remains unresolved. Methods: In initially cognitively unimpaired, late middle-aged participants (N = 1215; baseline age, M [standard deviation] = 59.3 [6.7] years) from the Wisconsin Registry for Alzheimer's Prevention (WRAP), we investigated the influence of the Lifestyle for Brain Health (LIBRA) index, a lifestyle-based dementia risk score, on AD-related cognitive trajectories and amyloid beta (Aß) plaque accumulation. Results: Overall, lower baseline LIBRA, denoting healthier lifestyle and lower dementia risk, was related to better overall cognitive performance, but did not moderate apolipoprotein E ε4 or Aß-related longitudinal cognitive trajectories. LIBRA was not significantly associated with Aß accumulation or estimated age of Aß onset. Discussion: In WRAP, late-midlife LIBRA scores were related to overall cognitive performance, but not AD-related cognitive decline or Aß accumulation in the preclinical timeframe. Highlights: The Lifestyle for Brain Health (LIBRA) index was associated with cognitive performance in late-midlife.LIBRA did not moderate apolipoprotein E ε4 or amyloid-related cognitive decline.LIBRA was not associated with the onset or accumulation of amyloid plaques.

Preliminary assessment of connected speech and language as marker for cognitive change in late middle-aged Black/African American adults at risk for Alzheimer's disease.

Background: Connected speech-language (CSL) has been a promising measure of assessing cognitive decline in populations at-risk for Alzheimer's disease and related dementias (ADRD) populations. A common way to obtain CSL is through using picture description tasks such as the most frequently used image Cookie Theft (CT). However, questions have been raised about using CT for diverse communities. Little is known about the CSL produced in response to this task in Black/African American (BAA) adults aged 48-74. Goals: The present study's goals were to characterize CSL in BAA adults by sex and APOE-ε4 status from Milwaukee in the Wisconsin Registry for Alzheimer's Prevention (WRAP) study when presented with the CT picture description task and to identify differences in CSL output between BAAs and non-Hispanic Whites (NHW). Methods and Procedures: We collected CSL samples from the CT picture from 48 BAA participants and 30 NHW participants from the WRAP participants in Milwaukee, WI group. CSL was analyzed using chi-square tests, T-tests, and ANCOVA. Linear mixed effect regression models were used to determine the association between cognitive status and longitudinal CSL in BAA participants with more than 1 timepoint. Outcomes and Results: Declines in CSL of BAA participants were associated with subtle declines in cognition. Among BAA participants, we found no significant differences in speech measures in terms of sex and APOE-ε4 status. Our results showed no significant differences in speech measures between BAA and NHW groups. Conclusions: CSL analysis provides an inexpensive way to evaluate preclinical changes in cognitive status that may not be as affected by other factors, such as ethnocultural background. Future studies with larger sample sizes and participants from other geographic locations can clarify these findings.

Item-Level Story Recall Predictors of Amyloid-Beta in Late Middle-Aged Adults at Increased Risk for Alzheimer's Disease.

Background: Story recall (SR) tests have shown variable sensitivity to rate of cognitive decline in individuals with Alzheimer's disease (AD) biomarkers. Although SR tasks are typically scored by obtaining a sum of items recalled, item-level analyses may provide additional sensitivity to change and AD processes. Here, we examined the difficulty and discrimination indices of each item from the Logical Memory (LM) SR task, and determined if these metrics differed by recall conditions, story version (A vs. B), lexical categories, serial position, and amyloid status. Methods: n = 1,141 participants from the Wisconsin Registry for Alzheimer's Prevention longitudinal study who had item-level data were included in these analyses, as well as a subset of n = 338 who also had amyloid positron emission tomography (PET) imaging. LM data were categorized into four lexical categories (proper names, verbs, numbers, and "other"), and by serial position (primacy, middle, and recency). We calculated difficulty and discriminability/memorability by item, category, and serial position and ran separate repeated measures ANOVAs for each recall condition, lexical category, and serial position. For the subset with amyloid imaging, we used a two-sample t-test to examine whether amyloid positive (Aß+) and amyloid negative (Aß-) groups differed in difficulty or discrimination for the same summary metrics. Results: In the larger sample, items were more difficult (less memorable) in the delayed recall condition across both story A and story B. Item discrimination was higher at delayed than immediate recall, and proper names had better discrimination than any of the other lexical categories or serial position groups. In the subsample with amyloid PET imaging, proper names were more difficult for Aß+ than Aß-; items in the verb and "other" lexical categories and all serial positions from delayed recall were more discriminate for the Aß+ group compared to the Aß- group. Conclusion: This study provides empirical evidence that both LM stories are effective at discriminating ability levels and amyloid status, and that individual items vary in difficulty and discrimination by amyloid status, while total scores do not. These results can be informative for the future development of sensitive tasks or composite scores for early detection of cognitive decline.

Discourse Performance in Adults With Mild Traumatic Brain Injury, Orthopedic Injuries, and Moderate to Severe Traumatic Brain Injury, and Healthy Controls.

INTRODUCTION: Adults with mild traumatic brain injury (mTBI) are at risk for communication disorders, yet studies exploring cognitive-communication performance are currently lacking. AIMS: This aim of this study was to characterize discourse-level performance by adults with mTBI on a standardized elicitation task and compare it to (a) healthy adults, (b) adults with orthopedic injuries (OIs), and (c) adults with moderate to severe TBI. METHOD: This study used a cross-sectional design. The participants included mTBI and OI groups recruited prospectively from an emergency medicine department. Moderate to severe TBI and healthy data were acquired from TalkBank. One-way analyses of variance were used to compare mean linguistic scores. RESULTS: Seventy participants across all groups were recruited. Groups did not differ on demographic variables. The study found significant differences in both content and productivity measures among the groups. Variables did not appear sensitive to differentiate between mTBI and OI groups. DISCUSSION: Cognitive and language performance of adults with mTBI is a pressing clinical issue. Studies exploring language with carefully selected control groups can influence the development of sensitive measures to identify individuals with cognitive-communication deficits.

Spatio-Semantic Graphs From Picture Description: Applications to Detection of Cognitive Impairment.

Clinical assessments often use complex picture description tasks to elicit natural speech patterns and magnify changes occurring in brain regions implicated in Alzheimer's disease and dementia. As The Cookie Theft picture description task is used in the largest Alzheimer's disease and dementia cohort studies available, we aimed to create algorithms that could characterize the visual narrative path a participant takes in describing what is happening in this image. We proposed spatio-semantic graphs, models based on graph theory that transform the participants' narratives into graphs that retain semantic order and encode the visuospatial information between content units in the image. The resulting graphs differ between Cognitively Impaired and Unimpaired participants in several important ways. Cognitively Impaired participants consistently scored higher on features that are heavily associated with symptoms of cognitive decline, including repetition, evidence of short-term memory lapses, and generally disorganized narrative descriptions, while Cognitively Unimpaired participants produced more efficient narrative paths. These results provide evidence that spatio-semantic graph analysis of these tasks can generate important insights into a participant's cognitive performance that cannot be generated from semantic analysis alone.

Validity Evidence for the Research Category, "Cognitively Unimpaired - Declining," as a Risk Marker for Mild Cognitive Impairment and Alzheimer's Disease.

While clinically significant cognitive impairment is the key feature of the symptomatic stages of the Alzheimer's disease (AD) continuum, subtle cognitive decline is now known to occur years before a clinical diagnosis of mild cognitive impairment (MCI) or dementia due to AD is made. The primary aim of this study was to examine criterion validity evidence for an operational definition of "cognitively unimpaired-declining" (CU-D) in the Wisconsin Registry for Alzheimer's Prevention (WRAP), a longitudinal cohort study following cognition and risk factors from mid-life and on. Cognitive status was determined for each visit using a consensus review process that incorporated internal norms and published norms; a multi-disciplinary panel reviewed cases first to determine whether MCI or dementia was present, and subsequently whether CU-D was present, The CU-D group differed from CU-stable (CU-S) and MCI on concurrent measures of cognition, demonstrating concurrent validity. Participants who changed from CU-S to CU-D at the next study visit demonstrated greater declines than those who stayed CU-S. In addition, those who were CU-D were more likely to progress to MCI or dementia than those who were CU-S (predictive validity). In a subsample with positron emission tomography (PET) imaging, the CU-D group also differed from the CU-S and MCI/Dementia groups on measures of amyloid and tau burden, indicating that biomarker evidence of AD was elevated in those showing sub-clinical (CU-D) decline. Together, the results corroborate other studies showing that cognitive decline begins long before a dementia diagnosis and indicate that operational criteria can detect subclinical decline that may signal AD or other dementia risk.

Amyloid beta associations with connected speech in cognitively unimpaired adults.

INTRODUCTION: Connected speech and language (CSL) decline has been associated with early cognitive decline, but associations between CSL and Alzheimer's disease (AD) biomarkers remain a gap in the literature. Our goal was to examine associations with amyloid beta (Aß) and longitudinal CSL trajectories in cognitively unimpaired adults at increased AD risk. METHODS: Using data from the Wisconsin Registry for Alzheimer's Prevention, CSL measures were automatically extracted from digitally recorded picture descriptions. Positron emission tomography determined Aß status. Linear mixed effects models assessed the interaction between age and Aß on CSL trajectories. RESULTS: Participants who were Aß positive experienced more rapid decline on specific word content, when controlling for age, sex, and literacy. There were no differences between groups in lexical diversity measures over time. DISCUSSION: These results indicate that declines in connected speech may be related to preclinical AD. CSL may be a promising, inexpensive, and easy-to-collect digital cognitive marker for AD studies.