Alzheimer's & Dementia最新文献

INTRODUCTION

Associations of short-term use of menopausal hormone therapy (mHT) with Alzheimer's disease (AD) and structural magnetic resonance imaging (MRI) biomarkers were investigated 10 years after an mHT trial.

METHODS

Recently menopausal women with good cardiovascular health were randomized to oral conjugated equine estrogens (oCEE) or transdermal 17β-estradiol (tE2) and micronized progesterone, or placebo for 4 years. Amyloid beta (Aβ) on positron emission tomography, hippocampal atrophy, and dorsolateral prefrontal cortex thickness on MRI were assessed 10 years after completion of the mHT trial (n = 266).

RESULTS

Aβ and structural MRI biomarkers were not different in the oCEE and tE2 groups compared to placebo. Apolipoprotein E ε4 status did not modify the findings.

DISCUSSION

There was no evidence of adverse effects or benefits associated with 4 years of use of oral or transdermal mHT on Aβ and structural MRI biomarkers in relatively healthy women, 10 years after mHT. Findings support the long-term safety of short-term use of mHT on brain health.

CLINICAL TRIALS REGISTRATION

NCT00154180 Kronos Early Estrogen Prevention Study (KEEPS)

Highlights

Alzheimer's disease (AD) research has entered a new era where public-private partnerships are reigniting the pursuit of disease-modifying therapies targeting mechanisms beyond amyloid and tau. This perspective outlines how Monument Biosciences was founded to advance novel therapies by translating National Institutes of Health (NIH) -supported discoveries from the TaRget Enablement to Accelerate Therapy Development for AD (TREAT-AD) and the Model Organism Development and Evaluation for Late-onset AD (MODEL-AD) consortia into a venture-backed pipeline focused on neuroinflammation. Monument Bio strategically builds on genetic validation and high-quality, nondilutive-funded research and serves as a case study in how academic research can reduce risk in early-stage biotech development to advance novel therapies. The company exemplifies a novel academic-startup collaboration model, emphasizing robust biomarker strategies to streamline clinical development. Aligned with the framework presented by Richardson et al., in this issue, this approach supports a new generation of neuroscience companies grounded in open science, strong target validation, and disease-relevant endpoints.

Highlights

INTRODUCTION

Choroid plexus (ChP) enlargement is a neuroimaging biomarker of neuroinflammation and neurodegeneration. However, evidence of ChP structural and perfusion alterations in long coronavirus disease (COVID) and their clinical relevance remains limited.

METHODS

This study included 86 long COVID, 67 recovered COVID, and 26 COVID-negative healthy controls (HCs). ChP volume and cerebral blood flow (CBF) were quantified, and their associations with Alzheimer's disease (AD) symptoms and plasma biomarkers were examined.

RESULTS

Both patient groups showed higher ChP volume and lower CBF than HC. Relative to recovered COVID, long COVID patients had a larger ChP volume, but no significant difference in CBF. ChP volume correlated positively with glial fibrillary acidic protein (r = 0.35) and phosphorylated tau217 (p-tau217; r = 0.54), while CBF correlated negatively with p-tau217 (r = –0.56). Both ChP volume and CBF were associated with cognitive decline measured with Mini-Mental State Examination and Clinical Dementia Rating.

DISCUSSION

These findings suggest that ChP differences in long COVID are associated with AD-related cognitive decline and increased plasma biomarkers.

Highlights

INTRODUCTION

While current blood-based biomarkers for Alzheimer's disease (AD) are effective for determining amyloid beta (Aβ) pathology positivity/negativity, they are insufficient for quantifying Aβ plaque deposition.

METHODS

We profiled 325 plasma proteins in a Hong Kong Chinese cohort using the Nucleic Acid Linked Immuno‑Sandwich Assay (NULISAseq) platform. We analyzed the dysregulation trajectories of the blood proteome along Aβ pathology progression and used machine learning to develop a biomarker panel to quantify Aβ pathology.

RESULTS

We identified 43 blood proteins correlated with Aβ plaque accumulation and selected 8 proteins to construct a model. This model was strongly correlated with amyloid positron emission tomography Centiloid values (r = 0.89), enabling quantification of Aβ deposition and classification of early-stage pathology (area under the curve = 0.93).

DISCUSSION

This study provides a systematic profile of dynamic protein alterations during Aβ pathology progression. Moreover, we developed a biomarker assay that accurately quantifies Aβ pathology, offering a potential tool to facilitate early screening and monitoring of amyloid pathology.

INTRODUCTION

We investigated stage-specific alterations in functional connectivity (FC) of the default mode network (DMN) across the Alzheimer's disease (AD) continuum and tested whether early amyloid beta (Aβ)–related changes in within-DMN FC (DMN-FC_within) predicted longitudinal alterations in DMN between-network connectivity (DMN-FC_between).

METHODS

Resting-state functional magnetic resonance imaging (fMRI) data were analyzed from 396 older adults: Aβ-negative cognitively normal (CN−, n = 213), Aβ-positive CN (CN+, n = 37), Aβ-positive mild cognitive impairment (MCI+, n = 72), and Aβ-positive dementia (dementia+, n = 74). Cross-sectional analyses compared DMN-FC across groups and examined associations with continuous Aβ burden at baseline. Longitudinal analyses in 171 CN participants with 2-year follow-up (CN−, n = 147; CN+, n = 24) tested whether baseline DMN-FC_within predicted changes in DMN-FC_between.

RESULTS

CN+ individuals showed elevated DMN-FC_within and reduced DMN-FC_between relative to other groups. In CN, Aβ burden was associated with FC, and baseline DMN-FC_within predicted longitudinal increases in DMN-FC_between only in CN+.

DISCUSSION

Aβ-related hyperconnectivity characterizes preclinical AD and may drive progressive network-level vulnerability.

Highlights

INTRODUCTION

The apolipoprotein E ε4 (APOE ε4) allele is a major genetic risk factor for Alzheimer's disease, but its relevance to cognition in intracranial atherosclerosis (ICAS) remains unclear. We investigated the association between APOE ε4 and cognition in ICAS.

METHODS

Baseline data from a multicenter cohort were analyzed. Patients with radiologically confirmed ICAS underwent APOE genotyping, plasma biomarker assays, magnetic resonance imaging assessment of cerebral small vessel disease (CSVD) and brain atrophy, and standardized cognitive testing.

RESULTS

Among 409 patients (mean age 60 years, 55% male), 16% carried APOE ε4. Carriers showed more frequent cognitive impairment (63% vs 48%), greater stenosis burden, and lower plasma amyloid beta (Aβ)42/40 ratios, whereas other Alzheimer's biomarkers, CSVD burden, and atrophy scores showed no difference. After adjustment, APOE ε4remained associated with cognitive impairment (odds ratio [OR] 1.86). The association was pronounced in women (OR 4.43) but absent in men.

DISCUSSION

APOE ε4 is linked to cognitive impairment in ICAS, particularly in women, through mechanisms beyond Alzheimer's pathology.

Highlights