APOE4 and infectious diseases jointly contribute to brain glucose hypometabolism, a biomarker of Alzheimer's pathology: New findings from the ADNI.

Background: Impaired brain glucose metabolism is a preclinical feature of neurodegenerative diseases such as Alzheimer's disease (AD). Infections may promote AD-related pathology. Therefore, we investigated the interplay between infections and APOE4, a strong genetic risk factor for AD.

Elevated blood glucose levels are associated with the progression of brain hypometabolism, and HDL-C and add to this association.

Background: Brain glucose hypometabolism has consistently been found in neurodegenerative disorders, including Alzheimer's disease (AD). High blood glucose and HDL cholesterol (HDL-C) levels have also been linked to neurodegeneration and AD. However, there is limited understanding of the relationships between dementia-related risk factors in the brain and blood.

Methods for joint modelling of longitudinal omics data and time-to-event outcomes: Applications to lysophosphatidylcholines in connection to aging and mortality in the Long Life Family Study.

Studying relationships between longitudinal changes in omics variables and risks of events requires specific methodologies for joint analyses of longitudinal and time-to-event outcomes. We applied two such approaches (joint models [JM], stochastic process models [SPM]) to longitudinal metabolomics data from the Long Life Family Study focusing on understudied associations of longitudinal changes in lysophosphatidylcholines (LPC) with mortality and aging-related outcomes (23 LPC species, 5,790 measurements of each in 4,011 participants, 1,431 of whom died during follow-up). JM analyses found that higher levels of the majority of LPC species were associated with lower mortality risks, with the largest effect size observed for LPC 15:0/0:0 (hazard ratio: 0.

The association between rs6859 in gene and Alzheimer's disease is partly mediated by pTau.

Introduction: Emerging evidence suggests a connection between vulnerability to infections and Alzheimer's disease (AD). The nectin cell adhesion molecule 2 gene coding for a membrane component of adherens junctions is involved in response to infection, and its single nucleotide polymorphism (SNP) rs6859 was significantly associated with AD risk in several human cohorts. It is unclear, however, how exactly rs6859 influences the development of AD pathology.

Overweight as a Causal Factor Contributing to Better Survival at the Oldest Old Ages: A Mendelian Randomization Study.

Overweight, defined by a body mass index (BMI) between 25 and 30, has been associated with enhanced survival among older adults in some studies. However, whether being overweight is causally linked to longevity remains unclear. To investigate this, we conducted a Mendelian randomization (MR) study of lifespan 85+ years, using overweight as an exposure variable and data from the Health and Retirement Study and the Long Life Family Study.

End of Life Events and Causes of Death in Danish Long-Lived Siblings: Reduced Dementia Risk Compared to Sporadic Long-Livers.

Background: Better physical robustness and resilience of long-lived siblings compared to sporadic long-livers has been demonstrated in several studies. However, it is unknown whether long-lived siblings also end their lives better.

Objective: To investigate end-of-life (EoL) events (dementia diagnosis, medication, hospitalizations in the last 5 years of life), causes of death, and location of death in long-lived siblings compared to matched sporadic long-livers from the Danish population.

Prior infections are associated with smaller hippocampal volume in older women.

Accumulating evidence suggests that infections may play a major role in Alzheimer's disease (AD), however, mechanism is unclear, as multiple pathways may be involved. One possibility is that infections could contribute to neurodegeneration directly by promoting neuronal death. We explored relationships between history of infections and brain hippocampal volume (HV), a major biomarker of neurodegeneration, in a subsample of the UK Biobank (UKB) participants.

Associations of infections and vaccines with Alzheimer's disease point to a role of compromised immunity rather than specific pathogen in AD.

Introduction: Diverse pathogens (viral, bacterial, fungal) have been associated with Alzheimer's disease (AD) and related traits in various studies. This suggests that compromised immunity, rather than specific microbes, may play a role in AD by increasing an individual's vulnerability to various infections, which could contribute to neurodegeneration. If true, then vaccines that have heterologous effects on immunity, extending beyond protection against the targeted disease, may hold a potential for AD prevention.

How are APOE4, changes in body weight, and longevity related? Insights from a causal mediation analysis.

The ε4 allele of the APOE gene () is known for its negative association with human longevity; however, the mechanism is unclear. is also linked to changes in body weight, and the latter changes were associated with survival in some studies. Here, we explore the role of aging changes in weight in the connection between and longevity using the causal mediation analysis (CMA) approach to uncover the mechanisms of genetic associations.

Systemic inflammation in relation to exceptional memory in the Long Life Family Study (LLFS).

Background And Objectives: We previously found a substantial familial aggregation of healthy aging phenotypes, including exceptional memory (EM) in long-lived persons. In the current study, we aim to assess whether long-lived families with EM and without EM (non-EM) differ in systemic inflammation status and trajectory.

Methods: The current study included 4333 participants of the multi-center Long Life Family Study (LLFS).

The SNP rs6859 in NECTIN2 gene is associated with underlying heterogeneous trajectories of cognitive changes in older adults.

Background: Functional decline associated with dementia, including in Alzheimer's disease (AD), is not uniform across individuals, and respective heterogeneity is not yet fully explained. Such heterogeneity may in part be related to genetic variability among individuals. In this study, we investigated whether the SNP rs6859 in nectin cell adhesion molecule 2 (NECTIN2) gene (a major risk factor for AD) influences trajectories of cognitive decline in older participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI).

Graves disease is associated with increased risk of clinical Alzheimer's disease: evidence from the Medicare system.

Background: Identification of modifiable risk factors for Alzheimer's Disease (AD) onset is an important aspect of controlling the burden imposed by this disease on an increasing number of older U.S. adults.

Genome-Related Mechanisms Contributing to Differences in Alzheimer's Disease Incidence Between White and Black Older US Adults.

In this manuscript, we leverage a modified GWAS algorithm adapted for use with multidimensional Cox models and data from the Health and Retirement Study to explore how genetic variation influences the size of the disparity in Alzheimer's disease (AD) incidence between older Black and White US adults. We identified four loci that were associated with higher AD incidence levels in older Black adults: (1) rs11077034 (hazard ratio (HR), 4.98) from the RBFOX1 gene; (2) rs7144494 (HR, 1.

Patterns of Aging Changes in Bodyweight May Predict Alzheimer's Disease.

Relationships between patterns of aging-changes in bodyweight and AD are not fully understood. We compared mean age-trajectories of weight between those who did and did not develop late-onset-AD, and evaluated impact of age at maximum weight (AgeMax), and slope of decline in weight, on AD risk. Women with late-onset-AD had lower weight three or more decades before AD onset, and ∼10 years younger AgeMax, compared to AD-free women.

Associations of infections and vaccines with Alzheimer's disease point to a major role of compromised immunity rather than specific pathogen in AD.

Introduction: Diverse pathogens (viral, bacterial, fungal) have been linked to Alzheimer's disease (AD) indicating a possibility that the culprit may be compromised immunity rather than particular microbe. If true, then vaccines with broad beneficial effects on immunity might be protective against AD.

Methods: We estimated associations of common adult infections, including herpes simplex, zoster (shingles), pneumonia, and recurrent mycoses, as well as vaccinations against shingles and pneumonia, with the risk of AD in a pseudorandomized sample of the Health and Retirement Study.

Graves Disease is Associated with Increased Risk of Clinical Alzheimer's Disease: Evidence from the Medicare System.

Background: Identification of modifiable risk factors for Alzheimer's Disease (AD) onset is an important aspect of controlling the burden imposed by this disease on an increasing number of older U.S. adults.

The Construction of a Multidomain Risk Model of Alzheimer's Disease and Related Dementias.

Background: Alzheimer's disease (AD) and related dementia (ADRD) risk is affected by multiple dependent risk factors; however, there is no consensus about their relative impact in the development of these disorders.

Objective: To rank the effects of potentially dependent risk factors and identify an optimal parsimonious set of measures for predicting AD/ADRD risk from a larger pool of potentially correlated predictors.

Methods: We used diagnosis record, survey, and genetic data from the Health and Retirement Study to assess the relative predictive strength of AD/ADRD risk factors spanning several domains: comorbidities, demographics/socioeconomics, health-related behavior, genetics, and environmental exposure.

Vaccination Against Pneumonia May Provide Genotype-Specific Protection Against Alzheimer's Disease.

Vaccine repurposing that considers individual genotype may aid personalized prevention of Alzheimer's disease (AD). In this retrospective cohort study, we used Cardiovascular Health Study data to estimate associations of pneumococcal polysaccharide vaccine and flu shots received between ages 65-75 with AD onset at age 75 or older, taking into account rs6859 polymorphism in NECTIN2 gene (AD risk factor). Pneumococcal vaccine, and total count of vaccinations against pneumonia and flu, were associated with lower odds of AD in carriers of rs6859 A allele, but not in non-carriers.

Interactions between genes involved in physiological dysregulation and axon guidance: role in Alzheimer's disease.

Dysregulation of physiological processes may contribute to Alzheimer's disease (AD) development. We previously found that an increase in the level of physiological dysregulation (PD) in the aging body is associated with declining resilience and robustness to major diseases. Also, our genome-wide association study found that genes associated with the age-related increase in PD frequently represented pathways implicated in axon guidance and synaptic function, which in turn were linked to AD and related traits (e.

Methionine restriction-induced sulfur deficiency impairs antitumour immunity partially through gut microbiota.

Restriction of methionine (MR), a sulfur-containing essential amino acid, has been reported to repress cancer growth and improve therapeutic responses in several preclinical settings. However, how MR impacts cancer progression in the context of the intact immune system is unknown. Here we report that while inhibiting cancer growth in immunocompromised mice, MR reduces T cell abundance, exacerbates tumour growth and impairs tumour response to immunotherapy in immunocompetent male and female mice.