Olfactory loss is a predisposing factor for depression, while olfactory enrichment is an effective treatment for depression.

The loss of olfactory stimulation correlates well with at least 68 widely differing neurological disorders, including depression, and we raise the possibility that this relationship may be causal. That is, it seems possible that olfactory loss makes the brain vulnerable to expressing the symptoms of these neurological disorders, while daily olfactory enrichment may decrease the risk of expressing these symptoms. This situation resembles the cognitive reserve that is thought to protect people with Alzheimer's neuropathology from expressing the functional deficit in memory through the cumulative effect of intellectual stimulation.

Effect of Aducanumab Approval on Willingness to Participate in Preclinical Alzheimer's Disease Trials.

Background: Clinical trials now test promising therapies in the preclinical stages of Alzheimer's disease (AD). Participant willingness to enroll in different types of preclinical AD trials is understudied and whether the FDA approval of aducanumab affected these attitudes is unknown.

Objective: To evaluate preferences toward three preclinical AD trial scenarios and whether the FDA approval of aducanumab changed willingness to participate among potential trial participants.

Blood pressure variability and plasma Alzheimer's disease biomarkers in older adults.

Blood pressure variability is an emerging risk factor for Alzheimer's disease in older adults, independent of average blood pressure levels. Growing evidence suggests increased blood pressure variability is linked to Alzheimer's disease pathophysiology indexed by cerebrospinal fluid and positron emission tomography markers, but relationships with plasma Alzheimer's disease markers have not been investigated. In this cross-sectional study of 54 community-dwelling older adults (aged 55-88, mean age 69.

Immunogenicity of MultiTEP platform technology-based Tau vaccine in non-human primates.

Pathological forms of Tau protein are directly associated with neurodegeneration and correlate with Alzheimer's Disease (AD) symptoms, progression, and severity. Previously, using various mouse models of Tauopathies and AD, we have demonstrated the immunogenicity and efficacy of the MultiTEP-based adjuvanted vaccine targeting the phosphatase activating domain (PAD) of Tau, AV-1980R/A. Here, we analyzed its immunogenicity in non-human primates (NHP), the closest phylogenic relatives to humans with a similar immune system, to initiate the transition of this vaccine into clinical trials.

Modulation of hepatic amyloid precursor protein and lipoprotein receptor-related protein 1 by chronic alcohol intake: Potential link between liver steatosis and amyloid-β.

Heavy alcohol consumption is a known risk factor for various forms of dementia and the development of Alzheimer's disease (AD). In this work, we investigated how intragastric alcohol feeding may alter the liver-to-brain axis to induce and/or promote AD pathology. Four weeks of intragastric alcohol feeding to mice, which causes significant fatty liver (steatosis) and liver injury, caused no changes in AD pathology markers in the brain [amyloid precursor protein (APP), presenilin], except for a decrease in microglial cell number in the cortex of the brain.

Metformin and Dementia Risk: A Systematic Review with Respect to Time Related Biases.

Background: When studying drug effects using observational data, time-related biases may exist and result in spurious associations. Numerous observational studies have investigated metformin and dementia risk, but have reported inconsistent findings, some of which might be caused by unaddressed time-related biases. Immortal time bias biases the results toward a "protective" effect, whereas time-lag and time-window biases can lead to either a "detrimental" or "protective" effect.

Preclinical Alzheimer Disease and the Electronic Health Record: Balancing Confidentiality and Care.

Because information technologies are increasingly used to improve clinical research and care, personal health information (PHI) has wider dissemination than ever before. The 21st Century Cures Act in the United States now requires patient access to many components of the electronic health record (EHR). Although these changes promise to enhance communication and information sharing, they also bring higher risks of unwanted disclosure, both within and outside of health systems.

White matter microstructural correlates of associative learning in the oldest-old.

The ability to learn associations between events is critical for everyday functioning (e.g., decision making, social interactions) and has been attributed to structural differences in white matter tracts connecting cortical regions to the hippocampus (e.

Older Adults With Higher Blood Pressure Variability Exhibit Cerebrovascular Reactivity Deficits.

Background: Elevated blood pressure (BP) variability is predictive of increased risk for stroke, cerebrovascular disease, and other vascular brain injuries, independent of traditionally studied average BP levels. However, no studies to date have evaluated whether BP variability is related to diminished cerebrovascular reactivity, which may represent an early marker of cerebrovascular dysfunction presaging vascular brain injury.

Methods: The present study investigated BP variability and cerebrovascular reactivity in a sample of 41 community-dwelling older adults (mean age 69.

Truncation mutations in MYRF underlie primary angle closure glaucoma.

Mutations in myelin regulatory factor (MYRF), a gene mapped to 11q12-q13.3, are responsible for autosomal dominant high hyperopia and seem to be associated with angle closure glaucoma, which is one of the leading causes of irreversible blindness worldwide. Whether there is a causal link from the MYRF mutations to the pathogenesis of primary angle-closure glaucoma (PACG) remains unclear at this time.

Economic hardships of Korean American family caregivers of persons with dementia: a mixed-methods study.

This study examined the relationships between economic hardships (i.e. perceived financial hardship and job interference) and caregiver burden among Korean American family caregivers of persons with dementia and explored their lived experience caring for their loved ones.

Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer's disease.

Tau aggregation in neurofibrillary tangles (NFTs) is closely associated with neurodegeneration and cognitive decline in Alzheimer's disease (AD). However, the molecular signatures that distinguish between aggregation-prone and aggregation-resistant cell states are unknown. We developed methods for the high-throughput isolation and transcriptome profiling of single somas with NFTs from the human AD brain, quantified the susceptibility of 20 neocortical subtypes for NFT formation and death, and identified both shared and cell-type-specific signatures.

Platelet-derived growth factor-BB and white matter hyperintensity burden in carriers.

Background: The apolipoprotein-e4 () gene increases risk for developing late-onset Alzheimer's disease (AD) and has been linked to increased microvascular dysfunction, including pericyte degeneration and blood-brain barrier breakdown. Platelet-derived growth factor-BB (PDGF-BB) is a glycoprotein involved in blood-brain barrier and pericyte maintenance. Increased PDGF-BB levels have been reported in white matter in AD brain tissue.

Hippocampal dentate gyrus integrity revealed with ultrahigh resolution diffusion imaging predicts memory performance in older adults.

Medial temporal lobe (MTL) atrophy is a core feature of age-related cognitive decline and Alzheimer's disease (AD). While regional volumes and thickness are often used as a proxy for neurodegeneration, they lack the sensitivity to serve as an accurate diagnostic test and indicate advanced neurodegeneration. Here, we used a submillimeter resolution diffusion weighted MRI sequence (ZOOMit) to quantify microstructural properties of hippocampal subfields in older adults (63-98 years old) using tensor derived measures: fractional anisotropy (FA) and mean diffusivity (MD).

Inhibiting BDNF Signaling Upregulates Hippocampal H3K9me3 in a Manner Dependent On Aging and Oxidative Stress.

Histone modifications are key contributors to the cognitive decline that occurs in aging and Alzheimer's disease. Our lab has previously shown that elevated H3K9me3 in aged mice is correlated with synaptic loss, cognitive impairment and a reduction in brain derived neurotrophic factor (BDNF). However, the mechanism of H3K9me3 regulation remains poorly understood.

Temporal endurance of exercise-induced benefits on hippocampus-dependent memory and synaptic plasticity in female mice.

Exercise facilitates hippocampal neurogenesis and neuroplasticity that in turn, promotes cognitive function. Our previous studies have demonstrated that in male mice, voluntary exercise enables hippocampus-dependent learning in conditions that are normally subthreshold for long-term memory formation in sedentary animals. Such cognitive enhancement can be maintained long after exercise has ceased and can be re-engaged by a subsequent subthreshold exercise session, suggesting exercise-induced benefits are temporally dynamic.

Perceptions of Research Burden and Retention Among Participants in ADRC Cohorts.

Objectives: Alzheimer disease (AD) and related dementias clinical research is associated with significant participant burden. The Perceived Research Burden Assessment (PeRBA) measures participants' perceptions of logistical, psychological, and physical burdens. The purpose of this study was to assess PeRBA's psychometric properties, perceptual sources, and behavioral consequences with participants in a multisite study of participant retention in longitudinal cohort studies of Alzheimer disease and related dementias.

Selective vulnerability of medial temporal regions to short-term blood pressure variability and cerebral hypoperfusion in older adults.

Blood pressure variability is an emerging risk factor for stroke, cognitive impairment, and dementia, possibly through links with cerebral hypoperfusion. Recent evidence suggests visit-to-visit (e.g.

Protocol for single-nucleus ATAC sequencing and bioinformatic analysis in frozen human brain tissue.

Single-nucleus ATAC sequencing (snATAC-seq) employs a hyperactive Tn5 transposase to gain precise information about the cis-regulatory elements in specific cell types. However, the standard protocol of snATAC-seq is not optimized for all tissues, including the brain. Here, we present a modified protocol for single-nuclei isolation from postmortem frozen human brain tissue, followed by snATAC-seq library preparation and sequencing.

Cholesterol and matrisome pathways dysregulated in astrocytes and microglia.

The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice. Population and isogenic models demonstrate that APOE4 local haplotype, rather than a single risk allele, contributes to risk.

Immunogenicity of MultiTEP-Platform-Based Recombinant Protein Vaccine, PV-1950R, Targeting Three B-Cell Antigenic Determinants of Pathological α-Synuclein.

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are characterized by the aberrant accumulation of intracytoplasmic misfolded and aggregated α-synuclein (α-Syn), resulting in neurodegeneration associated with inflammation. The propagation of α-Syn aggregates from cell to cell is implicated in the spreading of pathological α-Syn in the brain and disease progression. We and others demonstrated that antibodies generated after active and passive vaccinations could inhibit the propagation of pathological α-Syn in the extracellular space and prevent/inhibit disease/s in the relevant animal models.