Participant attrition from statewide, population-based Survey of the Health of Wisconsin into the longitudinal SHOW COVID-19 cohort.

PURPOSE: Longitudinal studies are essential for examining how social and institutional determinants of health, historical and contemporary, affect disparities in COVID-19 related outcomes. The unequal impacts of COVID-19 likely exacerbated selected attrition in longitudinal research. This study examines attrition and survey mode effects in the SHOW COVID-19 study which recruited from a statewide, representative cohort. MATERIALS & METHODS: Participants were recruited from the Survey of the Health of Wisconsin (SHOW) cohort. Online surveys, or phone interviews, were administered at three timepoints during 2020-2021. The surveys captured social, behavioral, and structural determinants of health and the lived experience. Univariate and multivariate logistic regression was used to examine predictors of participation and survey mode effects. RESULTS: A total of 2304 adults completed at least one COVID-19 online survey. Participants were more educated, older, and more likely to be female, married, non-Hispanic, and White compared to non-participants. Phone participants were older, less educated, and more likely be non-White, food insecure, and have co-morbidities compared to online participants. Mode effects were seen with reporting COVID-19 beliefs, loneliness, and anxiety. CONCLUSION: The SHOW COVID-19 cohort offers unique longitudinal data but suffered from selected attrition. Phone interview is an important mode for retention and representation.

Midlife sensory and motor functions improve prediction of blood-based measures of neurodegeneration and Alzheimer's disease in late middle-age.

INTRODUCTION: We assessed whether midlife sensory and motor functions added to prediction models using the Cardiovascular Risk Factors, Aging, and Incidence of Dementia Score (CAIDE) and Framingham Risk Score (FRS) improve risk predictions of 10-year changes in biomarkers of neurodegeneration and Alzheimer's disease. METHODS: Longitudinal data of N = 1529 (mean age 49years) Beaver Dam Offspring Study participants from baseline, 5-year, and 10-year follow-up were included. We tested whether including baseline sensory (hearing, vision, olfactory) impairment and motor function measures improves CAIDE or FRS risk predictions of 10-year incidence of biomarker positivity of serum-based neurofilament light chain (NfL) and amyloid beta (Aß)42/Aß40 using logistic regression. RESULTS: Adding sensory and motor measures to CAIDE-only and FRS-only models significantly improved NfL and Aß42/Aß40 positivity predictions in adults above the age of 55. DISCUSSION: Including midlife sensory and motor function improved long-term biomarker positivity predictions. Non-invasive sensory and motor assessments could contribute to cost-effective screening tools that identify individuals at risk for neurodegeneration early to target interventions and preventions. Highlights: Sensory and motor measures improve risk prediction models of neurodegenerative biomarkersSensory and motor measures improve risk prediction models of AD biomarkersPrediction improvements were strongest in late midlife (adults >55 years of age)Sensory and motor assessments may help identify high-risk individuals early.

Whole-body metabolic modelling reveals microbiome and genomic interactions on reduced urine formate levels in Alzheimer's disease.

In this study, we aimed to understand the potential role of the gut microbiome in the development of Alzheimer's disease (AD). We took a multi-faceted approach to investigate this relationship. Urine metabolomics were examined in individuals with AD and controls, revealing decreased formate and fumarate concentrations in AD. Additionally, we utilised whole-genome sequencing (WGS) data obtained from a separate group of individuals with AD and controls. This information allowed us to create and investigate host-microbiome personalised whole-body metabolic models. Notably, AD individuals displayed diminished formate microbial secretion in these models. Additionally, we identified specific reactions responsible for the production of formate in the host, and interestingly, these reactions were linked to genes that have correlations with AD. This study suggests formate as a possible early AD marker and highlights genetic and microbiome contributions to its production. The reduced formate secretion and its genetic associations point to a complex connection between gut microbiota and AD. This holistic understanding might pave the way for novel diagnostic and therapeutic avenues in AD management.

Midlife sensory and motor functions improve long-term predictions of cognitive decline and incidence of cognitive impairment.

INTRODUCTION: We aimed to assess whether midlife sensory and motor functions improve risk prediction of 10-year cognitive decline and impairment when added to risk prediction models using the Cardiovascular Risk Factors, Aging, and Incidence of Dementia Score (CAIDE) and Framingham Risk Score (FRS). METHODS: Longitudinal data of N = 1529 (mean age 49 years; 54% women) Beaver Dam Offspring Study (BOSS) participants from baseline, 5 and 10-year follow-up were included. We tested whether including baseline sensory (hearing, vision, olfactory) impairment and motor function improves CAIDE or FRS risk predictions of 10-year cognitive decline or cognitive impairment incidence using logistic regressions. RESULTS: Adding sensory and motor measures to CAIDE-only and FRS-only models significantly improved areas under the curve for cognitive decline and impairment models. DISCUSSION: Including midlife sensory and motor function improved risk predictions of long-term cognitive decline and impairment in middle-aged to older adults. Sensory and motor assessments could contribute to cost-effective and non-invasive screening tools that identify high-risk individuals earlier to target intervention and prevention strategies. Highlights: Sensory and motor measures improve risk prediction models of cognitive decline.Sensory and motor measures improve risk prediction models of cognitive impairment.Prediction improvements were strongest in midlife (adults < 55 years of age).Sensory and motor changes may help identify high-risk individuals early.

Apolipoprotein E moderates the association between non-APOE polygenic risk score for Alzheimer's disease and aging on preclinical cognitive function.

INTRODUCTION: Variation in preclinical cognitive decline suggests additional genetic factors related to Alzheimer's disease (eg, a non-APOE polygenic risk score [PRS]) may interact with the APOE ε4 allele to influence cognitive decline. METHODS: We tested the PRS × APOE ε4 × age interaction on preclinical cognition using longitudinal data from the Wisconsin Registry for Alzheimer's Prevention. All analyses were fitted using a linear mixed-effects model and adjusted for within individual/family correlation among 1190 individuals. RESULTS: We found statistically significant PRS × APOE ε4 × age interactions on immediate learning (P = 0.038), delayed recall (P < 0.001), and Preclinical Alzheimer's Cognitive Composite 3 score (P = 0.026). PRS-related differences in overall and memory-related cognitive domains between people with and without APOE ε4 emerge around age 70, with a much stronger adverse PRS effect among APOE ε4 carriers. The findings were replicated in a population-based cohort. DISCUSSIONS: APOE ε4 can modify the association between PRS and cognition decline. HIGHLIGHTS: APOE ε4 can modify the association between polygenic risk scores (PRSs) and longitudinal cognition decline, with the modifying effects more pronounced when the PRS is constructed using a conservative P threshold (eg, P < 5e-8 ). The adverse genetic effect caused by the combined effect of the currently known genetic variants is more detrimental among APOE Îµ4 carriers around age 70. Individuals who are APOE Îµ4 carriers with high PRSs are the most vulnerable to the harmful effects caused by genetic burden.

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.

CSF metabolites associated with biomarkers of Alzheimer's disease pathology.

Introduction: Metabolomics technology facilitates studying associations between small molecules and disease processes. Correlating metabolites in cerebrospinal fluid (CSF) with Alzheimer's disease (AD) CSF biomarkers may elucidate additional changes that are associated with early AD pathology and enhance our knowledge of the disease. Methods: The relative abundance of untargeted metabolites was assessed in 161 individuals from the Wisconsin Registry for Alzheimer's Prevention. A metabolome-wide association study (MWAS) was conducted between 269 CSF metabolites and protein biomarkers reflecting brain amyloidosis, tau pathology, neuronal and synaptic degeneration, and astrocyte or microglial activation and neuroinflammation. Linear mixed-effects regression analyses were performed with random intercepts for sample relatedness and repeated measurements and fixed effects for age, sex, and years of education. The metabolome-wide significance was determined by a false discovery rate threshold of 0.05. The significant metabolites were replicated in 154 independent individuals from then Wisconsin Alzheimer's Disease Research Center. Mendelian randomization was performed using genome-wide significant single nucleotide polymorphisms from a CSF metabolites genome-wide association study. Results: Metabolome-wide association study results showed several significantly associated metabolites for all the biomarkers except Aß42/40 and IL-6. Genetic variants associated with metabolites and Mendelian randomization analysis provided evidence for a causal association of metabolites for soluble triggering receptor expressed on myeloid cells 2 (sTREM2), amyloid ß (Aß40), α-synuclein, total tau, phosphorylated tau, and neurogranin, for example, palmitoyl sphingomyelin (d18:1/16:0) for sTREM2, and erythritol for Aß40 and α-synuclein. Discussion: This study provides evidence that CSF metabolites are associated with AD-related pathology, and many of these associations may be causal.

Whole-body modelling reveals microbiome and genomic interactions on reduced urine formate levels in Alzheimer's disease.

In this study, we aimed to understand the potential role of the gut microbiome in the development of Alzheimer's disease (AD). We took a multi-faceted approach to investigate this relationship. Urine metabolomics were examined in individuals with AD and controls, revealing decreased formate and fumarate concentrations in AD. Additionally, we utilized whole-genome sequencing (WGS) data obtained from a separate group of individuals with AD and controls. This information allowed us to create and investigate host-microbiome personalized models. Notably, AD individuals displayed diminished formate microbial secretion in these models. Additionally, we identified specific reactions responsible for the production of formate in the host, and interestingly, these reactions were linked to genes that have correlations with AD. This study suggests formate as a possible early AD marker and highlights genetic and microbiome contributions to its production. The reduced formate secretion and its genetic associations point to a complex connection between gut microbiota and AD. This holistic understanding might pave the way for novel diagnostic and therapeutic avenues in AD management.

Apolipoprotein E moderates the association between Non-APOE Polygenic Risk Score for Alzheimer's Disease and Aging on Preclinical Cognitive Function.

INTRODUCTION: Variation in preclinical cognitive decline suggests additional genetic factors related to Alzheimer's disease (e.g., a non-APOE polygenic risk scores [PRS]) may interact with the APOE ε4 allele to influence cognitive decline. METHODS: We tested the PRS×APOE ε4×age interaction on preclinical cognition using longitudinal data from the Wisconsin Registry for Alzheimer's Prevention. All analyses were fitted using a linear mixed-effects model and adjusted for within individual/family correlation among 1,190 individuals. RESULTS: We found statistically significant PRS×APOE ε4×age interactions on immediate learning (P=0.038), delayed recall (P<0.001), and Preclinical Alzheimer's Cognitive Composite 3 score (P=0.026). PRS-related differences in overall and memory-related cognitive domains between people with and without APOE ε4 emerge around age 70, with a much stronger adverse PRS effect among APOE ε4 carriers. The findings were replicated in a population-based cohort. DISCUSSION: APOE ε4 can modify the association between PRS and cognition decline.

Associations of Midlife Lifestyle and Health Factors with Long-Term Changes in Blood-Based Biomarkers of Alzheimer's Disease and Neurodegeneration.

BACKGROUND: Pathological biomarkers of Alzheimer's disease (AD) and other dementias can change decades before clinical symptoms. Lifestyle and health factors might be relevant modifiable risk factors for dementia. Many previous studies have been focusing on associations of lifestyle and health-related factors with clinical outcomes later in life. OBJECTIVE: We aimed to determine to what extent midlife factors of lifestyle, inflammation, vascular, and metabolic health were associated with long-term changes in blood-based biomarkers of AD (amyloid beta (Aß)) and neurodegeneration (neurofilament light chain (NfL); total tau(TTau)). METHODS: In 1,529 Beaver Dam Offspring Study (BOSS) participants (mean age 49 years, standard deviation (SD) = 9; 54% were women), we applied mixed-effects models with baseline risk factors as determinants and 10-year serum biomarker change as outcomes. RESULTS: We found that education and inflammatory markers were associated with levels and/or change over time across all three markers of AD and neurodegeneration in the blood. There were baseline associations of measures of cardiovascular health with lower Aß42/Aß40. TTau changed little over time and was higher in individuals with diabetes. Individuals with lower risk in a number of cardiovascular and metabolic risk factors, including diabetes, hypertension, and atherosclerosis had slower accumulation of neurodegeneration over time, as determined by NfL levels. CONCLUSION: Various lifestyle and health factors, including education and inflammation, were associated with longitudinal changes of neurodegenerative and AD biomarker levels in midlife. If confirmed, these findings could have important implications for developing early lifestyle and health interventions that could potentially slow processes of neurodegeneration and AD.

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.

Large-scale proteome and metabolome analysis of CSF implicates altered glucose and carbon metabolism and succinylcarnitine in Alzheimer's disease.

INTRODUCTION: A hallmark of Alzheimer's disease (AD) is the aggregation of proteins (amyloid beta [A] and hyperphosphorylated tau [T]) in the brain, making cerebrospinal fluid (CSF) proteins of particular interest. METHODS: We conducted a CSF proteome-wide analysis among participants of varying AT pathology (n = 137 participants; 915 proteins) with nine CSF biomarkers of neurodegeneration and neuroinflammation. RESULTS: We identified 61 proteins significantly associated with the AT category (P < 5.46 × 10-5 ) and 636 significant protein-biomarker associations (P < 6.07 × 10-6 ). Proteins from glucose and carbon metabolism pathways were enriched among amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, whose associations with tau were replicated in an independent cohort (n = 717). CSF metabolomics identified and replicated an association of succinylcarnitine with phosphorylated tau and other biomarkers. DISCUSSION: These results implicate glucose and carbon metabolic dysregulation and increased CSF succinylcarnitine levels with amyloid and tau pathology in AD. HIGHLIGHTS: Cerebrospinal fluid (CSF) proteome enriched for extracellular, neuronal, immune, and protein processing. Glucose/carbon metabolic pathways enriched among amyloid/tau-associated proteins. Key glucose/carbon metabolism protein associations independently replicated. CSF proteome outperformed other omics data in predicting amyloid/tau positivity. CSF metabolomics identified and replicated a succinylcarnitine-phosphorylated tau association.

Identification of plasma metabolites associated with modifiable risk factors and endophenotypes reflecting Alzheimer's disease pathology.

Modifiable factors can influence the risk for Alzheimer's disease (AD) and serve as targets for intervention; however, the biological mechanisms linking these factors to AD are unknown. This study aims to identify plasma metabolites associated with modifiable factors for AD, including MIND diet, physical activity, smoking, and caffeine intake, and test their association with AD endophenotypes to identify their potential roles in pathophysiological mechanisms. The association between each of the 757 plasma metabolites and four modifiable factors was tested in the wisconsin registry for Alzheimer's prevention cohort of initially cognitively unimpaired, asymptomatic middle-aged adults. After Bonferroni correction, the significant plasma metabolites were tested for association with each of the AD endophenotypes, including twelve cerebrospinal fluid (CSF) biomarkers, reflecting key pathophysiologies for AD, and four cognitive composite scores. Finally, causal mediation analyses were conducted to evaluate possible mediation effects. Analyses were performed using linear mixed-effects regression. A total of 27, 3, 23, and 24 metabolites were associated with MIND diet, physical activity, smoking, and caffeine intake, respectively. Potential mediation effects include beta-cryptoxanthin in the association between MIND diet and preclinical Alzheimer cognitive composite score, hippurate between MIND diet and immediate learning, glutamate between physical activity and CSF neurofilament light, and beta-cryptoxanthin between smoking and immediate learning. Our study identified several plasma metabolites that are associated with modifiable factors. These metabolites can be employed as biomarkers for tracking these factors, and they provide a potential biological pathway of how modifiable factors influence the human body and AD risk.

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.

Liver-Specific Polygenic Risk Score Is Associated with Alzheimer's Disease Diagnosis.

BACKGROUND: Our understanding of the pathophysiology underlying Alzheimer's disease (AD) has benefited from genomic analyses, including those that leverage polygenic risk score (PRS) models of disease. The use of functional annotation has been able to improve the power of genomic models. OBJECTIVE: We sought to leverage genomic functional annotations to build tissue-specific AD PRS models and study their relationship with AD and its biomarkers. METHODS: We built 13 tissue-specific AD PRS and studied the scores' relationships with AD diagnosis, cerebrospinal fluid (CSF) amyloid, CSF tau, and other CSF biomarkers in two longitudinal cohort studies of AD. RESULTS: The AD PRS model that was most predictive of AD diagnosis (even without APOE) was the liver AD PRS: n = 1,115; odds ratio = 2.15 (1.67-2.78), p = 3.62×10-9. The liver AD PRS was also statistically significantly associated with cerebrospinal fluid biomarker evidence of amyloid-ß (Aß42:Aß40 ratio, p = 3.53×10-6) and the phosphorylated tau:amyloid-ß ratio (p = 1.45×10-5). CONCLUSION: These findings provide further evidence of the role of the liver-functional genome in AD and the benefits of incorporating functional annotation into genomic research.

Neuropathology-based APOE genetic risk score better quantifies Alzheimer's risk.

INTRODUCTION: Apolipoprotein E (APOE) ε4-carrier status or ε4 allele count are included in analyses to account for the APOE genetic effect on Alzheimer's disease (AD); however, this does not account for protective effects of APOE ε2 or heterogeneous effect of ε2, ε3, and ε4 haplotypes. METHODS: We leveraged results from an autopsy-confirmed AD study to generate a weighted risk score for APOE (APOE-npscore). We regressed cerebrospinal fluid (CSF) amyloid and tau biomarkers on APOE variables from the Wisconsin Registry for Alzheimer's Prevention (WRAP), Wisconsin Alzheimer's Disease Research Center (WADRC), and Alzheimer's Disease Neuroimaging Initiative (ADNI). RESULTS: The APOE-npscore explained more variance and provided a better model fit for all three CSF measures than APOE ε4-carrier status and ε4 allele count. These findings were replicated in ADNI and observed in subsets of cognitively unimpaired (CU) participants. DISCUSSION: The APOE-npscore reflects the genetic effect on neuropathology and provides an improved method to account for APOE in AD-related analyses.

Cognitive trajectories diverge by genetic risk in a preclinical longitudinal cohort.

INTRODUCTION: We sought to characterize the timing of changes in cognitive trajectories related to genetic risk using the apolipoprotein E (APOE) score, a continuous measure of Alzheimer's disease (AD) risk. We also aimed to determine whether that timing was different when genetic risk was measured using an AD polygenic risk score (PRS) that contains APOE. METHODS: We analyzed trajectories (N ≈1135) for four neuropsychological composite scores using mixed effects regression for longitudinal change across APOE scores and PRS of participants in the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of adults aged 40 to 70 at baseline, with a median participant follow-up time of 7.8 years. RESULTS: We found a significant non-linear age-by-APOE score interaction in predicting cognitive decline. Cognitive trajectories diverged by APOE score at approximately 65 years of age. A 0.5 standard deviation difference in cognition between extreme percentiles of the PRS was predicted to occur 1 to 2 years before that of the APOE score. DISCUSSION: Cognitive decline differs across time and APOE score. Estimates did not substantially shift with the AD PRS. HIGHLIGHTS: The apolipoprotein E (APOE) score, a continuous measure, accounts for non-linear genetic risk of Alzheimer's disease. Non-linear age interacts with the APOE score to affect cognition. Cognitive decline starts to differ by APOE score levels at approximately age 65. Cognitive decline timing by polygenic risk (including APOE) is similar to APOE alone.

AD-associated CSF biomolecular changes are attenuated in KL-VS heterozygotes.

Introduction: Dementia as an inevitable aging consequence has been challenged and underscores the need for investigations of the factors that confer resilience. We examine whether the functionally advantageous KL-VS variant of the putative aging suppressor KLOTHO gene attenuates age-related cognitive decline and deleterious biomolecular changes. Methods: Trajectories of change in memory and executive function (N = 360; 2-12 visits) and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers-amyloid beta (Aß)42, total tau (t-tau), phosphorylated tau (p-tau) (N = 112; 2-4 samplings)-were compared between KL-VS non-carriers and heterozygotes in middle-aged and older adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center studies. Results: Memory and executive function declined (p's ≤ 0.001) and CSF t-tau, p-tau, t-tau/Aß42, and p-tau/Aß42 levels increased (all p's ≤ 0.004) with age. The rate of p-tau accumulation was attenuated for KL-VS heterozygotes (p = 0.03). Discussion: KL-VS heterozygosity may confer resilience to AD-associated biomolecular changes.

Associations of sensory and motor function with blood-based biomarkers of neurodegeneration and Alzheimer's disease in midlife.

Pathological biomarkers of dementia and Alzheimer's disease (AD) change decades before clinical symptoms. Common sensory and motor changes in aging adults may be early markers of neurodegeneration. We investigated if midlife sensory and motor functions in Beaver Dam Offspring Study (BOSS) participants (N = 1529) were associated with longitudinal changes in blood-based biomarkers of neurodegeneration (neurofilament light chain (NfL); total tau (TTau)) and AD (amyloid beta (Aß)). Mixed-effects models with baseline sensory and motor function as determinants and 10-year biomarker change as outcome were used. Participants with hearing impairment and worse motor function (among women) showed faster increases in NfL level over time (0.8% per year; 0.3% per year, respectively). There were no significant associations with TTau or Aß. We found consistent relationships between worse baseline hearing and motor function with a faster increase in neurodegeneration, specifically serum NfL level. Future studies with longer follow-up should determine if sensory and motor changes are more reflective of general neurodegeneration than AD-specific pathology and whether sensory and motor tests may be useful screening tools for neurodegeneration risk.

Circulating Klotho Is Higher in Cerebrospinal Fluid than Serum and Elevated Among KLOTHO Heterozygotes in a Cohort with Risk for Alzheimer's Disease.

BACKGROUND: Klotho is a longevity and neuroprotective hormone encoded by the KLOTHO gene, and heterozygosity for the KL-VS variant confers a protective effect against neurodegenerative disease. OBJECTIVE: Test whether klotho concentrations in serum or cerebrospinal fluid (CSF) vary as a function of KLOTHO KL-VS genotype, determine whether circulating klotho concentrations from serum and CSF differ from one another, and evaluate whether klotho levels are associated with Alzheimer's disease risk factors. METHODS: Circulating klotho was measured in serum (n = 1,116) and CSF (n = 183) of cognitively intact participants (aged 62.4 ± 6.5 years; 69.5% female). KLOTHO KL-VS zygosity (non-carrier; heterozygote; homozygote) was also determined. Linear regression was used to test whether klotho hormone concentration varied as a function of KL-VS genotype, specimen source, and demographic and clinical characteristics. RESULTS: Serum and CSF klotho were higher in KL-VS carriers than non-carriers. Klotho concentration was higher in CSF than in serum. Females had higher serum and CSF klotho, while younger age was associated with higher klotho in CSF. CONCLUSION: In a cohort enriched for risk for Alzheimer's disease, heterozygotic and homozygotic carriers of the KL-VS allele, females, and younger individuals have higher circulating klotho. Fluid source, KL-VS genotype, age, and sex should be considered in analyses of circulating klotho on brain health.