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The recently reportedTNIP1/GPX3locus from AD GWAS studies was investigated. Using proteomics and other functional omics data, we identified evidence for a functional mechanism linking variants in this locus to decreased CSF GPX3 levels as AD progresses, suggesting a new potential target for intervention.

Background The brain is the most cholesterol‐rich organ and myelin contains 70% of total brain cholesterol. Statins are potent cholesterol‐lowing medications used by millions of adults for prevention of vascular disease, yet the effect of statins on cholesterol‐rich brain white matter (WM) is largely unknown. Methods We used longitudinal neuroimaging data acquired from 73 healthy, cognitively unimpaired, statin‐naïve, middle‐aged adults during an 18‐month randomized controlled trial of simvastatin 40 mg daily (n = 35) or matching placebo (n = 38). ANCOVA models (covariates: age, sex, APOE‐ɛ4) tested the effect of treatment group on percent change in WM, gray matter (GM), and WM hyperintensity (WMH) neuroimaging measures at each study visit. Mediation analysis tested the indirect effects of simvastatin on WM microstructure through change in serum total cholesterol levels. Results At 18 months, the simvastatin group showed a significant preservation in global WM fractional anisotropy (β = 0.88%, 95% CI 0.27 to 1.50, P = 0.005), radial diffusivity (β = −1.10%, 95% CI −2.13 to −0.06, P = 0.039), and WM volume (β = 0.72%, 95% CI 0.13 to 1.32, P = 0.018) relative to the placebo group. There was no significant effect of simvastatin on GM or WMH volume. Change in serum total cholesterol mediated approximately 30% of the effect of simvastatin on WM microstructure. Conclusions Simvastatin treatment in healthy, middle‐aged adults resulted in preserved WM microstructure and volume at 18 months. The partial mediation by serum cholesterol reduction suggests both peripheral and central mechanisms. Future studies are needed to determine whether these effects persist and translate to cognitive outcomes. Trial Registration NCT00939822 (ClinicalTrials.gov).

Age-related disease may be mediated by low levels of chronic inflammation (“inflammaging”). Recent work suggests that gut microbes may contribute to inflammation via degradation of the intestinal barrier. While aging and age-related diseases including Alzheimer’s disease (AD) are linked to altered microbiome composition and higher levels of gut microbial components in systemic circulation, the role of intestinal inflammation and permeability per se remains unclear. To test whether greater gut inflammation is associated with older age and AD pathology, we assessed fecal samples from older adults to measure calprotectin, an established marker of intestinal inflammation which is elevated in diseases of gut barrier integrity. Here we found that calprotectin levels are higher with age, and that higher calprotectin was associated with greater amyloid burden among participants with an amyloid-confirmed AD dementia diagnosis. Calprotectin was also associated with cerebrospinal fluid markers of AD pathology and axonal degeneration, as well as with lower verbal memory function among cognitively unimpaired participants. Together, these findings suggest that intestinal inflammation may play a role in pathology development, and that it may exacerbate the progression toward AD.SummaryIntestinal inflammation is correlated with older age, Alzheimer’s disease (AD) dementia, and greater amyloid burden in participants with AD.

INTRODUCTIONMetabolomics 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.METHODSThe relative abundance of untargeted metabolites was assessed in 161 individuals. 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. Mendelian randomization was performed using genome-wide significant single nucleotide polymorphisms from a CSF metabolites genome-wide association study.RESULTSMWAS results showed several significantly associated metabolites for all the biomarkers except Aβ42/40 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 β (Aβ40), α-synuclein, total tau, phosphorylated tau, and neurogranin, for example, palmitoyl sphingomyelin (d18:1/16:0) for sTREM2, and erythritol for Aβ40 and α-synuclein.DISCUSSIONThis study provides evidence that CSF metabolites are associated with AD-related pathology, and many of these associations may be causal.

Background: There is growing consensus that non-genetic determinants of dementia can be linked to various risk- and resiliency-enhancing factors accumulating throughout the lifespan, including socioeconomic conditions, early life experiences, educational attainment, lifestyle behaviors, and physical/mental health. Yet, the causal impact of these diverse factors on dementia risk remain poorly understood due to few longitudinal studies prospectively characterizing these influences across the lifespan. Objective: The Initial Lifespan’s Impact on Alzheimer’s Disease and Related Dementia (ILIAD) study aims to characterize dementia prevalence in the Wisconsin Longitudinal Study (WLS), a 60-year longitudinal study documenting life course trajectories of educational, family, occupational, psychological, cognitive, and health measures. Methods: Participants are surveyed using the modified Telephone Interview for Cognitive Status (TICS-m) to identify dementia risk. Those scoring below cutoff undergo home-based neuropsychological, physical/neurological, and functional assessments. Dementia diagnosis is determined by consensus panel and merged with existing WLS data for combined analysis. Results: Preliminary findings demonstrate the initial success of the ILIAD protocol in detecting dementia prevalence in the WLS. Increasing age, hearing issues, lower IQ, male sex, APOE4 positivity, and a steeper annualized rate of memory decline assessed in the prior two study waves, all increased likelihood of falling below the TICS-m cutoff for dementia risk. TICS-m scores significantly correlated with standard neuropsychological performance and functional outcomes. Conclusion: We provide an overview of the WLS study, describe existing key lifespan variables relevant to studies of dementia and cognitive aging, detail the current WLS-ILIAD study protocol, and provide a first glimpse of preliminary study findings.

ObjectiveTo test the hypothesis that neighborhood-level disadvantage is associated with longitudinal measures of neurodegeneration and cognitive decline in an unimpaired cohort.MethodsLongitudinal 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.ResultsIn 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.ConclusionsIn 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.

Background: To fully characterize the risk for dementia associated with cigarette smoking, studies must consider competing risks that hinder the observation of dementia or modify the chance that dementia occurs (i.e., death). Extant research examining the competing risks fails to account for the occurrence of death following dementia, limiting our understanding of the relation between smoking and dementia. Objective: Examine the impact of smoking status, lifetime smoking exposure, and duration of abstinence on incident dementia, death following dementia, and death without dementia. Methods: Multi-state models estimated hazard ratios (HR) for 95% confidence interval (CI) of 10,681 cognitively healthy adults for transition from baseline to dementia, baseline to death, and dementia to death based on smoking status, lifetime cigarette exposure, and abstinence duration. Results: Compared to never smokers, current smokers had increased risk of dementia (HR = 1.66; 95% CI 1.18– 2.32; p = 0.004), and death from baseline (HR = 2.98; 95% CI 2.24– 3.98; p

Background: Identification of new genetic variants that modify Alzheimer’s disease (AD) risk will elucidate novel targets for curbing the disease progression or delaying symptom onset. Objective: To examine whether the functionally advantageous KLOTHO gene KL-VS variant attenuates age-related alteration in cerebrospinal fluid (CSF) biomarkers or cognitive function in middle-aged and older adults enriched for AD risk. Methods: Sample included non-demented adults (N = 225, mean age = 63±8, 68% women) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center who were genotyped for KL-VS, underwent CSF sampling and had neuropsychological testing data available proximal to CSF draw. Covariate-adjusted multivariate regression examined relationships between age group (Younger versus Older; mean split at 63 years), AD biomarkers, and neuropsychological performance tapping memory and executive function, and whether these relationships differed between KL-VS non-carriers (KL-VSNC) and heterozygote (KL-VSHET). Results: In the pooled analyses, older age was associated with higher levels of total tau (tTau), phosphorylated tau (pTau), and their respective ratios to amyloid-β (Aβ)42 (ps ≤ 0.002), and with poorer performance on neuropsychological tests (ps ≤ 0.001). In the stratified analyses, KL-VSNC exhibited this age-related pattern of associations with CSF biomarkers (all ps ≤ 0.001), and memory and executive function (ps ≤ 0.003), which were attenuated in KL-VSHET (ps ≥ 0.14). Conclusion: Worse memory and executive function, and higher tau burden with age were attenuated in carriers of a functionally advantageous KLOTHO variant. KL-VS heterozygosity seems to be protective against age-related cognitive and biomolecular alterations that confer risk for AD.

Study Objectives Fast frequency sleep spindles are reduced in aging and Alzheimer’s disease (AD), but the mechanisms and functional relevance of these deficits remain unclear. The study objective was to identify AD biomarkers associated with fast sleep spindle deficits in cognitively unimpaired older adults at risk for AD. Methods Fifty-eight cognitively unimpaired, β-amyloid-negative, older adults (mean ± SD; 61.4 ± 6.3 years, 38 female) enriched with parental history of AD (77.6%) and apolipoprotein E (APOE) ε4 positivity (25.9%) completed the study. Cerebrospinal fluid (CSF) biomarkers of central nervous system inflammation, β-amyloid and tau proteins, and neurodegeneration were combined with polysomnography (PSG) using high-density electroencephalography and assessment of overnight memory retention. Parallelized serial mediation models were used to assess indirect effects of age on fast frequency (13 to Results Glial activation was associated with prefrontal fast frequency sleep spindle expression deficits. While adjusting for sex, APOE ε4 genotype, apnea–hypopnea index, and time between CSF sampling and sleep study, serial mediation models detected indirect effects of age on fast sleep spindle expression through microglial activation markers and then tau phosphorylation and synaptic degeneration markers. Sleep spindle expression at these electrodes was also associated with overnight memory retention in multiple regression models adjusting for covariates. Conclusions These findings point toward microglia dysfunction as associated with tau phosphorylation, synaptic loss, sleep spindle deficits, and memory impairment even prior to β-amyloid positivity, thus offering a promising candidate therapeutic target to arrest cognitive decline associated with aging and AD.

Introduction This study examines the utility of a multipanel of cerebrospinal fluid (CSF) biomarkers complementing Alzheimer's disease (AD) biomarkers in a clinical research sample. We compared biomarkers across groups defined by clinical diagnosis and pTau181 /Aβ42 status (+/-) and explored their value in predicting cognition. Methods CSF biomarkers amyloid beta (Aβ)42 , pTau181 , tTau, Aβ40 , neurogranin, neurofilament light (NfL), α-synuclein, glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), S100 calcium binding protein B (S100B), and interleukin 6 (IL6), were measured with the NeuroToolKit (NTK) for 720 adults ages 40 to 93 years (mean age = 63.9 years, standard deviation [SD] = 9.0; 50 with dementia; 54 with mild cognitive impairment [MCI], 616 unimpaired). Results Neurodegeneration and glial activation biomarkers were elevated in pTau181 /Aβ42 + MCI/dementia participants relative to all pTau181 /Aβ42 - participants. Neurodegeneration biomarkers increased with clinical severity among pTau181 /Aβ42 + participants and predicted worse cognitive performance. Glial activation biomarkers were unrelated to cognitive performance. Discussion The NTK contains promising markers that improve the pathophysiological characterization of AD. Neurodegeneration biomarkers beyond tTau improved statistical prediction of cognition and disease stages.

Objective:This study investigated the latent factor structure of the NIH Toolbox Cognition Battery (NIHTB-CB) and its measurement invariance across clinical diagnosis and key demographic variables including sex, race/ethnicity, age, and education for a typical Alzheimer’s disease (AD) research sample.Method:The NIHTB-CB iPad English version, consisting of 7 tests, was administered to 411 participants aged 45–94 with clinical diagnosis of cognitively unimpaired, dementia, mild cognitive impairment (MCI), or impaired not MCI. The factor structure of the whole sample was first examined with exploratory factor analysis (EFA) and further refined using confirmatory factor analysis (CFA). Two groups were classified for each variable (diagnosis or demographic factors). The confirmed factor model was next tested for each group with CFA. If the factor structure was the same between the groups, measurement invariance was then tested using a hierarchical series of nested two-group CFA models.Results:A two-factor model capturing fluid cognition (executive function, processing speed, and memory) versus crystalized cognition (language) fit well for the whole sample and each group except for those with age < 65. This model generally had measurement invariance across sex, race/ethnicity, and education, and partial invariance across diagnosis. For individuals with age < 65, the language factor remained intact while the fluid cognition was separated into two factors: (1) executive function/processing speed and (2) memory.Conclusions:The findings mostly supported the utility of the battery in AD research, yet revealed challenges in measuring memory for AD participants and longitudinal change in fluid cognition.

Background Midlife cardiovascular risk factors increase risk for Alzheimer's disease (AD). Despite disproportionately high cardiovascular disease and dementia rates, African Americans are under-represented in studies of AD risk and research-based guidance on targeting vascular risk factors is lacking. Objective This study investigated relationships between specific cardiovascular risk factors and cerebral perfusion in White and African American adults enriched for AD risk. Methods Participants included 397 cognitively unimpaired White (n = 330) and African American (n = 67) adults enrolled in the Wisconsin Alzheimer's Disease Research Center who underwent pseudo-continuous arterial spin labeling MRI. Multiple linear regression models examined independent relationships between cardiovascular risk factors and mean cerebral perfusion. Subsequent interaction and stratified models assessed the role for APOE genotype and race. Results When risk factor p-values were FDR-adjusted, diastolic blood pressure was significantly associated with mean perfusion. Tobacco use, triglycerides, waist-to-hip ratio, and a composite risk score were not associated with perfusion. Without FDR adjustment, a relationship was also observed between perfusion and obesity, cholesterol, and fasting glucose. Neither APOE genotype nor race moderated relationships between risk factors and perfusion. Conclusion Higher diastolic blood pressure predicted lower perfusion more strongly than other cardiovascular risk factors. This relationship did not vary by racial group or genetic risk for AD, although the African American sample had greater vascular risk burden and lower perfusion rates. Our findings highlight the need to prioritize inclusion of underrepresented groups in neuroimaging studies and to continue exploring the link between modifiable risk factors, cerebrovascular health, and AD risk in underrepresented populations.

With increased longevity and growth in the number of older adults comes rising rates of individuals with cognitive impairment and dementia. The expansion of this population has important implications for research on aging and dementia syndromes, namely increased enrollment of older individuals in clinical research. Ethical prerogatives, as well as historical underrepresentation of persons with dementia in research studies due to the perceived burden of traditional decisional capacity evaluations, necessitates the development of pragmatic approaches to ascertain decisional abilities in research settings. We outline a protocol used in the Wisconsin Alzheimer’s Disease Research Center (ADRC) that adopts a stepped approach to the evaluation of decisional capacity meant to maximize study visit efficiency while preserving participant safety and autonomy. The protocol specifies the structure of the consent process and incorporates a brief semi-structured interview based on Appelbaum & Grisso’s theoretical model for evaluating a patient’s decisional capacity to provide informed consent to participate in research. This protocol is easily implemented in a research study visit and is designed to minimize participant burden and ensure reliable assessment of decisional capacity in older adults across a wide range of research protocols. The protocol emphasizes capacity optimization, using memory aids and other compensatory strategies to preserve participant autonomy while protecting welfare.

Blood-based Alzheimer's disease (AD) biomarkers show promise, but pre-analytical protocol differences may pose problems. We examined seven AD blood biomarkers (amyloid beta [Plasma and serum were obtained from cerebrospinal fluid or amyloid positron emission tomography-positive and -negative participants (N = 38) in the Wisconsin Registry for Alzheimer's Prevention. We modeled AD biomarker values observed in EDTA plasma versus heparin plasma and serum, and assessed correspondence with brain amyloidosis.Results suggested bias due to tube type, but crosswalks are possible for some analytes, with excellent model fit for NfL (AD biomarker concentrations vary by tube type. However, correlations for some biomarkers support harmonization across types, suggesting cautious optimism for use in banked blood.

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.We examined trajectories of Clinical Dementia Rating-Sum of Boxes (CDR-SB) relative to estimated years of amyloid positivity (A+) inThe 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.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.

Site-specific O-glycoproteome mapping in complex biological systems provides a molecular basis for understanding the structure-function relationships of glycoproteins and their roles in physiological and pathological processes. Previous O-glycoproteome analysis in cerebrospinal fluid (CSF) focused on sialylated glycoforms, while missing information on other glycosylation types. In order to achieve an unbiased O-glycosylation profile, we developed an integrated strategy combining universal boronic acid enrichment, high-pH fractionation, and electron-transfer and higher-energy collision dissociation (EThcD) for enhanced intact O-glycopeptide analysis. We applied this strategy to analyze the O-glycoproteome in CSF, resulting in the identification of 308 O-glycopeptides from 110 O-glycoproteins, covering both sialylated and nonsialylated glycoforms. To our knowledge, this is the largest data set of O-glycoproteins and O-glycosites reported for CSF to date. We also developed a peptidomics workflow that utilized the EThcD and a three-step database searching strategy for comprehensive PTM analysis of endogenous peptides, including N-glycosylation, O-glycosylation, and other common peptide PTMs. Interestingly, among the 1411 endogenous peptides identified, 89 were O-glycosylated, and only one N-glycosylated peptide was found, indicating that CSF endogenous peptides were predominantly O-glycosylated. Analyses of the O-glycoproteome and endogenous peptidome PTMs were also conducted in the CSF of MCI and AD patients to provide a landscape of glycosylation patterns in different disease states. Our results showed a decreasing trend in fucosylation and an increasing trend of endogenous peptide O-glycosylation, which may play an important role in AD progression.

A major hallmark of Alzheimer’s disease (AD) is the aggregation of proteins (β-amyloid (A) and hyperphosphorylated tau (T)) in the brain, which makes the AD proteome in cerebrospinal fluid (CSF) of particular interest. Here, we conducted a CSF proteome-wide analysis among participants with and without AD pathology (n = 137 total participants: 56 A-T-, 39 A+T-, and 42 A+T+; 915 proteins analyzed), using a panel of 9 CSF biomarkers for neurodegeneration and neuroinflammation. We identified 61 proteins significantly associated with AT category (P < 5.46 x 10-5; strongest was SMOC1, P = 1.87 x 10-12) and 636 significant protein-biomarker associations (P < 6.07 x 10-6; strongest was a positive association between neurogranin and EPHA4, P = 2.42 x 10-25). Community network and pathway enrichment analyses highlighted three biomarker-associated protein networks centered around amyloid and tau measures, neurogranin, and the remaining biomarkers. Glucose metabolic pathways were enriched primarily among the amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, both of which were associated with CSF phosphorylated tau levels in an independent replication cohort of 717 participants (P = 8.65 x 10-56and P = 1.35 x 10-45). Follow-up interrogation of related CSF metabolite levels in the same samples as the discovery proteomics analysis identified increasing levels of succinylcarnitine with ptau and numerous other CSF biomarkers (P < 0.00056) that were replicated in an independent sample of 363 participants. Together, these results implicate glucose metabolic dysregulation and increased CSF succinylcarnitine levels as amyloid and tau pathology emerge in AD.One Sentence Summary:Combining cerebrospinal fluid proteomics data with neurodegeneration and neuroinflammation biomarkers, genomics, and cerebrospinal fluid metabolomics, we identify and replicate a theme of altered glucose metabolism proteins and the metabolite succinylcarnitine across amyloid and tau progression in Alzheimer’s disease.

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 suppressorTrajectories of change in memory and executive function (Memory and executive function declined (KL-VS heterozygosity may confer resilience to AD-associated biomolecular changes.