Factors associated with age at tau pathology onset and time from tau onset to dementia in Alzheimer's disease.

Introduction: Elevated tau (T+) is temporally proximal to dementia onset but less is known about factors influencing T+ onset age and time to dementia after T+ in Alzheimer's disease (AD). We used sampled iterative local approximation (SILA) estimated T+ onset age (ETOA) to investigate factors associated with T+ age and time from T+ to dementia onset in the Alzheimer's Disease Neuroimaging Initiative.

Methods: Using SILA-estimated amyloid positivity and T+ onset ages derived from F-Flortaucipir, F-Florbetapir, and F-Florbetaben positron emission tomography and Cox proportional hazards and accelerated failure time models, we analyzed apolipoprotein E (APOE), sex, amyloid burden, age, educational attainment, and literacy associations with ETOA and time from T+ to dementia.

Polygenic Scores of Core-1 Alzheimer's Disease Biomarkers Predict Early Cognitive and Pathological Change.

Background: Core-1 biomarkers, such as amyloid PET, capture the earliest biological changes leading to Alzheimer's disease (AD). While is a major genetic factor, the contribution of other variants to Core-1 biomarkers remains unclear. The goal of this study is to determine whether genetic regulators of Core-1 biomarker levels predict AD pathology better than genetic regulators of clinical AD.

Gut bacterial metabolite imidazole propionate potentiates Alzheimer's disease pathology.

The gut microbiome modulates metabolic, immune, and neurological functions and has been implicated in Alzheimer's disease (AD), though the specific mechanisms remain poorly defined. The bacterial metabolite imidazole propionate (ImP) has been previously associated with several AD comorbidities, such as type 2 diabetes and cardiovascular disease. Here, we show that elevated plasma ImP levels are associated with lower cognitive scores and AD biomarkers in a cohort of >1,100 cognitively unimpaired individuals.

Sex-Specific Genetic Drivers of Memory, Executive Functioning, and Language Performance in Older Adults.

We previously identified sex-specific genetic loci associated with memory performance, a strong Alzheimer's disease (AD) endophenotype. Here, we expand on this work by conducting sex-specific, cross-ancestral, genome-wide meta-analyses of three cognitive domains (memory, executive functioning, and language) in 33,918 older adults (57% female; 41% cognitively impaired; mean age=73 years) from 10 aging and AD cohorts. All three domains were comparably heritable across sexes.

Factors associated with age at tau pathology onset and time from tau onset to dementia.

Introduction: Elevated tau is temporally proximal to dementia onset but less is known about factors influencing T+ onset age and time to dementia following T+ in Alzheimer's disease. We used sampled iterative localized approximation (SILA) estimated T+ onset age (ETOA) to investigate factors associated with T+ age and time from T+ to dementia onset in ADNI.

Methods: Using SILA-estimated A+ and T+ onset ages derived from F-Flortaucipir, F-Florbetapir, and F-Florbetaben PET and Cox proportional hazards and accelerated failure time models, we analyzed , sex, amyloid burden, age, educational attainment, and literacy associations with ETOA and time from T+ to dementia.

Novel modelling approaches to elucidate the genetic architecture of resilience to Alzheimer's disease.

Up to 30% of older adults meet pathological criteria for a diagnosis of Alzheimer's disease at autopsy yet never show signs of cognitive impairment. Recent work has highlighted genetic drivers of this resilience, or better-than-expected cognitive performance given a level of neuropathology, that allow the aged brain to protect itself from the downstream consequences of amyloid and tau deposition. However, models of resilience have been constrained by reliance on measures of neuropathology, substantially limiting the number of participants available for analysis.

COSIME: Cooperative multi-view integration and Scalable and Interpretable Model Explainer.

Single-omics approaches often provide a limited view of complex biological systems, whereas multiomics integration offers a more comprehensive understanding by combining diverse data views. However, integrating heterogeneous data types and interpreting the intricate relationships between biological features-both within and across different data views-remains a bottleneck. To address these challenges, we introduce COSIME (Cooperative Multi-view Integration and Scalable Interpretable Model Explainer).

Characterization of gene-environment interactions for vitamin D through variance quantitative trait loci: a UK Biobank-based genetic epidemiology study.

Background: Understanding gene-environment interactions associated with vitamin D status may refine nutrition and public health strategies for vitamin D deficiency. Recent methodological advances have enabled the identification of variance quantitative trait loci (vQTLs) where gene-environment interactions are enriched.

Objectives: The study aims to identify vQTLs for serum 25-hydroxy vitamin D (25OHD) concentrations and characterize potential gene-environment interactions of vQTLs.

Evaluating the association of genotype and cognitive resilience in SuperAgers.

Introduction: "SuperAgers" are oldest-old adults (ages 80+) whose memory performance more closely resembles middle-aged adults. The present study examined allele frequency in non-Hispanic Black (NHB) and non-Hispanic White (NHW) SuperAgers compared to controls and Alzheimer's disease dementia cases.

Methods: In 18,080 participants from eight cohorts, harmonized clinical diagnostics and memory, executive function, and language domain scores were used to identify SuperAgers, cases, and controls across age-defined bins.

Evaluating Life Simple Seven's influence on brain health outcomes: The intersection of lifestyle and dementia.

Background: Lifestyle factors have been studied for dementia risk, but few have comprehensively assessed both Alzheimer's disease (AD) and cerebrovascular disease (CBVD) pathologies.

Objective: Our research aims to determine the relationships between lifestyle and various dementia pathologies, challenging conventional research paradigms.

Methods: Analyzing 1231 Wisconsin Registry for Alzheimer's Prevention (WRAP) study participants, we focused on Life Simple Seven (LS7) score calculations from questionnaire data and clinical vitals.

Mid-to-Late Life Healthy Lifestyle Modifies Genetic Risk for Longitudinal Cognitive Aging among Asymptomatic Individuals.

Importance: Genetic and lifestyle factors contribute to an individual's risk of developing Alzheimer's disease. However, it is unknown whether and how adherence to healthy lifestyles can mitigate the genetic risk of Alzheimer's.

Objective: The aim of this study is to investigate whether adherence to healthy lifestyles can modify the impact of genetic predisposition to Alzheimer's disease on later-life cognitive decline.

Post-GWAS multiomic functional investigation of the TNIP1 locus in Alzheimer's disease highlights a potential role for GPX3.

Introduction: Recent genome-wide association studies (GWAS) have reported a genetic association with Alzheimer's disease (AD) at the TNIP1/GPX3 locus, but the mechanism is unclear.

Methods: We used cerebrospinal fluid (CSF) proteomics data to test (n = 137) and replicate (n = 446) the association of glutathione peroxidase 3 (GPX3) with CSF biomarkers (including amyloid and tau) and the GWAS-implicated variants (rs34294852 and rs871269).

Results: CSF GPX3 levels decreased with amyloid and tau positivity (analysis of variance P = 1.

Biobank-wide association scan identifies risk factors for late-onset Alzheimer's disease and endophenotypes.

Rich data from large biobanks, coupled with increasingly accessible association statistics from genome-wide association studies (GWAS), provide great opportunities to dissect the complex relationships among human traits and diseases. We introduce BADGERS, a powerful method to perform polygenic score-based biobank-wide association scans. Compared to traditional approaches, BADGERS uses GWAS summary statistics as input and does not require multiple traits to be measured in the same cohort.

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  = 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 (Aβ)/Aβ using logistic regression.

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  = 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.

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).

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.

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.

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.

Apolipoprotein E moderates the association between Non- 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- polygenic risk scores [PRS]) may interact with the ε4 allele to influence cognitive decline.