Characterizing brain tau and cognitive decline along the amyloid timeline in Alzheimer's disease.

Recent longitudinal PET imaging studies have established methods to estimate the age at which amyloid becomes abnormal at the level of the individual. Here we recontextualized amyloid levels into the temporal domain to better understand the downstream Alzheimer's disease processes of tau neurofibrillary tangle (NFT) accumulation and cognitive decline. This cohort study included a total of 601 individuals from the Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center that underwent amyloid and tau PET, longitudinal neuropsychological assessments and met clinical criteria for three clinical diagnosis groups: cognitively unimpaired (n = 537); mild cognitive impairment (n = 48); or dementia (n = 16). Cortical 11C-Pittsburgh compound B (PiB) distribution volume ratio (DVR) and sampled iterative local approximation were used to estimate amyloid positive (A+; global PiB DVR > 1.16 equivalent to 17.1 centiloids) onset age and years of A+ duration at tau PET (i.e. amyloid chronicity). Tau PET burden was quantified using 18F-MK-6240 standardized uptake value ratios (70-90 min, inferior cerebellar grey matter reference region). Whole-brain and region-specific approaches were used to examine tau PET binding along the amyloid timeline and across the Alzheimer's disease clinical continuum. Voxel-wise 18F-MK-6240 analyses revealed that with each decade of A+, the spatial extent of measurable tau spread (i.e. progressed) from regions associated with early to late NFT tau stages. Regional analyses indicated that tau burden in the entorhinal cortex was detectable, on average, within 10 years of A+ onset. Additionally, the entorhinal cortex was the region most sensitive to early amyloid pathology and clinical impairment in this predominantly preclinical sample. Among initially cognitively unimpaired (n = 472) individuals with longitudinal cognitive follow-up, mixed effects models showed significant linear and non-linear interactions of A+ duration and entorhinal tau on cognitive decline, suggesting a synergistic effect whereby greater A+ duration, together with a higher entorhinal tau burden, increases the likelihood of cognitive decline beyond their separable effects. Overall, the amyloid time framework enabled a spatiotemporal characterization of tau deposition patterns across the Alzheimer's disease continuum. This approach, which examined cross-sectional tau PET data along the amyloid timeline to make longitudinal disease course inferences, demonstrated that A+ duration explains a considerable amount of variability in the magnitude and topography of tau spread, which largely recapitulated NFT staging observed in human neuropathological studies. By anchoring disease progression to the onset of amyloid, this study provides a temporal disease context, which may help inform disease prognosis and timing windows for anti-amyloid therapies.

CSF Biomarkers in Longitudinal Alzheimer Disease Cohorts: Pre-Analytic Challenges.

BACKGROUND: The sensitivity of amyloid to pre-analytic factors complicates cerebrospinal fluid (CSF) diagnostics for Alzheimer disease. We report reliability and validity evidence for automated immunoassays from frozen and fresh CSF samples in an ongoing, single-site research program. METHODS: CSF samples were obtained from 2 Wisconsin cohorts (1256 measurements; 727 participants). Levels of amyloid beta 1-42 (Aß42), phosphorylated tau 181 (pTau181), and total tau (tTau) were obtained using an Elecsys cobas e 601 platform. Repeatability and fixed effects of storage tube type, extraction method, and freezing were assessed via mixed models. Concordance with amyloid positron emission tomography (PET) was investigated with 238 participants having a temporally proximal PET scan. RESULTS: Repeatability was high with intraclass correlation (ICC) ≥0.9, but tube type strongly affected measurements. Discriminative accuracy for PET amyloid positivity was strong across tube types (area under the curve [AUC]: Aß42, 0.87; pTau181Aß42 , 0.96), although optimal thresholds differed. CONCLUSIONS: Under real-world conditions, the Elecsys platform had high repeatability. However, strong effects of pre-analytic factors suggest caution in drawing longitudinal inferences.

Determinants of Plasma Alzheimer's Disease Biomarker Use by Primary Care Providers and Dementia Specialists.

BACKGROUND: The efficiencies of plasma Alzheimer's disease (AD) biomarkers could facilitate early AD diagnosis. Unfortunately, limited knowledge exists about whether and how they would be used by clinicians. OBJECTIVE: To identify and compare determinants of plasma AD biomarker use reported by primary care providers and dementia specialists. DESIGN: Semi-structured interviews with clinicians organized using Rogers' Diffusion of Innovations theory and analyzed using an iterative coding approach. PARTICIPANTS: The subjects were internal and family medicine, neurology, and geriatrics providers with varying degrees of expertise in dementia diagnosis and care. MAIN MEASURES: Factors influencing a clinician's decision to use or not use plasma AD biomarkers in clinical practice. KEY RESULTS: We interviewed 30 clinicians (16 family or internal medicine providers, 8 geriatricians, and 6 neurologists). Fifteen were dementia specialists. Hesitance to use plasma AD biomarkers was due to perceived lack of effective treatments for AD, limited access to supports, and stigma. Plasma AD biomarkers would be more readily adopted by clinicians with dementia expertise. CONCLUSIONS: Several factors will influence clinical use of plasma AD biomarkers. Some of them may inform the design of interventions to promote the effective and appropriate clinical translation of these tests.

Alzheimer's disease biomarker burden in primary motor cortices is associated with poorer dexterity performance.

INTRODUCTION: Motor function has correlated with longevity and functionality; however, there is limited research on those with Alzheimer's disease (AD). We studied the association between motor functionality and AD pathology in primary motor and medial temporal cortices. METHODS: A total of 206 participants with a clinical diagnosis of cognitively healthy, AD, or mild cognitive impairment (MCI) underwent imaging and motor assessment. Linear regressions and analyses of variance were applied to test the prediction from AD imaging biomarkers to motor performance and the diagnosis group differences in motor performance. RESULTS: Increased neurodegeneration was associated with worsening dexterity and lower walking speed, and increased amyloid and tau were associated with worsening dexterity. AD and MCI participants had lower motor performance than the cognitively healthy participants. DISCUSSION: Increased AD pathology is associated with worsening dexterity performance. The decline in dexterity in those with AD pathology may offer an opportunity for non-pharmacological therapy intervention. HIGHLIGHTS: Noted worsening dexterity performance was associated with greater Alzheimer's disease (AD) pathology (tau, amyloid beta, and neurodegeneration) in primary motor cortices. Similarly, increased neurodegeneration and tau pathology in parahippocampal, hippocampal, and entorhinal cortices is associated with worsening dexterity performance. Motor performance declined in those with clinical and preclinical AD among an array of motor assessments.

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.

Anticipated Psychological or Behavioral Reactions to Learning Alzheimer Biomarker Results: Associations With Contextual Factors.

BACKGROUND: As Alzheimer disease (AD) biomarker testing becomes more widely available, adults may opt to learn results. Considering potential reactions to learning biomarker results can guide prebiomarker and postbiomarker testing education and counseling programs. METHODS: Cognitively healthy adults enrolled in observational Alzheimer research responded to a telephone survey about learning AD risk information (n=334; 44% Black or African American; mean age=64.9±7.0). Multiple linear regression models tested if contextual factors predicted anticipated psychological impact (distress, stigma, and cognitive symptoms) or behavior change (planning and risk-reduction). Secondary analyses tested for differences in relationships by racial identity. RESULTS: Internal health locus of control, concern about AD, self-identified sex, education, family dementia history, and belief in AD modifiability predicted anticipated psychological impact. Concern about AD, age, racial identity, belief in AD modifiability, research attitudes, and exposure to brain health-related social norms predicted anticipated behavior change. For Black respondents, there were no sex differences in anticipated distress, whereas there were stronger relationships between health locus of control, brain health social norms, and education on outcomes compared with White respondents. CONCLUSIONS: Results may inform personalized and culturally tailored biomarker testing education and counseling to minimize psychological impacts and increase behavior change related to learning AD risk information.

New horizons in understanding oral health and swallowing function within the context of frailty.

Frailty is a complex and multidimensional condition wherein declines in physiologic reserve and function place individuals in a state of heightened vulnerability and decreased resiliency. There has been growing interest in both research and clinical settings to understand how to best define, assess and characterise frailty in older adults. To this end, various models and clinical assessment tools have been used to define and measure frailty. While differences exist among these models and tools, a common unifying theme is a focus on physical function and activity. Notably absent across many available conceptual models and clinical tools are items directly related to oral and swallowing function. This is an important oversight as widespread changes to both oral and swallowing function are evident in older adults. Indeed, emerging evidence suggests many of the functional domains affected in frail older adults, such as nutrition and sarcopenia, have cyclical relationships with impairments in oral (oral hypofunction) and swallowing function (dysphagia) as well. The increasing appreciation for the interrelationships among oral hypofunction, dysphagia and frailty provides an opportunity for refinement of frailty assessment and characterisation in older adults to incorporate metrics specific to oral and swallowing function.

Biomarker disclosure protocols in prodromal Alzheimer's disease clinical trials.

INTRODUCTION: The development of biomarkers for Alzheimer's disease (AD) has allowed researchers to increase sample homogeneity and test candidate treatments earlier in the disease. The integration of biomarker "screening" criteria should be met with a parallel implementation of standardized methods to disclose biomarker testing results to research participants; however, the extent to which protocolized disclosure occurs in trials is unknown. METHODS: We reviewed the literature to identify prodromal AD trials published in the past 10 years. From these, we quantified the frequency of biomarker disclosure reporting and the depth of descriptions provided. RESULTS: Of 30 published trials using positron emission tomography or cerebrospinal fluid-based amyloid positivity as an eligibility criterion, only one mentioned disclosure, with no details on methods. DISCUSSION: Possible reasons for and implications of this information gap are discussed. Recommendations are provided for trialists considering biomarker screening as part of intervention trials focused on prodromal AD. HIGHLIGHTS: Few prodromal Alzheimer's disease (AD) trial papers discuss biomarker disclosure. Disclosure has implications for participants, family members, and trial success. Disclosure must be consistently integrated and reported in prodromal AD trials. Best practice guidelines and training resources for disclosure are needed.

Predictors of Willingness to Enroll in Hypothetical Alzheimer Disease Biomarker Studies that Disclose Personal Results.

INTRODUCTION: We examined factors related to willingness to enroll in hypothetical Alzheimer disease (AD) biomarker studies. METHODS: Using linear regression, we assessed the relationship among enrollment willingness and demographics, family dementia history, research attitudes, concern about AD, experiences of discrimination, and belief in AD risk modifiability. Inductive coding was used to assess qualitative data. RESULTS: In middle-aged and older adult AD research participants (n=334), willingness to enroll in biomarker studies was driven by biomarker collection method, research attitudes, and disclosure of personal results. Predictors of willingness were similar for Black and White participants. Themes associated with increased willingness included a desire to learn biomarker results and support research. DISCUSSION: Research attitudes were an important predictor of biomarker study willingness regardless of race. As seen elsewhere, Black participants were more hesitant to participate in biomarker research. Disclosure of biomarker results/risk can bolster willingness to enroll in biomarker studies, particularly for Black participants.

Comparing emergency department use among individuals with varying levels of cognitive impairment.

INTRODUCTION: As the population ages, Alzheimer's disease and related dementias (ADRD) are becoming increasingly common in patients presenting to the emergency department (ED). This study compares the frequency of ED use among a cohort of individuals with well-defined cognitive performance (cognitively intact, mild cognitive impairment (MCI), and ADRD). METHODS: We performed a retrospective cohort study of English-speaking, community-dwelling individuals evaluated at four health system-based multidisciplinary memory clinics from 2014-2016. We obtained demographic and clinical data, including neuropsychological testing results, through chart review and linkage to electronic health record data. We characterized the frequency and quantity of ED use within one year (6 months before and after) of cognitive evaluation and compared ED use between the three groups using bivariate and multivariate approaches. RESULTS: Of the 779 eligible patients, 89 were diagnosed as cognitively intact, 372 as MCI, and 318 as ADRD. The proportion of subjects with any annual ED use did not increase significantly with greater cognitive impairment: cognitively intact (16.9%), MCI (26.1%), and ADRD (28.9%) (p = 0.072). Average number of ED visits increased similarly: cognitively intact (0.27, SD 0.72), MCI (0.41, SD 0.91), and ADRD (0.55, SD 1.25) (p = 0.059). Multivariate logistic regression results showed that patients with MCI (odds ratio (OR) 1.62; CI = 0.87-3.00) and ADRD (OR 1.84; CI = 0.98-3.46) did not significantly differ from cognitively intact adults in any ED use. Multivariate negative binomial regression found patients with MCI (incidence rate ratio (IRR) 1.38; CI = 0.79-2.41) and ADRD (IRR 1.76, CI = 1.00-3.10) had elevated but non-significant risk of an ED visit compared to cognitively intact individuals. CONCLUSION: Though there was no significant difference in ED use in this small sample from one health system, our estimates are comparable to other published work. Results suggested a trend towards higher utilization among adults with MCI or ADRD compared to those who were cognitively intact. We must confirm our findings in other settings to better understand how to optimize systems of acute illness care for individuals with MCI and ADRD.

Cardiology clinic patient attitudes toward and potential personal utility of genetic testing: Findings from a unique multiracial clinical sample.

As more is understood about the hereditary nature of disease risk, the utility of genetic testing within cardiovascular medicine is increasingly being explored. Although testing may afford more personalized risk stratification, there is a paucity of information regarding patient knowledge, attitudes, and beliefs toward genetic testing among cardiology patients. Participants (n = 530) recruited primarily from a cardiology clinic filled out a 41-item written questionnaire assessing knowledge, beliefs, and attitudes toward genetic testing, motivators and detractors for considering genetic testing, and perceived likelihood for behavior change after hypothetical genetic testing risk stratification. Path analysis was used to test the hypothetical models predicting the likelihood of getting a genetic test and making behavior changes following genetic testing. The patient population was late-middle-aged (59.0 ± 14.5 years), majority women (61.5%), and about half reported having a bachelor's degree. 58.1% of participants self-identified as White, 25.7% as African American or Black, 6.8% as Spanish, Latino, or Hispanic, 3.0% as Asian or Pacific Islander, and 0.5% as Native American. Gender (being a woman) and more years of education were related to greater knowledge about genetic testing. Racial identity and years of education were related to beliefs about genetic testing. Beliefs, but not knowledge, were related to more positive attitudes and a higher likelihood of pursuing genetic testing. Positive attitudes were related to greater perceived personal control (PPC). Furthermore, attitudes and PPC were related to higher likelihood of lifestyle change after genetic testing. These results highlight the need to integrate the experiences of racialized communities into education/counseling efforts. Most educational counseling efforts lack a nuanced discussion of social determinants of health or beliefs. In addition to factual information, educational counseling must also address people's beliefs, concerns, and the intersecting experiences and identities, which shape patients' relationships with the evolving landscape of healthcare and personalized medicine.

Moving beyond disclosure: Stages of care in preclinical Alzheimer's disease biomarker testing.

Alzheimer's disease (AD) begins with an asymptomatic "preclinical" phase, in which abnormal biomarkers indicate risk for developing cognitive impairment. Biomarker information is increasingly being disclosed in research settings, and is moving toward clinical settings with the development of cheaper and non-invasive testing. Limited research has focused on the safety and psychological effects of disclosing biomarker results to cognitively unimpaired adults. However, less is known about how to ensure equitable access and robust counseling for decision-making before testing, and how to effectively provide long-term follow-up and risk management after testing. Using the framework of Huntington's disease, which is based on extensive experience with disclosing and managing risk for a progressive neurodegenerative condition, this article proposes a conceptual model of pre-disclosure, disclosure, and post-disclosure phases for AD biomarker testing. Addressing research questions in each phase will facilitate the transition of biomarker testing into clinical practice.

Interaction of amyloid and tau on cortical microstructure in cognitively unimpaired adults.

INTRODUCTION: Neurite orientation dispersion and density imaging (NODDI), a multi-compartment diffusion-weighted imaging (DWI) model, may be useful for detecting early cortical microstructural alterations in Alzheimer's disease prior to cognitive impairment. METHODS: Using neuroimaging (NODDI and T1-weighted magnetic resonance imaging [MRI]) and cerebrospinal fluid (CSF) biomarker data (measured using Elecsys® CSF immunoassays) from 219 cognitively unimpaired participants, we tested the main and interactive effects of CSF amyloid beta (Aß)42 /Aß40 and phosphorylated tau (p-tau) on cortical NODDI metrics and cortical thickness, controlling for age, sex, and apolipoprotein E ε4. RESULTS: We observed a significant CSF Aß42 /Aß40 × p-tau interaction on cortical neurite density index (NDI), but not orientation dispersion index or cortical thickness. The directionality of these interactive effects indicated: (1) among individuals with lower CSF p-tau, greater amyloid burden was associated with higher cortical NDI; and (2) individuals with greater amyloid and p-tau burden had lower cortical NDI, consistent with cortical neurodegenerative changes. DISCUSSION: NDI is a particularly sensitive marker for early cortical changes that occur prior to gross atrophy or development of cognitive impairment.

Amyloid and tau imaging biomarkers explain cognitive decline from late middle-age.

This study investigated differences in retrospective cognitive trajectories between amyloid and tau PET biomarker stratified groups in initially cognitively unimpaired participants sampled from the Wisconsin Registry for Alzheimer's Prevention. One hundred and sixty-seven initially unimpaired individuals (baseline age 59 ± 6 years; 115 females) were stratified by elevated amyloid-ß and tau status based on 11C-Pittsburgh compound B (PiB) and 18F-MK-6240 PET imaging. Mixed effects models were used to determine if longitudinal cognitive trajectories based on a composite of cognitive tests including memory and executive function differed between biomarker groups. Secondary analyses investigated group differences for a variety of cross-sectional health and cognitive tests, and associations between 18F-MK-6240, 11C-PiB, and age. A significant group × age interaction was observed with post hoc comparisons indicating that the group with both elevated amyloid and tau pathophysiology were declining approximately three times faster in retrospective cognition compared to those with just one or no elevated biomarkers. This result was robust against various thresholds and medial temporal lobe regions defining elevated tau. Participants were relatively healthy and mostly did not differ between biomarker groups in health factors at the beginning or end of study, or most cognitive measures at study entry. Analyses investigating association between age, MK-6240 and PiB indicated weak associations between age and 18F-MK-6240 in tangle-associated regions, which were negligible after adjusting for 11C-PiB. Strong associations, particularly in entorhinal cortex, hippocampus and amygdala, were observed between 18F-MK-6240 and global 11C-PiB in regions associated with Braak neurofibrillary tangle stages I-VI. These results suggest that the combination of pathological amyloid and tau is detrimental to cognitive decline in preclinical Alzheimer's disease during late middle-age. Within the Alzheimer's disease continuum, middle-age health factors likely do not greatly influence preclinical cognitive decline. Future studies in a larger preclinical sample are needed to determine if and to what extent individual contributions of amyloid and tau affect cognitive decline. 18F-MK-6240 shows promise as a sensitive biomarker for detecting neurofibrillary tangles in preclinical Alzheimer's disease.

Association between enrollment factors and incident cognitive impairment in Blacks and Whites: Data from the Alzheimer's Disease Center.

INTRODUCTION: We examined the influence of enrollment factors demonstrated to differ by race on incident mild cognitive impairment and dementia using Alzheimer's Disease Center data. METHODS: Differences in rates of incident impairment between non-Latino Whites and Blacks (n = 12,242) were examined with age-at-progression survival models. Models included race, sex, education, source of recruitment, health factors, and family history of dementia. RESULTS: No significant race differences in progression were observed in cognitively unimpaired participants. In those with mild cognitive impairment at baseline, Whites evidenced greater risk for progression than Blacks. Enrollment factors, for example, referral source, were significantly related to progression. DISCUSSION: The finding that Blacks demonstrated lower rate of progression than Whites is contrary to the extant literature. Nested-regression analyses suggested that selection-related factors, differing by race, may account for these findings and influence our ability to accurately estimate risk for progression. It is potentially problematic to make racial comparisons using Alzheimer's Disease Center data sets.

Hypertension and obesity moderate the relationship between ß-amyloid and cognitive decline in midlife.

BACKGROUND: This study tested if central obesity, hypertension, or depressive symptoms moderated the relationship between ß-amyloid (Aß) and longitudinal cognitive performance in late middle-aged adults enriched for Alzheimer's disease (AD) risk. METHODS: Participants (n = 207; ages = 40-70 years; 73% parental AD) in the Wisconsin Registry for Alzheimer's Prevention study completed 3+ neuropsychological evaluations and a [11C]PiB positron emission tomography scan or lumbar puncture. Linear mixed-effects regression models tested interactions of risk factor × Aß × visit age on longitudinal Verbal Learning & Memory and Speed & Flexibility factor scores. RESULTS: The relationship between Aß and Verbal Learning & Memory decline was moderated by hypertension (χ2(1) = 3.85, P = .04) and obesity (χ2(1) = 6.12, P = .01); those with both elevated Aß and the risk factor declined at faster rates than those with only elevated Aß or elevated risk factors. CONCLUSION: In this cohort, hypertension and obesity moderated the relationship between Aß and cognitive decline.