Alzheimer's & Dementia最新文献

Tauopathy is one of the pathological features of Alzheimer's disease and related dementias (ADRD). At present, there have been many studies on the formation, deposition, and intercellular transmission of tau in neurons and immune cells. The vasculature is an important component of the central nervous system. This review discusses the interaction between vasculature and tau in detail from three aspects. (1) The vascular risk factors (VRFs) discussed in this review include diabetes mellitus (DM), abnormal blood pressure (BP), and hypercholesterolemia. (2) In ADRD pathology, the hyperphosphorylation and deposition of tau interact with disrupted vasculature, such as different cells (endothelial cells, smooth muscular cells, and pericytes), the blood−brain barrier (BBB), and the cerebral lymphatic system. (3) The functions of vasculature are regulated by various signaling transductions. Endothelial nitric oxide synthase/nitric oxide, calcium signaling, Rho/Rho-associated coiled-coil containing Kinase, and receptors for advanced glycation end products are discussed in this review. Our findings indicate that the prevention and treatment of vascular health may be a potential target for ADRD combination therapy.

Highlights

The Nun Study is an iconic longitudinal study of aging and dementia on a cohort of 678 Catholic nuns from the School Sisters of Notre Dame. Participants consented to undergoing annual neuropsychological assessments, allowing researchers access to convent archives and medical records and post mortem brain donation. This study investigated the associations between epidemiological factors, cognitive function, and brain pathology. By examining published literature that reports on or utilizes Nun Study data, we provide an overview of its methodology and key findings, emphasizing its significant contributions to understanding cognitive impairment and related neuropathologies. Seminal findings on early-life factors affecting cognitive health, clinicopathological correlations, and apparent resistance and resilience to neuropathology are discussed. Decades of Nun Study research have made critical contributions to our understanding of Alzheimer's disease and related dementias and highlight continuing objectives for future research.

Highlights

INTRODUCTION

Epidemiological studies indicate a link between attention-deficit/hyperactivity disorder (ADHD) and elevated risk of dementia. However, the impact of ADHD on cognition and Alzheimer's disease (AD) biomarkers in individuals with cognitive impairment remains unclear.

METHODS

We computed weighted ADHD polygenic risk scores (ADHD-PRS) in 938 cognitively impaired participants (674 mild cognitive impairment [MCI] and 264 dementia; mean age 73.5 years). A subset underwent cerebrospinal fluid (CSF) analysis for amyloid beta (Aβ) and phosphorylated tau, as well as fluorodeoxyglucose positron emission tomography ([¹⁸F]FDG-PET).

RESULTS

We observed lower executive function in individuals with high ADHD-PRS for both MCI and dementia participants. Higher levels of CSF phosphorylated tau, but not Aβ, were observed in dementia participants with higher ADHD-PRS. Increased ADHD-PRS was associated with glucose hypometabolism in the frontal and parietal cortices.

DISCUSSION

ADHD-PRS is associated with a more severe disease presentation in individuals with cognitive impairment due to dementia, characterized by impaired executive function, elevated tau pathology, and hypometabolism in the frontal and parietal cortices.

Highlights

INTRODUCTION

To investigate the associations of metabotropic glutamate receptor 5 (mGluR5) with tau deposition and cognitive ability in patients with early Alzheimer's disease (AD).

METHODS

Twenty-six cognitively impaired (CI) and 14 cognitively unimpaired (CU) individuals underwent mGluR5 positron emission tomography (PET) ([¹⁸F]PSS232), amyloid PET ([¹⁸F]florbetapir), and tau PET ([¹⁸F]MK6240), and neuropsychological assessment. The relationships among mGluR5 availability, tau deposition, and neuropsychological assessment were analyzed using Spearman's correlation and mediation analyses.

RESULTS

CI patients had lower mGluR5 in the hippocampus than CU (standardized uptake value ratio [SUVr]: 2.03 ± 0.25 vs 1.79 ± 0.17, p = 0.003). Hippocampal mGluR5 was negatively associated with hippocampal tau deposition (r = −.46, p = 0.003) and positively associated with cognitive performance, but only in women. Hippocampal tau deposition mediated the effect of mGluR5 on cognitive performance.

DISCUSSION

Reduced hippocampal mGluR5 is negatively related with tau deposition in most cortical regions and positively associated with cognitive performance, making it a promising biomarker for AD diagnosis and therapy.

Highlights

INTRODUCTION

Alzheimer's disease (AD) is the most prevalent form of dementia. While many AD-associated genetic determinants have been identified, few studies have analyzed individuals of non-European ancestry.

METHODS

We conducted a multi-ancestry genome-wide association study (GWAS) of clinically diagnosed AD and AD-by-proxy using whole genome sequencing data from the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS), National Institute of Mental Health, UK Biobank (UKB), and All of Us (AoU) consisting of 49,149 cases (12,074 clinically diagnosed and 37,075 AD-by-proxy) and 383,225 controls. Nearly half of NIAGADS and AoU participants were of non-European ancestry.

RESULTS

For clinically diagnosed AD, we identified 14 new loci—five common (FBN2/SCL27A6, AC090115.1, DYM, KCNG1/AL121785.1, TIAM1) and nine rare (VWA5B1, RNU6-755P/LMX1A, MOB1A, MORC1-AS1, LINC00989, PDE4D, RNU2-49P/CDO1, NEO1, and SLC35G3/AC022916.1). Meta-analysis of UKB and AoU AD-by-proxy cases yielded two new rare loci (RPL23/LASP1 and CEBPA/AC008738.6), also nominally significant in NIAGADS.

DISCUSSION

In summary, we provide evidence for 16 novel AD loci and advocate for more studies using whole genome sequencing–based GWAS of diverse cohorts.

Highlights

INTRODUCTION

Blood-based biomarkers for Alzheimer's disease (AD) have been widely studied, but direct comparisons of several biomarkers in clinical settings remain limited.

METHODS

In this cross-sectional study, plasma biomarkers from 197 participants in the BIODEGMAR cohort (Hospital del Mar, Barcelona) were analyzed. Participants were classified based on AD cerebrospinal fluid (CSF) core biomarkers. We assessed the ability of plasma p-tau181, p-tau217, p-tau231, t-tau, and Aβ42/40 to classify Aβ pathology status.

RESULTS

Plasma p-tau biomarkers had a greater diagnostic performance and larger effect sizes compared to t-tau and Aβ42/40 assays in detecting Aβ pathology. Among them, plasma p-tau217 consistently outperformed the others, demonstrating superior area under the curves. Furthermore, p-tau217 showed the strongest correlation between plasma and CSF levels, underscoring its potential as a reliable surrogate for CSF biomarkers.

DISCUSSION

Several plasma biomarkers, targeting different epitopes and using different platforms, demonstrated high performance in detecting AD in a memory clinic setting.

Highlights

INTRODUCTION

The prognostic utility of plasma proteomics for cognitive decline and dementia in a Southeast Asian population characterized by high cerebrovascular disease (CeVD) burden is underexplored.

METHODS

We examined this in a Singaporean memory clinic cohort of 528 subjects (n = 300, CeVD; n = 167, incident cognitive decline) followed-up for 4 years.

RESULTS

Of 1441 plasma proteins surveyed, a 12-protein signature significantly predicted cognitive decline (q-value < .05). Sixteen diverse biological processes were implicated in cognitive decline. Ten proteins independently predicted incident dementia (q-value < .05). A unified prediction model combining plasma proteins with clinical risk factors increased the area under the curve for outcome prediction from 0.62 to 0.85. External validation in the cerebrospinal fluid proteome of an independent Caucasian cohort replicated four of the significantly predictive plasma markers for cognitive decline namely: GFAP, NEFL, AREG, and PPY.

DISCUSSION

The prognostic proteins prioritized in our study provide robust signals in two different biological matrices, representing potential mechanistic targets for dementia and cognitive decline.

Highlights

INTRODUCTION

Studies use multiple different instruments to measure dementia-related outcomes, making head-to-head comparisons of interventions difficult.

METHODS

To address this gap, we developed two methods to crosswalk estimated treatment effects on cognitive outcomes that are flexible, broadly applicable, and do not rely on strong distributional assumptions.

RESULTS

We present two methods to crosswalk effect estimates using one measure to estimates using another measure, illustrated with global cognitive measures from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Specifically, we develop crosswalks for the following measures and associated change scores over time: the clinical dementia rating scale sum of box (CDR-SB), Montreal Cognitive Assessment (MoCA), and Mini-Mental State Examination (MMSE) scores. Finally, a setting in which crosswalking is not appropriate is illustrated with plasma phosphorylated tau (p-tau) concentration and global cognitive measures.

DISCUSSION

Given the inconsistent collection and reporting of dementia and cognitive outcomes across studies, these crosswalking methods offer a valuable approach to harmonizing and comparing results reported on different scales.

Highlights

INTRODUCTION

Growing evidence suggests a connection between insulin resistance and apolipoprotein E (APOE) genotype in Alzheimer's disease (AD) pathogenesis, but the mechanisms are unclear. We examined effects of insulin resistance and APOE genotype on blood–brain barrier (BBB) integrity in AD.

METHODS

BBB integrity was measured in 196 biologically-confirmed non-diabetic patients with AD evaluating CSF/serum albumin ratio, kappa and lambda free light chains (FLCs). Insulin resistance was assessed using triglyceride–glucose index (TyG). The impact of TyG on BBB integrity, and its interaction with APOE genotypes, was analyzed using multivariate models.

RESULTS

Sixty-four percent of patients with AD showed altered TyG, with the 21.8% classified as high TyG. TyG subgroups were associated with BBB abnormalities, with similar AD clinical and biomarkers profile. A significant interaction between TyG and APOE ε4/ε4 genotype on BBB permeability was found in multivariate analyses.

DISCUSSION

Insulin resistance is a common feature in non-diabetic AD and correlates with altered BBB permeability, interacting synergistically with APOE genotype.

Highlights