Assessing the Biological Mechanisms Linking Smoking Behavior and Cognitive Function: A Mediation Analysis of Untargeted Metabolomics.

(1) Smoking is the most significant preventable health hazard in the modern world. It increases the risk of vascular problems, which are also risk factors for dementia. In addition, toxins in cigarettes increase oxidative stress and inflammation, which have both been linked to the development of Alzheimer's disease and related dementias (ADRD). This study identified potential mechanisms of the smoking-cognitive function relationship using metabolomics data from the longitudinal Wisconsin Registry for Alzheimer's Prevention (WRAP). (2) 1266 WRAP participants were included to assess the association between smoking status and four cognitive composite scores. Next, untargeted metabolomic data were used to assess the relationships between smoking and metabolites. Metabolites significantly associated with smoking were then tested for association with cognitive composite scores. Total effect models and mediation models were used to explore the role of metabolites in smoking-cognitive function pathways. (3) Plasma N-acetylneuraminate was associated with smoking status Preclinical Alzheimer Cognitive Composite 3 (PACC3) and Immediate Learning (IMM). N-acetylneuraminate mediated 12% of the smoking-PACC3 relationship and 13% of the smoking-IMM relationship. (4) These findings provide links between previous studies that can enhance our understanding of potential biological pathways between smoking and cognitive function.

Effect of Pathway-Specific Polygenic Risk Scores for Alzheimer's Disease (AD) on Rate of Change in Cognitive Function and AD-Related Biomarkers Among Asymptomatic Individuals.

BACKGROUND: Genetic scores for late-onset Alzheimer's disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan. OBJECTIVE: In this study, we leveraged longitudinal data from the Wisconsin Registry for Alzheimer's Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways. METHODS: PRS and p-PRSs with and without APOE were constructed separately based on the significant SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared to APOE alone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers in a subset. Replication analyses were performed in an independent sample. RESULTS: We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of PRS/p-PRSs on rate of change in cognition, amyloid-ß, and tau outcomes are dependent on age and appear earlier in the lifespan when APOE is included in these risk scores compared to when APOE is excluded. CONCLUSION: In addition to APOE, the p-PRSs can predict age-dependent changes in amyloid-ß, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating amyloid-ß and tau, long before the onset of clinical symptoms.

Association of Age at Menopause and Hormone Therapy Use With Tau and ß-Amyloid Positron Emission Tomography.

Importance: Postmenopausal females represent around 70% of all individuals with Alzheimer disease. Previous literature shows elevated levels of tau in cognitively unimpaired postmenopausal females compared with age-matched males, particularly in the setting of high ß-amyloid (Aß). The biological mechanisms associated with higher tau deposition in female individuals remain elusive. Objective: To examine the extent to which sex, age at menopause, and hormone therapy (HT) use are associated with regional tau at a given level of Aß, both measured with positron emission tomography (PET). Design, Setting, and Participants: This cross-sectional study included participants enrolled in the Wisconsin Registry for Alzheimer Prevention. Cognitively unimpaired males and females with at least 1 18F-MK-6240 and 11C-Pittsburgh compound B PET scan were analyzed. Data were collected between November 2006 and May 2021. Exposures: Premature menopause (menopause at younger than 40 years), early menopause (menopause at age 40-45 years), and regular menopause (menopause at older than 45 years) and HT user (current/past use) and HT nonuser (no current/past use). Exposures were self-reported. Main Outcomes and Measures: Seven tau PET regions that show sex differences across temporal, parietal, and occipital lobes. Primary analyses examined the interaction of sex, age at menopause or HT, and Aß PET on regional tau PET in a series of linear regressions. Secondary analyses investigated the influence of HT timing in association with age at menopause on regional tau PET. Results: Of 292 cognitively unimpaired individuals, there were 193 females (66.1%) and 99 males (33.9%). The mean (range) age at tau scan was 67 (49-80) years, 52 (19%) had abnormal Aß, and 106 (36.3%) were APOEε4 carriers. There were 98 female HT users (52.2%) (past/current). Female sex (standardized ß = -0.41; 95% CI, -0.97 to -0.32; P < .001), earlier age at menopause (standardized ß = -0.38; 95% CI, -0.14 to -0.09; P < .001), and HT use (standardized ß = 0.31; 95% CI, 0.40-1.20; P = .008) were associated with higher regional tau PET in individuals with elevated Aß compared with male sex, later age at menopause, and HT nonuse. Affected regions included medial and lateral regions of the temporal and occipital lobes. Late initiation of HT (>5 years following age at menopause) was associated with higher tau PET compared with early initiation (ß = 0.49; 95% CI, 0.27-0.43; P = .001). Conclusions and Relevance: In this study, females exhibited higher tau compared with age-matched males, particularly in the setting of elevated Aß. In females, earlier age at menopause and late initiation of HT were associated with increased tau vulnerability especially when neocortical Aß elevated. These observational findings suggest that subgroups of female individuals may be at higher risk of pathological burden.

Normative Cerebral Hemodynamics in Middle-aged and Older Adults Using 4D Flow MRI: Initial Analysis of Vascular Aging.

Background Characterizing cerebrovascular hemodynamics in older adults is important for identifying disease and understanding normal neurovascular aging. Four-dimensional (4D) flow MRI allows for a comprehensive assessment of cerebral hemodynamics in a single acquisition. Purpose To establish reference intracranial blood flow and pulsatility index values in a large cross-sectional sample of middle-aged (45-65 years) and older (>65 years) adults and characterize the effect of age and sex on blood flow and pulsatility. Materials and Methods In this retrospective study, patients aged 45-93 years (cognitively unimpaired) underwent cranial 4D flow MRI between March 2010 and March 2020. Blood flow rates and pulsatility indexes from 13 major arteries and four venous sinuses and total cerebral blood flow were collected. Intraobserver and interobserver reproducibility of flow and pulsatility measures was assessed in 30 patients. Descriptive statistics (mean ± SD) of blood flow and pulsatility were tabulated for the entire group and by age and sex. Multiple linear regression and linear mixed-effects models were used to assess the effect of age and sex on total cerebral blood flow and vessel-specific flow and pulsatility, respectively. Results There were 759 patients (mean age, 65 years ± 8 [SD]; 506 female patients) analyzed. For intra- and interobserver reproducibility, median intraclass correlation coefficients were greater than 0.90 for flow and pulsatility measures across all vessels. Regression coefficients ß ± standard error from multiple linear regression showed a 4 mL/min decrease in total cerebral blood flow each year (age ß = -3.94 mL/min per year ± 0.44; P < .001). Mixed effects showed a 1 mL/min average annual decrease in blood flow (age ß = -0.95 mL/min per year ± 0.16; P < .001) and 0.01 arbitrary unit (au) average annual increase in pulsatility over all vessels (age ß = 0.011 au per year ± 0.001; P < .001). No evidence of sex differences was observed for flow (ß = -1.60 mL/min per male patient ± 1.77; P = .37), but pulsatility was higher in female patients (sex ß = -0.018 au per male patient ± 0.008; P = .02). Conclusion Normal reference values for blood flow and pulsatility obtained using four-dimensional flow MRI showed correlations with age. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Steinman in this issue.

Effect of Pathway-specific Polygenic Risk Scores for Alzheimer's Disease (AD) on Rate of Change in Cognitive Function and AD-related Biomarkers among Asymptomatic Individuals.

Background: Genetic scores for late-onset Alzheimer's disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan. Objective: In this study, we leveraged 10 years of longitudinal data from initially cognitively unimpaired individuals in the Wisconsin Registry for Alzheimer's Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways. Methods: PRS and p-PRSs with and without apolipoprotein E ( APOE ) were constructed separately based on the significant SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared to APOE alone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and global/domain-specific cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers for beta-amyloid 42 (Aß42), Aß42/40 ratio, total tau, and phosphorylated tau in a subset. Replication analyses were performed in an independent sample. Results: We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of p-PRSs/PRS on rate of change in cognition, beta-amyloid, and tau outcomes are dependent on age and appear earlier in the lifespan when APOE is included in these risk scores compared to when APOE is excluded. Conclusion: In addition to APOE , the p-PRSs can predict age-dependent changes in beta-amyloid, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating beta-amyloid and tau, long before the onset of clinical symptoms.

Trajectory of clinical symptoms in relation to amyloid chronicity.

Introduction: While it is generally appreciated that amyloid precedes symptomatic Alzheimer's disease (AD) by decades, a greater understanding of this timeline may increase prognostic accuracy, planning, and care of persons who are on the AD continuum. Methods: We examined trajectories of Clinical Dementia Rating-Sum of Boxes (CDR-SB) relative to estimated years of amyloid positivity (A+) in n = 123 participants who were all A+ based on [C-11]Pittsburgh compound B positron emission tomography. Results: The average amyloid chronicity at CDR-SB of 2.5 was 20.1 years. The average trajectory of CDR-SB accelerated after 10 years of elevated amyloid and varied greatly between 10 and 30 years. Exploratory analyses suggested that older age and higher volume of white matter hyperintensities shortened the interval between amyloid onset and cognitive impairment. Discussion: The recontextualization of amyloid burden into the time domain will facilitate studies of disease progression, the influence of co-pathology, and factors that hasten or slow cognitive impairment.

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.

Multi-method investigation of factors influencing amyloid onset and impairment in three cohorts.

Alzheimer's disease biomarkers are becoming increasingly important for characterizing the longitudinal course of disease, predicting the timing of clinical and cognitive symptoms, and for recruitment and treatment monitoring in clinical trials. In this work, we develop and evaluate three methods for modelling the longitudinal course of amyloid accumulation in three cohorts using amyloid PET imaging. We then use these novel approaches to investigate factors that influence the timing of amyloid onset and the timing from amyloid onset to impairment onset in the Alzheimer's disease continuum. Data were acquired from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Baltimore Longitudinal Study of Aging (BLSA) and the Wisconsin Registry for Alzheimer's Prevention (WRAP). Amyloid PET was used to assess global amyloid burden. Three methods were evaluated for modelling amyloid accumulation using 10-fold cross-validation and holdout validation where applicable. Estimated amyloid onset age was compared across all three modelling methods and cohorts. Cox regression and accelerated failure time models were used to investigate whether sex, apolipoprotein E genotype and e4 carriage were associated with amyloid onset age in all cohorts. Cox regression was used to investigate whether apolipoprotein E (e4 carriage and e3e3, e3e4, e4e4 genotypes), sex or age of amyloid onset were associated with the time from amyloid onset to impairment onset (global clinical dementia rating ≥1) in a subset of 595 ADNI participants that were not impaired before amyloid onset. Model prediction and estimated amyloid onset age were similar across all three amyloid modelling methods. Sex and apolipoprotein E e4 carriage were not associated with PET-measured amyloid accumulation rates. Apolipoprotein E genotype and e4 carriage, but not sex, were associated with amyloid onset age such that e4 carriers became amyloid positive at an earlier age compared to non-carriers, and greater e4 dosage was associated with an earlier amyloid onset age. In the ADNI, e4 carriage, being female and a later amyloid onset age were all associated with a shorter time from amyloid onset to impairment onset. The risk of impairment onset due to age of amyloid onset was non-linear and accelerated for amyloid onset age >65. These findings demonstrate the feasibility of modelling longitudinal amyloid accumulation to enable individualized estimates of amyloid onset age from amyloid PET imaging. These estimates provide a more direct way to investigate the role of amyloid and other factors that influence the timing of clinical impairment in Alzheimer's disease.

Relationship of Cognitive and Social Engagement to Health and Psychological Outcomes in Community-Dwelling Older Adults.

BACKGROUND: Cognitive and social engagement is an important yet underdocumented aspect of older adult engagement and function. OBJECTIVE: The purpose of this study was to examine relationships between cognitive and social engagement and health and psychological outcomes in a cohort of community-dwelling older adults aged approximately 55-70 years. METHODS: Analysis of data from the Wisconsin Registry for Alzheimer's Prevention, a multiwave cohort study with 1,582 participants, using a 1:1 prospective case-control design to examine whether lower cognitive and social engagement at Visit 4 (baseline) is associated with worse health and psychological outcomes at Visit 5 (2 years after Visit 4). Wisconsin Registry for Alzheimer's Prevention participants were included in this study if they had complete data on cognitive and social engagement and self-rated health at both visits. RESULTS: After matching potential covariates using propensity scores, participants with low cognitive and social engagement (cases) at baseline continued to have significantly lower cognitive and social engagement than the controls (participants with high cognitive and social engagement at baseline) at Visit 5, and they had lower self-rated health and higher surgery rate. Depressive symptoms, cognitive status, and hospitalization at Visit 5 did not significantly differ between cases and controls. DISCUSSION: This study provides evidence supporting cognitive and social engagement as an important marker of early decline in activity engagement that may indicate a potential later decline in functional, psychological, and health outcomes.

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.

Insulin resistance is related to cognitive decline but not change in CSF biomarkers of Alzheimer's disease in non-demented adults.

INTRODUCTION: We investigated whether insulin resistance (IR) was associated with longitudinal age-related change in cognition and biomarkers of Alzheimer's disease (AD) pathology and neurodegeneration in middle-aged and older adults who were non-demented at baseline. METHODS: IR was measured with homeostatic model assessment of insulin resistance (HOMA2-IR). Core AD-related cerebrospinal fluid (CSF) biomarkers and cognition were assessed, respectively, on n = 212 (1 to 5 visits) and n = 1299 (1 to 6 visits). Linear mixed models tested whether HOMA2-IR moderated age-related change in CSF biomarkers and cognition. Linear regressions tested whether HOMA2-IR x apolipoprotein E ε4 allele (APOE ε4) carrier status predicted amyloid beta [Aß] chronicity (estimated duration of amyloid positron emission tomography [PET] positivity) (n = 253). RESULTS: Higher HOMA2-IR was associated with greater cognitive decline but not with changes in CSF biomarkers. HOMA2-IR x APOE4 was not related to Aß chronicity but was significantly associated with CSF phosphorylated tau (P-tau)181/Aß42 level. DISCUSSION: In non-demented adults IR may not be directly associated with age-related change in AD biomarkers. Additional research is needed to determine mechanisms linking IR to cognitive decline.

Measurement batch differences and between-batch conversion of Alzheimer's disease cerebrospinal fluid biomarker values.

INTRODUCTION: Batch differences in cerebrospinal fluid (CSF) biomarker measurement can introduce bias into analyses for Alzheimer's disease studies. We evaluated and adjusted for batch differences using statistical methods. METHODS: A total of 792 CSF samples from 528 participants were assayed in three batches for 12 biomarkers and 3 biomarker ratios. Batch differences were assessed using Bland-Altman plot, paired t test, Pitman-Morgan test, and linear regression. Generalized linear models were applied to convert CSF values between batches. RESULTS: We found statistically significant batch differences for all biomarkers and ratios, except that neurofilament light was comparable between batches 1 and 2. The conversion models generally had high R 2 except for converting P-tau between batches 1 and 3. DISCUSSION: Between-batch conversion allows harmonized CSF values to be used in the same analysis. Such method may be applied to adjust for other sources of variability in measuring CSF or other types of biomarkers.

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.

The relationship of glucose-stimulated insulin secretion to cerebral glucose metabolism and cognition in healthy middle-aged and older adults.

Insulin resistance (IR) has been related to reduced cerebral glucose metabolism in regions identified as hypometabolic in Alzheimer's clinical syndrome. Insulin secretion (IS) has been less studied than IR despite findings that decreased IS is an early indicator of future type 2 diabetes and a potential predictor of Alzheimer's clinical syndrome. We investigated whether higher IR and lower IS would be associated with greater age-related reductions in regional cerebral glucose metabolism and worse cognitive performance. Two-hour oral glucose tolerance testing and 18F-fluorodeoxyglucose positron emission tomography were performed on 1-2 occasions on a sample of healthy middle-aged and older adults from the Wisconsin Alzheimer's Disease Research Center. Neuropsychological tests were completed during Alzheimer's Disease Research Center Clinical Core visits. Pattern of findings suggested that lower (not higher) IS was related to higher regional cerebral glucose metabolism in middle aged but not older adults, and lower (not higher) IS was also related to better immediate recall. In the context of healthy insulin sensitivity, lower IS may be beneficial to brain health.

Association of Neighborhood Context, Cognitive Decline, and Cortical Change in an Unimpaired Cohort.

OBJECTIVE: To test the hypothesis that neighborhood-level disadvantage is associated with longitudinal measures of neurodegeneration and cognitive decline in an unimpaired cohort. METHODS: Longitudinal MRI and cognitive testing data were collected from 601 cognitively unimpaired participants in the Wisconsin Registry for Alzheimer's Prevention Study and the Wisconsin Alzheimer's Disease Research Center clinical cohort. Area Deprivation Index was geospatially determined based on participant residence geocode and ranked relative to state of residence. Linear regression models were fitted to test associations between neighborhood-level disadvantage and longitudinal change in cortical thickness and cognitive test performance. Mediation tests were used to assess whether neurodegeneration and cognitive decline were associated with neighborhood-level disadvantage along the same theoretical causal path. RESULTS: In our middle- to older-aged study population (mean baseline age 59 years), living in the 20% most disadvantaged neighborhoods (n = 19) relative to state of residence was associated with cortical thinning in Alzheimer signature regions (p = 0.002) and decline in the Preclinical Alzheimer's Disease Cognitive Composite (p = 0.04), particularly the Trail-Making Test, part B (p < 0.001), but not Rey Auditory Verbal Learning Test (p = 0.77) or Story Memory Delayed Recall (p = 0.49) subtests. Associations were attenuated but remained significant after controlling for racial and demographic differences between neighborhood-level disadvantage groups. Cortical thinning partially mediated the association between neighborhood-level disadvantage and cognitive decline. CONCLUSIONS: In this longitudinal study of cognitively unimpaired adults, living in the most highly disadvantaged neighborhoods was associated with accelerated degeneration in Alzheimer signature regions and cognitive decline. This study provides further evidence for neighborhood-level disadvantage as a risk factor for preclinical neurodegeneration and cognitive decline in certain populations. Limitations of the present study, including a small number of participants from highly disadvantaged neighborhoods and a circumscribed geographic setting, should be explored in larger and more diverse study cohorts.

Neurodegeneration, Alzheimer's disease biomarkers, and longitudinal verbal learning and memory performance in late middle age.

This study examined the effect of neurodegeneration, and its interaction with Alzheimer's disease (AD) cerebrospinal fluid biomarkers, on longitudinal verbal learning and memory performance in cognitively unimpaired (CU) late middle-aged adults. Three hundred and forty-two CU adults (cognitive baseline mean age = 58.4), with cerebrospinal fluid and structural MRI, completed 2-10 (median = 5) cognitive assessments. Learning and memory were assessed using the Rey Auditory Verbal Learning Test (RAVLT). We used sequential comparison of nested linear mixed effects models to analyze the data. Model selection preserved a significant ptau181/Aß42 × global atrophy × age interaction; individuals with less global atrophy and lower ptau181/Aß42 levels had less learning and delayed recall decline than individuals with more global atrophy and/or higher levels of ptau181/Aß42. The hippocampal volume × age × ptau181/Aß42 interaction was not significant. Findings suggest that in a sample of CU late middle-aged adults, individuals with AD biomarkers, global atrophy, or both evidence greater verbal learning and memory decline than individuals without either risk factor.

Metabolites Associated with Early Cognitive Changes Implicated in Alzheimer's Disease.

BACKGROUND: Understanding metabolic mechanisms associated with cognitive changes preceding an Alzheimer's disease (AD) diagnosis could advance our understanding of AD progression and inform preventive methods. OBJECTIVE: We investigated the metabolomics of the early changes in executive function and delayed recall, the earliest aspects of cognitive function to change in the course of AD development, in order to better understand mechanisms that could contribute to early stages and progression of this disease. METHODS: This investigation used longitudinal plasma samples from the Wisconsin Registry for Alzheimer's Prevention (WRAP), a cohort of participants who were dementia free at enrollment and enriched with a parental history of AD. Metabolomic profiles were quantified for 2,324 fasting plasma samples among 1,200 participants, each with up to three study visits, which occurred every two years. Metabolites were individually tested for association with executive function and delayed recall trajectories across age. RESULTS: Of 1,097 metabolites tested, levels of seven were associated with executive function trajectories, including an amino acid cysteine S-sulfate and three fatty acids, including erucate (22 : 1n9), while none were associated with delayed recall trajectories. Replication was attempted for four of these metabolites that were present in the Vietnam Era Twin Study of Aging (VETSA). Although none reached statistical significance, three of these associations showed consistent effectdirections. CONCLUSION: Our results suggest potential metabolomic mechanisms that could contribute to the earliest signs of cognitive decline. In particular, fatty acids may be associated with cognition in a manner that is more complex than previously suspected.

Serial position effects in the Logical Memory Test: Loss of primacy predicts amyloid positivity.

BACKGROUND: Story recall is a frequently used neuropsychological test of episodic memory with clinical populations and for screening participants in drug trials for Alzheimer's disease. However, it is unclear at this stage which underlying mechanisms confer the test its sensitivity. In this paper, we examined serial position effects, that is, better recall for items learned early and late on a list, in story recall, and their usefulness to predict early changes associated with neurodegenerative markers. METHODS: We analysed data from the Wisconsin Registry for Alzheimer's Prevention. First, we tested whether serial position effects were present in story recall (measured with the Wechsler Memory Scale Logical Memory Task; LMT) across individuals who were classified as cognitively unimpaired - stable, cognitively unimpaired - declining, or as having mild cognitive impairment (MCI). RESULTS: Our results showed clear serial position effects for all groups, except for delayed recall among individuals with MCI, where no primacy effect was observed. Second, we tested whether loss of primacy from immediate to delayed recall was associated with amyloid burden (as measured with PiB PET) in individuals who were cognitively unimpaired at baseline. We found that more primacy loss predicted amyloid positivity, above and beyond the LMT total score. CONCLUSIONS: This report is the first to show that loss of primacy between immediate and delayed story recall is associated with amyloid burden.

Self-Reported Hearing Loss and Longitudinal Cognitive Function in a Cohort Enriched with Risk for Alzheimer's Disease.

BACKGROUND: Growing evidence suggests hearing loss is a risk factor for mild cognitive impairment and dementia, but few studies have examined its relationship to sub-clinical cognitive outcomes. OBJECTIVE: To investigate the effect of self-reported hearing loss on longitudinal cognitive function in a risk-enriched cohort of clinically-unimpaired, late middle-aged adults. METHODS: 579 participants from the Wisconsin Registry for Alzheimer's Prevention (WRAP) were included. Hearing status was determined via self-reported history of diagnosed hearing loss. Each participant with self-reported hearing loss was age- and sex-matched to two participants who never reported hearing loss using nearest-neighbor matching. Linear mixed-effects models were used to examine associations between self-reported hearing loss and age-related cognitive trajectories with covariates of sex, literacy, and ethnicity, person-level random intercepts and age-related slopes. Cognitive outcomes encompassed measures of speed and flexibility, visuospatial memory, and verbal fluency. RESULTS: Participants with self-reported hearing loss exhibited significantly poorer performance on a speed and flexibility factor score and single test of psychomotor speed and executive function, relative to participants who never reported hearing loss. There was no association between self-reported hearing loss and visuospatial memory or verbal fluency. Longitudinally, self-reported hearing loss was associated with less rapid decline in speed and flexibility and no difference in rate of decline for any other cognitive measure. CONCLUSION: Self-reported hearing loss was associated with poorer speed and flexibility but not with accelerated decline in any domain studied, contrary to previous findings. Further studies involving behavioral auditory measures in this cohort would clarify the robustness of these findings.

Proper names from story recall are associated with beta-amyloid in cognitively unimpaired adults at risk for Alzheimer's disease.

Due to advances in the early detection of Alzheimer's disease (AD) biomarkers including beta-amyloid (Aß), neuropsychological measures that are sensitive to concurrent, subtle changes in cognition are critically needed. Story recall tasks have shown sensitivity to early memory declines in persons with mild cognitive impairment (MCI) and early stage dementia, as well as in persons with autosomal dominantly inherited AD up to 10 years prior to a dementia diagnosis. However, the evidence is inconclusive regarding relationships between evidence of Aß and story recall measures. Because story recall tasks require the encoding and delayed retrieval of several lexical-semantic categories, such as proper names, verbs, and numerical expressions, and because lexical categories have been shown to be differentially impaired in persons with MCI, we focused on item-level analyses of lexical-semantic retrieval from a quintessential story recall task, Logical Memory from the Wechsler Memory Scale-Revised. Our objective was to investigate whether delayed recall of lexical categories (proper names, verbs and/or numerical expressions), as well as the traditional total score measure, was associated with "preclinical AD," or cognitively unimpaired adults with positive Aß deposition on positron emission tomography (PET) neuroimaging using Pittsburgh Compound B (PiB). We developed an item-level scoring system, in which we parsed items into lexical categories and examined the immediate and delayed recall of these lexical categories from 217 cognitively unimpaired participants from the Wisconsin Registry for Alzheimer's Prevention (WRAP). We performed binary logistic regression models with story recall score as predictor and Aß status (positive/negative) as the outcome. Using baseline Logical Memory data, proper names from delayed story recall were significantly associated with Aß status, such that participants who recalled more proper names were less likely to be classified as PiB(+) (odds ratio = .58, p = .01). None of the other story recall variables, including total score, were associated with PiB status. Secondary analyses determined that immediate recall of proper names was not significantly associated with Aß, suggesting a retrieval deficit rather than that of encoding. The present findings suggest that lexical semantic retrieval measures from existing story recall tasks may be sensitive to Aß deposition, and may provide added utility to a widely-used, long-standing neuropsychological test for early detection of cognitive decline on the AD continuum.