Alzheimer's & Dementia最新文献

Introduction: Elevated plasma homocysteine (Hcy) is associated with an increased risk of developing neurodegenerative diseases; however, its relationship with the apolipoprotein E (APOE) ε4 allele has not been well characterized.

Methods: Participants clinically diagnosed with Alzheimer's disease or mild cognitive impairment (AD/MCI), frontotemporal dementia, Parkinson's disease, or cerebrovascular disease were stratified by the presence of the APOE ε4 allele. Volumetric magnetic resonance imaging, plasma amyloid/tau/neurodegeneration biomarkers, and cognitive performance were quantified.

Results: Across all diagnostic groups, Hcy was associated with lower brain parenchymal fraction and greater neurofilament light chain in APOE ε4 non-carriers only. In AD/MCI, Hcy was associated with phosphorylated tau 217 in APOE ε4 non-carriers, but not in carriers. Exploratory analyses revealed interactions between Hcy and APOE ε4 on memory and visuospatial function.

Discussion: Hcy may contribute to neurodegeneration depending on the presence of the APOE ε4 allele and specific disease processes. Trials on vitamin B12 supplementation may consider stratifying by APOE genotype. Highlights Homocysteine (Hcy) was associated with neurodegenerative biomarkers across disease groups. Relationships with Hcy were predominantly found in apolipoprotein E (APOE) ε4 non-carriers. In Alzheimer's disease, associations between Hcy and phosphorylated tau 217 were found in APOE ε4 non-carriers only. Significant interactions existed between Hcy and APOE ε4 status on cognition.

Introduction: Progression to Alzheimer's disease (AD) dementia from normal cognition (NC) can follow different trajectories, with most progressing through a recognizable mild cognitive impairment stage (NC-MCI-AD), while some individuals transition quickly from NC to AD dementia (NC-AD).

Methods: We compared demographic characteristics, health factors, and cognitive and functional assessments across three time points: the first NC visit, the last NC visit, and the first AD dementia visit.

Results: The NC-MCI-AD group showed greater impairment in cognitive and functional scores at AD dementia diagnosis, despite maintaining better cognitive function during the NC stage. Analysis of yearly changes revealed negligible differences during NC. However, the yearly change during the AD dementia stage suggested potentially more rapid functional decline in the NC-AD group.

Discussion: These findings highlight the heterogeneity in AD disease progression and emphasize the importance of considering diverse progression patterns in AD research and clinical practice.

Highlights: We investigated the disease progression difference between patients who converted to Alzheimer's disease (AD) dementia from normal cognition (NC) directly or through the mild cognitive impairment (MCI) stage. We found that the NC-MCI-AD group showed greater impairment in cognitive and functional scores at AD dementia diagnosis. We discovered that the NC-AD group had rapid functional decline once patients were confirmed with AD onset.

Introduction: Neighborhood environments may promote neurocognitive health in part by providing amenities that encourage physical activity. We examined associations between quantity of walkable facilities, including specifically physical activity facilities (e.g., gyms, recreation centers), with risk of incident dementia.

Methods: Participants included 2923 adults ≥ 65 years old from the Cardiovascular Health Cognition Study (1992-1999), with clinically adjudicated dementia classified over a median 6.0 years of follow-up. Walkable facilities were measured within 1 km (Euclidean) of home. Self-reported baseline physical activity was considered a moderator.

Results: In adjusted Cox models, participants with ≥ 2 (vs. 0) physical activity facilities had reduced risk of mixed/vascular dementia, but not Alzheimer's disease, particularly after excluding individuals in the bottom 20th percentile of physical activity (hazard ratio = 0.56, 95% confidence interval: 0.35-0.89).

Discussion: Neighborhood amenities that encourage physical activity may mitigate dementia risk via improved vascular health, especially for individuals with sufficient baseline mobility to use these resources.

Highlights: We examined associations between nearby walkable facilities and incident dementia. Facilities within 1 km were counted via the National Establishment Time Series Database. More physical activity facilities predicted lower risk of mixed/vascular dementia. No associations were found between walkable facilities and incident Alzheimer's disease.

Introduction: A key goal of the Alzheimer's Disease NeuroImaging Initiative (ADNI) positron emission tomography (PET) Core is to harmonize quantification of β-amyloid (Aβ) and tau PET image data across multiple scanners and tracers.

Methods: We developed an analysis pipeline (Berkeley PET Imaging Pipeline, B-PIP) for ADNI Aβ and tau PET images and applied it to PET data from other multisite studies. Steps include image pre-processing, refacing, magnetic resonance imaging (MRI)/PET co-registration, visual quality control (QC), quantification of tracer uptake, and standardization of Aβ and tau standardized uptake value ratios (SUVrs) across tracers.

Results: Measurements from 10,105 cross-sectional and longitudinal Aβ and tau PET scans acquired in several studies between 2010 and 2024 can be processed, harmonized, and directly merged across tracers and cohorts.

Discussion: The B-PIP developed in ADNI is a scalable image harmonization approach used in several observational studies and clinical trials that facilitates rigorous Aβ and tau PET quantification and data sharing.

Highlights: Quantitative results from ADNI Aβ and tau PET data are generated using a rigorous, scalable image processing pipeline This pipeline has been applied to PET data from several other large, multisite studies and trials Quantitative outcomes are harmonizable across studies and are shared with the scientific community.

Introduction: Marmosets spontaneously develop pathological hallmarks of Alzheimer's disease (AD) including amyloid beta plaques. However, tau expression in the marmoset brain has been understudied.

Methods: Isoforms of tau were examined by western blot, mass spectrometry, immunofluorescence, and immunohistochemical staining.

Results: 3R and 4R tau isoforms are expressed in marmoset brains at both the transcript and protein levels across ages. Mass spectrometry analysis revealed that tau peptides in marmoset corresponded to the 3R and 4R peptides in human brain, with 3R predominating at birth and an ≈40%:60% 3R:4R ratios in adolescents and adults; tau was distributed widely in neurons, with localization in the soma and synaptic regions. Phosphorylation residues were observed on Threonine (Thr) Thr181, Thr217, Thr231, Serine (Ser) Ser202/Thr205, and Ser396/Ser404.

Discussion: Our results confirm both 3R and 4R tau isoform expression and phosphorylation residues in the marmoset brain, and emphasize the significance of marmosets with natural expression of AD-related hallmarks as important translational models for AD. Highlights We report comprehensive characterization of tau isoform expression in marmoset brains across the lifespan. 3R and 4R tau isoforms are expressed in marmoset brains at both the transcript and protein levels across ages. These data emphasize the significance of marmosets with natural expression of primate-specific traits that are important for the study of Alzheimer's disease.

Background: Approximately 40% of people aged ≥ 65 experience memory loss, particularly in episodic memory. Identifying the genetic basis of episodic memory decline is crucial for uncovering its underlying causes.

Methods: We investigated common and rare genetic variants associated with episodic memory decline in 742 (632 for rare variants) Ashkenazi Jewish individuals (mean age 75) from the LonGenity study. All-atom molecular dynamics simulations were performed to uncover mechanistic insights underlying rare variants associated with episodic memory decline.

Results: In addition to the common polygenic risk of Alzheimer's disease, we identified and replicated rare variant associations in ITSN1 and CRHR2. Structural analyses revealed distinct memory pathologies mediated by interfacial rare coding variants such as impaired receptor activation of corticotropin releasing hormone and dysregulated L-serine synthesis.

Discussion: Our study uncovers novel risk loci for episodic memory decline. The identified underlying mechanisms point toward heterogenous memory pathologies mediated by rare coding variants.

Highlights: We demonstrated the contribution of the common polygenic risk of Alzheimer's disease to episodic memory decline. We discovered and replicated two risk genes associated with episodic memory decline implicated by rare variants, were discovered and replicated. We demonstrated molecular mechanisms and potential novel memory pathologies underlying interfacial rare coding variants. Molecular dynamics simulations were performed to understand the downstream effects of risk rare coding variants.

Introduction: Patterns of signal from tau positron emission tomography (tau-PET) confined to the medial temporal lobe (MTL) or extended into the neocortex may be relevant for Alzheimer's disease (AD) research if they are linked to differential biomarker levels and cognitive decline.

Methods: Visual assessment of Tau-PET [F-18]florquinitau (FQT) exams from 728 initially non-demented older adults yielded four uptake groups: tau-negative (T-), MTL-only (T+_MTL), neocortex-only (T+_Neo), or both (T+_MTL&Neo). Mixed effects models assessed group differences in retrospective cognitive and plasma pTau217 trajectories.

Results: T+_MTL&Neo was the most common T+ group (n = 97; 93% A+) and exhibited the sharpest worsening in cognitive and pTau217 trajectories before tau PET.

Discussion: The T+_MTL&Neo category represents an intermediate to advanced stage of AD preceded by rising ptau217 and progressive cognitive decline. The pTau217 finding suggests that A+, T+ in MTL or neocortex could represent early AD stages, with a higher likelihood of progressing to more advanced stages.

Highlights: Visual assessments of Tau-PET FQT revealed four distinct uptake groups: tau-negative (T-), MTL-only (T+_MTL), neocortex-only (T+_Neo), or both (T+_MTL&Neo). Amyloid positive participants in the T+_MTL and T+_MTL&Neo categories showed a retrospectively faster decline in their cognitive trajectories, and a sharper increase in pTau217 levels in plasma, compared to T-. The T+_MTL&Neo group displayed sharper trajectories compared with the other Tau positive groups in both their cognitive scores and pTau217 plasma levels. Our results suggest that participants with Tau present in both MTL and neocortex represent an intermediate to advanced stage of AD, whereas participants with signals confined to either MTL or neocortex could represent earlier AD stages.

Introduction: Older adults with mild cognitive impairment (MCI) exhibit deficits in cerebrovascular reactivity (CVR), suggesting CVR is a biomarker for vascular contributions to MCI. This study examined if spontaneous CVR is associated with MCI and memory impairment.

Methods: One hundred sixty-one older adults free of dementia or major neurological/psychiatric disorders were recruited. Participants underwent clinical interviews, cognitive testing, venipuncture for Alzheimer's disease (AD) biomarkers, and brain magnetic resonance imaging. Spontaneous CVR was quantified during 5 minutes of rest. Respiratory gases analyzed through nasal cannula to quantify end-tidal carbon dioxide (_ETCO₂) levels were used to estimate CVR.

Results: Whole brain CVR was negatively associated with age, but not MCI. Lower CVR in the parahippocampal gyrus (PHG) was found in participants with MCI and was linked to worse memory performance on memory tests. Results remained significant after adjusting for AD biomarkers and vascular risk factors.

Discussion: Spontaneous CVR deficits in the PHG are observed in older adults with MCI and memory impairment, suggesting medial temporal microvascular dysfunction is observed in cognitive decline.

Highlights: Aging is associated with decline in whole brain spontaneous cerebrovascular reactivity (CVR). Older adults with mild cognitive impairment exhibit deficits in spontaneous CVR in the parahippocampal gyrus (PHG). Memory impairment is correlated with reduced spontaneous CVR in the PHG.

Introduction: Cardiovascular drug use may help prevent dementia; however, current evidence is mixed. Using a case-control design, we investigated the association between duration and combination of multiple cardiovascular drug classes and incident dementia.

Methods: From the Swedish national registers, we included 88,065 incident dementia cases aged ≥ 70 at diagnosis between 2011 and 2016 and 880,650 age- and sex-matched controls. Cardiovascular drug use was ascertained from the Prescribed Drug Register.

Results: Long-term users (≥ 5 years) of antihypertensives, diuretics, lipid-lowering drugs (LLDs), and oral anticoagulants (OACs) had statistically significantly fewer dementia diagnoses (odds ratio [OR] 0.75-0.91) than non-users. Antiplatelets use was associated with more dementia diagnoses (OR 1.13-1.25). Use of antihypertensives in combination with diuretics, LLDs, and OACs for ≥ 5 years was associated with fewer dementia diagnoses (OR 0.66-0.84).

Discussion: Preventing dementia via cardiovascular drug pathways may be possible. It is however important to consider the potential long-term negative cognitive effect of antiplatelets.

Highlights: Use ≥ 5 years of common cardiovascular drugs was associated with lower dementia risk. Common cardiovascular drug combination use was associated with lower dementia risk. Anti-platelet use of any duration was associated with higher dementia risk.