Estimating dementia prevalence using remote diagnoses and algorithmic modelling: a population-based study of a rural region in South Africa.

Background: Dementia is a leading cause of global death and disability. High-quality data describing dementia prevalence and burden remain scarce in sub-Saharan Africa. Health and Aging in Africa: A Longitudinal Study in South Africa (HAALSI) fills evidence gaps with longitudinal data on cognition, biomarkers, and everyday function in a population-based cohort of Black South Africans, aged 40 years and older, in a rural subdistrict.

APOE ε4-associated heterogeneity of neuroimaging biomarkers across the Alzheimer's disease continuum.

Introduction: While the role of apolipoprotein E (APOE) ε4 in Alzheimer's disease (AD) susceptibility has been studied extensively, much less is known about the differences in disease presentation in APOE ε4 carriers versus non-carriers.

Methods: To help elucidate these differences, we performed a broad analysis comparing the regional levels of six different neuroimaging biomarkers in the brains of APOE ε4 carriers versus non-carriers who participated in the Alzheimer's Disease Neuroimaging Initiative (ADNI).

Results: We observed significant APOE ε4-associated heterogeneity in regional amyloid beta deposition, tau accumulation, glucose uptake, brain volume, cerebral blood flow, and white matter hyperintensities within each AD diagnostic group.

Generating iAstrocytes From Human Induced Pluripotent Stem Cells by Combining Low-Density Passaging of Neural Progenitor Cells and Transcription Factor NFIA Transdifferentiation.

Astrocytes are key regulators of central nervous system (CNS) homeostasis, and their dysfunction is implicated in neurological and neurodegenerative disorders. Here, we describe a two-step protocol to generate astrocytes from human induced pluripotent stem cells (hiPSCs) using a bankable neural progenitor cell (NPC) intermediate, followed by low-density passaging and overexpression of the gliogenic transcription factor NFIA. A bankable NPC intermediate allows for facile differentiation into both purified neuronal and astrocyte cell types in parallel from the same genetic background, depending on the experimental needs.

A microglia-containing cerebral organoid model to study early life immune challenges.

Prenatal infections and activation of the maternal immune system have been proposed to contribute to causing neurodevelopmental disorders (NDDs), chronic conditions often linked to brain abnormalities. Microglia are the resident immune cells of the brain and play a key role in neurodevelopment. Disruption of microglial functions can lead to brain abnormalities and increase the risk of developing NDDs.

Pathologic subtyping of Alzheimer's disease brain tissue reveals disease heterogeneity.

In recent years, multiple groups have shown that what is currently thought of as "Alzheimer's Disease" (AD) may be usefully viewed as several related disease subtypes. As these efforts have continued, a related issue is how common co-pathologies and ethnicity intersect with AD subtypes. The goal of this study was to use a dataset constituting 153 pathologic variables recorded on 666 AD brain autopsies to better define how co-pathologies and ethnicity relate to established AD subtypes.

Spectris™ treatment preserves corpus callosum structure in Alzheimer's disease.

Objective: To examine the impact of 40Hz gamma stimulation on the preservation of the corpus callosum, a critical structure for interhemispheric connectivity, in people with mild cognitive impairment or Alzheimer's disease.

Methods: OVERTURE (NCT03556280) participants were randomized 2:1 (Active:Sham) to receive daily, 1-h, 40Hz gamma sensory stimulation or sham treatment for 6 months. Structural magnetic resonance imaging data were analyzed to assess changes in corpus callosum area ( = 50; 33 for active, 17 for sham).

An analysis of RNA quality metrics in human brain tissue.

Human brain tissue studies have historically used a range of metrics to assess RNA quality. However, few large-scale cross-comparisons of pre-sequencing quality metrics with RNA-seq quality have been published. Here, we analyze how well metrics gathered before RNA sequencing (post-mortem interval (PMI) and RNA integrity number RIN) relate to analyses of RNA quality after sequencing (Percent of counts in Top Ten genes (PTT), 5' bias, and 3' bias) as well as with individual gene counts across the transcriptome.

HDAC Inhibitors recapitulate Human Disease-Associated Microglia Signatures .

Disease-associated microglia (DAM), initially described in mouse models of neurodegenerative diseases, have been classified into two related states; starting from a TREM2-independent DAM1 state to a TREM2 dependent state termed DAM2, with each state being characterized by the expression of specific marker genes. Recently, single-cell (sc)RNA-Seq studies have reported the existence of DAMs in humans; however, whether DAMs play beneficial or detrimental roles in the context of neurodegeneration is still under debate. Here, we present a pharmacological approach to mimic human DAM by exposing different human microglia models to selected histone deacetylase (HDAC) inhibitors.

A cross-disease resource of living human microglia identifies disease-enriched subsets and tool compounds recapitulating microglial states.

Human microglia play a pivotal role in neurological diseases, but we still have an incomplete understanding of microglial heterogeneity, which limits the development of targeted therapies directly modulating their state or function. Here, we use single-cell RNA sequencing to profile 215,680 live human microglia from 74 donors across diverse neurological diseases and CNS regions. We observe a central divide between oxidative and heterocyclic metabolism and identify microglial subsets associated with antigen presentation, motility and proliferation.

The relationship between COMT, proline, and negative symptoms in clinical high risk and recent psychosis onset.

Individuals at clinical high-risk (CHR) of developing psychosis, as well as patients with recent psychosis onset (RO), experience significant negative symptoms that detrimentally impact daily-life functioning and are associated with poor outcomes, even in those who do not convert to psychosis. Targeting negative symptoms may thus hold promise for the treatment of CHR and RO patients. Building from previous findings we examined whether the catechol-O-methyltransferase (COMT) ValMet functional polymorphism and fasting peripheral proline concentration predicts the severity of negative symptoms experienced by adolescents and young adults at CHR or those with RO.

Socioeconomic and medical determinants of state-level subjective cognitive decline in the United States.

Introduction: It is important to understand the socioeconomic and medical determinants of subjective cognitive decline (SCD) at a population level in the United States.

Methods: The primary outcomes are state-level rates of SCD and SCD-related functional impairment in adults aged ≥ 45, both measured in the Behavioral Risk Factor Surveillance System from 2016 to 2022. The exposures are state-level rates of poverty, unemployment, homelessness, college education, racial and ethnic minorities, uninsurance, smoking, hypertension, diabetes, and obesity as well as household income and physician density.

CD33 and SHP-1/ Interaction in Alzheimer's Disease.

Large-scale genetic studies have identified numerous genetic risk factors that suggest a central role for innate immune cells in susceptibility to Alzheimer's disease (AD). CD33, an immunomodulatory transmembrane sialic acid binding protein expressed on myeloid cells, was identified as one such genetic risk factor associated with Alzheimer's disease. Several studies explored the molecular outcomes of genetic variation at the locus.

State Schooling Policies and Cognitive Performance Trajectories: A Natural Experiment in a National US Cohort of Black and White Adults.

Background: Education is strongly associated with cognitive outcomes at older ages, yet the extent to which these associations reflect causal effects remains uncertain due to potential confounding.

Methods: Leveraging changes in historical measures of state-level education policies as natural experiments, we estimated the effects of educational attainment on cognitive performance over 10 years in 20,248 non-Hispanic Black and non-Hispanic White participants, aged 45+ in the Reasons for Geographic and Racial Disparities in Stroke cohort (2003-2020) by (1) using state- and year-specific compulsory schooling laws, school-term length, attendance rate, and student-teacher ratio policies to predict educational attainment for US Census microsample data from 1980 and 1990, and (2) applying policy-predicted years of education (PPYEd) to predict memory, verbal fluency, and a cognitive composite. We estimated overall and race- and sex-specific effects of PPYEd on level and change in each cognitive outcome using random intercept and slope models, adjusting for age, year of first cognitive assessment, and indicators for state of residence at age 6.

Regulation of synapse density by Pumilio RNA-binding proteins.

The formation, stabilization, and elimination of synapses are tightly regulated during neural development and into adulthood. Pumilio RNA-binding proteins regulate the translation and localization of many synaptic mRNAs and are developmentally downregulated in the brain. We found that simultaneous downregulation of Pumilio 1 and 2 increases both excitatory and inhibitory synapse density in primary hippocampal neurons and promotes synapse maturation.

Association of Adherence to a MIND-Style Diet With the Risk of Cognitive Impairment and Decline in the REGARDS Cohort.

Background And Objectives: Diet may influence the development of cognitive impairment and affect cognitive decline, but whether this relationship varies between Black American and White American people is unclear. This study examined the association of Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) and incident cognitive impairment and cognitive trajectories in a biracial prospective cohort study.

Methods: Using data derived from the Food Frequency Questionnaire in the REasons for Geographic and Racial Differences in Stroke study, we compared MIND diet adherence with incident cognitive impairment and cognitive trajectory in Black participants and White participants.

Missense and loss-of-function variants at GWAS loci in familial Alzheimer's disease.

Background: Few rare variants have been identified in genetic loci from genome-wide association studies (GWAS) of Alzheimer's disease (AD), limiting understanding of mechanisms, risk assessment, and genetic counseling.

Methods: Using genome sequencing data from 197 families in the National Institute on Aging Alzheimer's Disease Family Based Study and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study.

Results: Eighty-six rare missense or loss-of-function (LoF) variants completely segregated in 17.