David Bennett

• Rush University Medical Center

The APOE locus is strongly associated with risk for developing Alzheimer's disease and dementia with Lewy bodies. In particular, the role of the APOE ϵ4 allele as a putative driver of α-synuclein pathology is a topic of intense debate. Here, we performed a comprehensive evaluation in 2466 dementia with Lewy bodies cases versus 2928 neurologically h...

Emerging evidence suggests that small vessel disease (SVD) is a risk factor for clinical dementia and may contribute to AD neuropathological changes. Watershed brain regions are located at the most distal areas between arterial territories, making them vulnerable to SVD-related changes. We examined the association of pathologic markers of SVD, spec...

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Co...

Background and Purpose There is increasing recognition of the importance of cortical microinfarcts to overall brain health, cognition, and Alzheimer dementia. Cerebral small vessel pathologies are associated with microinfarcts and frequently coexist with Alzheimer disease; however, the extent to which Aβ (amyloid beta) and tau pathology modulates m...

Introduction Excessive napping duration has been associated with cognitive decline. The effect of napping frequency is less understood, and little is known about the development of Alzheimer’s dementia associated with napping. We tested whether longer or more frequent naps in the elderly are linked to the development of incident Alzheimer’s dementi...

Introduction Daytime napping is common in elderly adults and has been associated with cognitive impairment. Prior studies have assessed napping at one time point, making it difficult to examine the longitudinal progression of napping and its association with cognitive aging. We examined objectively measured daytime napping longitudinally across dif...

Brain donation in studies on aging remains a critical pathway to discovering and improving preventive measures and treatments for Alzheimer’s dementia and related disorders. Brain donation for research is almost exclusively obtained from non-Latinx Whites of higher socioeconomic status in the United States. Despite persistent efforts, it has been d...

Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more th...

Abstract Background: Strawberries have been identified to have antioxidant and anti-inflammatory properties that improve neuronal function and cognition, mostly in animal studies. It is unknown if the consumption of strawberries or related bioactives may reduce the risk of Alzheimer’s dementia risk. Material and Methods: The study was conducted in...

Autopsy measures of Alzheimer’s disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer’s disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with...

Cognitive function relies on both molecular levels and cellular structures. However, systematic relationships between these two components of cognitive function, and their joint contribution to disease, are largely unknown. We utilize postmortem neuroimaging in tandem with gene expression and DNA methylation, from 222 deeply-phenotyped persons in a...

CpG‐related single nucleotide polymorphisms (CGS) have the potential to perturb DNA methylation; however, their effects on Alzheimer disease (AD) risk have not been evaluated systematically. We conducted a genome‐wide association study using a sliding‐window approach to measure the combined effects of CGSes on AD risk in a discovery sample of 24 Eu...

Transcriptome-wide association analysis is a powerful approach to studying the genetic architecture of complex traits. A key component of this approach is to build a model to impute gene expression levels from genotypes by using samples with matched genotypes and gene expression data in a given tissue. However, it is challenging to develop robust a...

Background: The role of the innate immune system in Alzheimer's disease (AD) and neurodegenerative disease susceptibility has recently been highlighted in genetic studies. However, we do not know whether risk for inflammatory disease predisposes unaffected individuals to late-life cognitive deficits or AD-related neuropathology. We investigated wh...

Temporal discounting, the tendency to select a smaller reward offered sooner over a larger reward offered at a later time, has been associated with a number of real-world decision-making outcomes important for health and wellbeing. Neurobiological mechanisms supporting temporal discounting have been explored among younger participants, and these ha...

Here we use deep sequencing to identify sources of variation in mRNA splicing in the dorsolateral prefrontal cortex (DLPFC) of 450 subjects from two aging cohorts. Hundreds of aberrant pre-mRNA splicing events are reproducibly associated with Alzheimer’s disease. We also generate a catalog of splicing quantitative trait loci (sQTL) effects: splicin...

Alzheimer's dementia commonly impacts the health of older adults and lacks any preventative therapy. While Alzheimer's dementia risk has a substantial genetic component, the specific molecular mechanisms and neuropathologies triggered by most of the known genetic variants are unclear. Resultantly, they have shown limited influence on drug developme...

Introduction: Apolipoprotein E (APOE) is a susceptibility gene for late-onset Alzheimer's disease neuropathology; less is known about the relationship between APOE and cerebrovascular disease (CVD) neuropathology. Methods: We investigated associations of APOE status with arteriolosclerosis, macroinfarcts and microinfarcts, and atherosclerosis in...

Introduction: Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signa...

The field of neurodegenerative disease research has seen tremendous advances over the last two decades as new technologies and analytic methods have enabled well-powered human genomic studies. Driven first by genetic studies and more recently by transcriptomic and epigenomic studies of proper size, we have uncovered a large repertoire of loci, gene...

Identifying preclinical Alzheimer’s disease (AD) is an important step toward developing approaches to early treatment and dementia prevention. We applied latent class analysis (LCA) to 10 baseline neuropsychological assessments for 1,345 participants from Einstein Aging Study. Time-to-event models for all-cause dementia and AD were run examining ev...

Background Disability in older adults is associated with low quality of life and higher mortality. Diet may be a potentially important public health strategy for disability prevention in aging. We examined the relations of the Mediterranean, DASH and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets to functional disability i...

Introduction: Healthy physiological systems exhibit fractal regulation (FR), generating similar fluctuation patterns in physiological outputs across different time scales. FR in motor activity is degraded in dementia, and the degradation correlates to cognitive decline. We tested whether degraded FR predicts Alzheimer's disease dementia. Methods:...

Background There are few data concerning the association between season and cognition and its neurobiological correlates in older persons—effects with important translational and therapeutic implications for the diagnosis and treatment of Alzheimer disease (AD). We aimed to measure these effects. Methods and findings We analyzed data from 3,353 pa...

Our hypothesis is that changes in gene and protein expression are crucial to the development of late-onset Alzheimer's disease. Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late-onset Alzheimer's disease. We have now examined how proteins are incorporated into net...

Multiple aspects of molecular regulation, including genetics, epigenetics, and mRNA collectively influence the development of age-related neurologic diseases. Therefore, with the ultimate goal of understanding molecular systems associated with cognitive decline, we infer directed interactions among regulatory elements in the local regulatory vicini...

Objective: To test whether race (specifically Black or White) moderates the relationship between memory complaints and depressive symptoms in cognitively normal older adults, and if these relationships vary by memory complaint characteristics. Methods: Data from Black (n = 551) and White (n = 1158) cognitively intact participants (Mage = 77.1, S...

We initiated the systematic profiling of the dorsolateral prefrontal cortex obtained from a subset of autopsied individuals enrolled in the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP), which are jointly designed prospective studies of aging and dementia with detailed, longitudinal cognitive phenotyping during life and a...

Cardiovascular (CV) and lifestyle associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV associated genes also increase risk for AD (genetic pleiotropy). Using large genome-wide association studi...

Background: Transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy in older adults frequently coexists with Alzheimer's disease pathology and hippocampal sclerosis. It is unclear whether there is a link between APOE ε4 and TDP-43 proteinopathy, and the role of APOE ε4 in the association of TDP-43 proteinopathy with hippocampal s...

Purpose Human females have a unique duration of post-reproductive longevity, during which sex-specific mechanisms ma influence later-life mechanisms of neuronal resilience and vulnerability. The maintenance of energy metabolism, through the oxidative phosphorylation (OXPHOS) apparatus, is essential for brain health. Given the known association betw...

Medical and epidemiological researchers commonly study ordinal measures of symptoms or pathology. Some of these studies involve two correlated ordinal measures. There is often an interest in including both measures in the modeling. It is common to see analyses that consider one of the measures as a predictor in the model for the other measure as an...

Categorizing people with late-onset Alzheimer's disease into biologically coherent subgroups is important for personalized medicine. We evaluated data from five studies (total n=4,050, of whom 2,431 had genome-wide single nucleotide polymorphism (SNP) data). We assigned people to cognitively-defined subgroups on the basis of relative performance in...

Objective: To examine associations of average and change in late-life blood pressure (BP) with cerebrovascular and Alzheimer disease (AD) neuropathology in a large group of decedents followed longitudinally in vivo. Methods: This clinical-pathologic study was derived from prospective, community-based cohort studies of aging with similar design a...

Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer’s disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF bio...

Objective: HIV infection sets off an immediate immune response and inflammatory cascade that can lead to neuronal injury and cognitive impairment, but the relationship between immune markers, regional brain volumes, and cognition remains understudied in HIV-infected adults. Methods: Cross-sectional associations were examined between serum immune...

Background: Lowering the likelihood of hospitalization in older adults is a major public health goal for modern health care systems. Emerging data suggest that financial literacy is an important determinant of health outcomes in old age, but the relationship with hospitalization has not been explored. Objective: To test the hypothesis that bette...

Microglia, the resident immune cells of the brain, have important roles in brain health. However, little is known about the regulation and consequences of microglial activation in the aging human brain. We assessed the effect of microglial activation in the aging human brain by calculating the proportion of activated microglia (PAM), based on morph...

Recent studies of bulk microglia have provided insights into the role of this immune cell type in central nervous system development, homeostasis and dysfunction. Nonetheless, our understanding of the diversity of human microglial cell states remains limited. Microglia are highly plastic and have multiple different roles, making the extent of pheno...

Aging and neurodegenerative disease are characterized by genomic instability in neurons, including aberrant activation and mobilization of transposable elements (TEs). Integrating studies of human postmortem brain tissue and Drosophila melanogaster models, we investigate TE activation in association with Tau pathology in Alzheimer's disease (AD). L...

There is a need for new therapeutic targets with which to prevent Alzheimer's disease (AD), a major contributor to aging-related cognitive decline. Here we report the construction and validation of a molecular network of the aging human frontal cortex. Using RNA sequence data from 478 individuals, we first build a molecular network using modules of...

Objective: Previous gene expression analysis identified a network of co‐expressed genes that is associated with β‐amyloid neuropathology and cognitive decline in older adults. The current work targeted influential genes in this network with quantitative proteomics to identify potential novel therapeutic targets. Methods: Data came from 834 communit...

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cogn...

Objectives: To determine whether assessment-to-assessment fluctuations in episodic memory (EM) reflect fluctuations in olfaction over time. Methods: Within-person coupled variation in EM and the Brief Smell Identification Test (BSIT) was examined in 565 participants aged 58-106 with autopsy data from the Rush Memory and Aging Project. A growth m...

Objective: To examine the association of the APOE ε2ε4 genotype with incident Alzheimer disease (AD), mild cognitive impairment (MCI), cognitive decline, and AD pathology in older adults. Methods: We used data from 2,151 older adults of European ancestry who were free of dementia at baseline and underwent structured annual clinical evaluation in...

Objective: This study examines the effect of antidepressant medication use and social engagement on the level of depressive symptoms at the time of initially meeting criteria for dementia. Method: Measures of social engagement, medication use, and depressive symptoms from 402 participants with incident dementia were utilized for the study. Proporti...

Importance The strongest genetic risk factor for Alzheimer disease (AD), the apolipoprotein E (APOE) gene, has a stronger association among women compared with men. Yet limited work has evaluated the association between APOE alleles and markers of AD neuropathology in a sex-specific manner. Objective To evaluate sex differences in the association...

TDP-43 pathology was investigated in the anterior temporal pole cortex (ATPC) and orbital frontal cortex (OFC), regions often degenerated in frontotemporal lobar degenerations (FTLD), in aging and Alzheimer's disease (AD). Diagnosis of dementia in the 1160 autopsied participants from 3 studies of community-dwelling elders was based on clinical eval...

Causal genes and variants within genome-wide association study (GWAS) loci can be identified by integrating GWAS statistics with expression quantitative trait loci (eQTL) and determining which variants underlie both GWAS and eQTL signals. Most analyses, however, consider only the marginal eQTL signal, rather than dissect this signal into multiple c...

Brain microinfarcts are common in aging and are associated with cognitive impairment. Anterior and posterior watershed border zones lie at the territories of the anterior, middle, and posterior cerebral arteries, and are more vulnerable to hypoperfusion than brain regions outside the watershed areas. However, little is known about microinfarcts in...

Introduction Human motor activity possesses fractal structures as characterized by similar fluctuation patterns across multiple time scales from seconds to hours. Such fractal regulation (FR) is robust in healthy young subjects and is degraded with aging. Evidence indicates a mechanistic link between fractal regulation and sleep/circadian control....

Introduction Healthy physiological systems exhibit fractal regulation, generating similar fluctuation patterns in physiological outputs across different time scales from seconds to hours. Evidence indicates a mechanistic link between fractal regulation and sleep/circadian control, both degraded with aging and in Alzheimer’s disease (AD). Recent stu...

Objective: To test the hypothesis that brain pathology is associated with total daily physical activity proximate to death in older adults. Methods: We studied brain autopsies from 428 decedents of the Rush Memory and Aging Project. The quantity of all physical activity was measured continuously for up to 10 days with actigraphy (Actical; Philip...

In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 20...