Alzheimer's Research & Therapy最新文献

Background: With the clinical implementation of amyloid-targeting therapies, accurately differentiating Alzheimer's disease (AD) from other neurodegenerative dementias is imperative. This systematic review and meta-analysis synthesized data on the diagnostic performance of three plasma phosphorylated tau (p-tau) isoforms identified through a comprehensive literature search, namely p-tau181, p-tau217, and p-tau231.

Methods: We searched major databases up to November 30, 2025, for studies comparing blood p-tau levels in AD versus biologically confirmed non-AD neurodegenerative disorders. Data were synthesized using bivariate random-effects models to calculate pooled sensitivity, specificity, area under the curve (AUC), and diagnostic odds ratio (DOR).

Results: Thirty-three studies comprising 6,138 participants were included. Blood p-tau biomarkers demonstrated robust overall accuracy (AUC 0.90) and a high positive likelihood ratio (PLR 3.77). Comparison of isoforms revealed that plasma p-tau217 exhibited superior performance (AUC 0.95; Sensitivity 0.93) with a remarkable DOR of 57.98, which was nearly six-fold higher than that of p-tau231 (DOR 9.83). Subgroup analyses showed exceptional specificity for differentiating AD from behavioral variant frontotemporal dementia (bvFTD) (0.91) and vascular dementia (0.83), but discriminative ability against dementia with Lewy bodies (DLB) was significantly lower (Specificity 0.69; DOR 7.54). Furthermore, plasma-based assays (AUC 0.92, 95% CI 0.88-0.96) significantly outperformed serum-based methods (AUC 0.76, 95% CI 0.74-0.78), as evidenced by non-overlapping confidence intervals.

Conclusions: Plasma p-tau217 is the superior biomarker for the differential diagnosis of AD, particularly for ruling out FTD, though distinguishing AD from DLB remains challenging due to mixed pathology. The distinct superiority of plasma over serum supports the exclusive use of plasma-based protocols for clinical implementation.

The accumulation of pathogenic tau protein is linked to cognitive decline and neuronal loss in Alzheimer's disease (AD), with tau oligomers identified as particularly neurotoxic. The 51 kDa FK506-binding protein (FKBP51) stabilizes these toxic tau oligomers and has been identified as a risk factor for several neurodegenerative diseases. FKBP51 levels increase with age and are especially high in AD brains, suggesting its involvement in disease progression. The development of the selective FKBP51 inhibitor, SAFit2, which can cross the blood-brain barrier, has shown promise in reducing stress hormones, improving stress responses, and mitigating protein-related pathologies in other neurodegenerative models. However, the effects of SAFit2 on tauopathies, such as those seen in AD, have not yet been investigated. Here, the effects of the FKBP51-selective inhibitor, SAFit2, were evaluated in PS19 tau transgenic mice. Mice received a 28-day regimen of SAFit2, followed by comprehensive behavioral, neuropathological, and proteomic analyses. SAFit2 demonstrated effective brain penetrance, with sex-dependent pharmacokinetics. Treatment slowed cognitive decline and depressive-like behavior, with pronounced benefits in male PS19 mice, including improved spatial memory and reduced tau oligomer burden. In females, SAFit2 promoted clearance of AT8-positive tau multimers with some benefit to recognition memory. Proteomic profiling revealed distinct molecular signatures underlying these sex-specific responses: males exhibited upregulation of RNA processing and ribosomal proteins, while females showed restoration of calcium signaling and synaptic drivers. Notably, behavioral recovery occurred independently of widespread neuroinflammation reversal. These findings provide the first in vivo evidence that FKBP51 inhibition by SAFit2 induces sex-specific remodeling of the brain proteome. This study also provides further evidence for the therapeutic benefits of targeting FKBP51 for tauopathies.

Background: Sleep is essential for healthy bodily functioning in many aspects, including physiology, psychology and cognition. Due to the reverse causation, it remains inconclusive whether sleep disturbances contribute to Alzheimer's disease (AD). The purpose of this meta-analysis was to investigate the association between sleep disturbances and AD risk.

Methods: PubMed, Embase, and Web of Science were searched for longitudinal cohort studies until May 2025. Random-effects models were employed to pool risk ratios (RRs) with 95% confidence intervals (CIs).

Results: Of the 2106 records, 31 studies from East Asia (23%), Europe (32%), and North America (45%) were eligible for inclusion, involving 13,109,323 participants. The pooled effect size showed that sleep disturbances were linked to higher risk of AD (RR 1.40, 95% CI 1.29 to 1.51), with the magnitude attenuated but still significant through multivariate adjustment (adj-RR 1.29, 95% CI 1.18 to 1.42). Similar effects persisted even after reducing effects of reverse causation, as implemented by stratified analysis on mid-life cohorts and longer follow-ups (5-15: RR 1.35, 95% CI 1.01 to 1.81; ≥ 15 years: RR 1.26, 95% CI 1.02 to 1.57). Dose-response analysis revealed a U-shaped correlation, with sleep duration < 6 or > 8 h associated with AD risk elevation. Neither baseline age, follow-up length, nor study quality significantly diluted the observed association.

Conclusions: This study adds to evidence that sleep disturbances are relevant to incident AD, even in mid-life cohorts and longer follow-ups, supporting sleep disturbances as a mid-life risk factor of AD.

Background: Alzheimer's disease (AD) is associated with strong genetic predisposition and early synaptic loss that correlates with cognitive decline. While genetic determinants are thought to contribute to synaptic vulnerability, their precise role in AD pathogenesis at the synaptic level remains unclear. BIN1, a major AD susceptibility gene, is expressed in multiple isoforms, but isoform-specific effects at synapses have not been well defined.

Methods: We investigated the impact of human BIN1 isoforms on synaptic structure and function using Drosophila and mammalian models. In flies, we overexpressed human BIN1 isoforms in retinal photoreceptor neurons and motoneurons, assessing synaptic function by electrophysiology and ultrastructural analyses. Morphological changes at neuromuscular junctions were also quantified. For both readouts, Rab11 modulation was tested as a potential rescue strategy. To determine conservation in mammals and distinguish presynaptic versus postsynaptic roles, we overexpressed BIN1 isoform 1 selectively in presynaptic or postsynaptic compartments of rat hippocampal neurons cultured in microfluidic devices. We assessed structural and functional connectivity using immunofluorescence and microelectrode arrays.

Results: Gain-of-function of BIN1 isoform 1, but not isoforms 8 or 9, induced early loss of synaptic transmission in Drosophila photoreceptor neurons indicating BIN1iso1 synaptotoxicity. Structural analyses revealed accumulation of abnormally large vesicles in photoreceptor terminals, resembling BIN1-induced endosomal defects in cell bodies. Moreover, Rab11 gain-of-function prevented BIN1iso1 synaptotoxicity, suggesting that it originates from endosomal trafficking defects. In motoneurons, BIN1iso1 overexpression induced synapse remodelling, altering bouton morphology, including increased bouton number, reduced bouton size, and formation of satellite boutons. Rab11 modulation was additive to BIN1 isoform 1 effects, suggesting a distinct mechanism. In rat hippocampal neurons, BIN1 isoform 1 decreased synaptic connectivity only when overexpressed presynaptically, a finding confirmed by microelectrode array recordings.

Conclusions: Our findings demonstrate that BIN1iso1 exerts isoform-specific, presynaptic disruption during synapse development and maintenance that compromises synaptic integrity across species. BIN1iso1 synaptotoxicity may contribute to early synapse loss observed in AD and provides mechanistic evidence that genetic determinants such as BIN1 predispose synapses to failure. These results highlight BIN1iso1 as a potential target for therapeutic strategies aimed at preserving synaptic function in AD.

Introduction: Olfactory deficits, especially in odor identification (OID), have been linked to Alzheimer's disease (AD), likely due to regional proteinopathy and atrophy in the olfactory brain circuit. Their cognitive and biological correlates across the clinical spectrum, particularly in individuals with no evident cognitive impairment, have been underexplored. This examination is relevant because many individuals of this group will not progress to dementia, and olfactory deficits may reflect ongoing pathological processes and could enrich risk stratification.

Methods: We analyzed data from a cohort of 233 subjective cognitive impairment (SCI, n=152), mild cognitive impairment (MCI, n=50), and AD dementia (n=31) individuals from the Karolinska University Hospital Memory Clinic (Solna, Sweden). We examined the association of performance on the 16-item Sniffin' Sticks OID test (free and total [free or cued] identification scores) with a range of markers: cognitive performance, cerebrospinal fluid biomarkers, AD- and olfactory-related brain volumes, and white matter hyperintensities volume. We performed correlation analyses, generalized additive models, and threshold regressions, adjusted for sociodemographic factors and APOE status.

Results: OID performance was better in SCI compared to MCI and AD. Aβ42/40 ratio was positively associated with OID in SCI and AD, with APOE ε4 carriers driving this association in SCI. Hippocampal volume was positively associated with OID in AD. Higher volume of white matter hyperintensities was negatively associated with OID in MCI. The relationships of OID with Aβ42/40 and hippocampal volume were linear in the whole cohort. Worse verbal episodic memory performance was associated with lower OID scores only in the AD group. Free OID showed a broader and stronger pattern of associations with episodic memory and biomarkers compared with total OID. Threshold regression between free OID and Aβ42/40 identified a subthreshold value (<0.94) above the clinical cutoff (<0.86), capturing nine non-demented individuals within the gray zone between these cutoffs.

Conclusions: Our findings support an association between amyloid levels and olfactory performance in the AD spectrum, underscoring the potential of smell tests as cost-effective tools in multimodal stratification frameworks. In dementia stages, medial temporal atrophy accompanied by memory impairment may be the main correlate of olfactory deficits.

Background: The hallmark lesions of the Alzheimer's disease (AD) brain are amyloid plaques consisting of the β-amyloid protein and neurofibrillary tangles comprised of hyperphosphorylated, aggregated tau protein, which both cause neuronal dysfunction and loss. One goal of neuroprotective therapies is to maintain normal neuronal function and survival in the presence of toxic pathologies such as plaques and tangles. A potential neuroprotective target is nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor, which regulates the expression of many antioxidant and detoxification genes. Nrf2 mRNA is decreased in AD brains, and deletion of the Nrf2 gene causes increased BACE1 and Aβ production and worsened cognitive deficits in amyloid pathology mouse models. Overexpression of Nrf2 in astrocytes has been shown to be protective against neurodegeneration, but the role of Nrf2 is neurons is unclear.

Methods: We overexpressed Nrf2 from birth in neurons of 5XFAD amyloid pathology model mice using AAV8, hypothesizing that neuronal Nrf2 overexpression decreases cortical neuron loss and reduces plaque load by decreasing BACE1 levels. We quantified protein levels by immunoblot and neuropathology by immunofluorescent staining, using two-way ANOVA to measure differences between genotypes and AAV treatments. To assess genetic changes, we performed bulk mRNA seq.

Results: While neuronal overexpression of Nrf2 in 5XFAD mice did not prevent neuronal loss as measured by NeuN labeling, decrease neuroinflammation by Iba1 or GFAP labeling, or reduce amyloid load by Aβ antibody or methoxy-XO4 staining, we show that increased Nrf2 expression reduces BACE1 protein levels, especially in swollen axonal dystrophic neurites around amyloid plaques. Other proteins that accumulate in dystrophic neurites were also reduced, indicating decreased dystrophic neurites overall. Immunoblot analysis suggested increased autophagy was unlikely to play a role, while bulk mRNA sequencing indicated changes in lipid metabolism and microtubule stability may have contributed to reduced dystrophic neurite formation.

Conclusions: Dystrophic neurites impair action potential conductance and contribute to tau seeding and spreading. Their reduction by neuronal Nrf2 overexpression may protect neurons against these pathologic changes. Further study of the mechanisms by which Nrf2 reduces dystrophic neurites may lead to therapeutic strategies that can limit neuritic damage caused by cerebral amyloid accumulation.

Purpose: White matter (WM) signal on ¹⁸F-florbetapir positron emission tomography (PET) is often regarded as nonspecific, yet its biological significance remains unclear. This study aimed to characterize the trajectory, clinical significance, and biomarker correlates of normal-appearing white matter (NAWM) ¹⁸F-florbetapir retention across the Alzheimer's disease (AD) continuum.

Methods: We analyzed NAWM ¹⁸F-florbetapir retention in 672 participants across the AD continuum from the Alzheimer's Disease Neuroimaging Initiative and two Chinese cohorts. Longitudinal PET, plasma, and cerebrospinal fluid (CSF) biomarkers, as well as lecanemab treatment effects, were evaluated.

Results: NAWM retention followed a distinct trajectory from cortical amyloid, increasing during preclinical stages and plateauing in symptomatic phases. Elevated NAWM ¹⁸F-florbetapir retention independently predicted cognitive decline, correlated with plasma p-tau217 and CSF p-tau/Aβ42 ratio, and showed significant reductions following lecanemab therapy. Combined assessment of cortical and NAWM PET improved diagnostic accuracy for amyloid positivity to 92%. NAWM retention also correlated strongly with plasma and CSF biomarkers in preclinical stages, and mediation analyses indicated that these fluid markers partly explained NAWM-cognition associations.

Conclusion: NAWM ¹⁸F-florbetapir retention represents a biologically valid and dynamic biomarker of AD progression, with potential utility for early detection, prognostication, and therapeutic monitoring.

Background: Early recognition of Alzheimer's disease (AD) is crucial for timely intervention and delaying disease progression. Electroencephalogram (EEG) technology provides a direct reflection of the brain's dynamic activity. However, the relationship between potential EEG features and cognitive function in early-stage AD patients, as well as cerebrospinal fluid (CSF) pathological biomarkers, remains unclear.

Methods: This study included 101 patients with mild cognitive impairment (MCI) and mild AD, alongside 69 healthy controls (HC) matched for gender, age, and educational attainment. Extracting EEG power spectral density (PSD) and microstates analysis features as training features for machine learning (ML), we employed five ML algorithms-Support Vector Machines (SVM), Logistic Regression (LR), Random Forests (RF), XGBoost, and LightGBM-for training and testing. Model performance was assessed using the area under the receiver operating characteristic curve (AUC). SHapley Additive exPlanations (SHAP) plots were employed to elucidate variable importance within the model, and sequential forward selection (SFS) was utilised to identify potential features. Correlation analysis and mediation analysis were conducted to investigate the relationships between EEG features, CSF pathological biomarkers, and cognitive function.

Results: The LR model demonstrated the highest average predictive performance in the training set (mean AUC = 0.859 ± 0.059). The model incorporating PSD and microstates features demonstrated optimal predictive performance in the test set (AUC = 0.949, 95% CI: 0.877-1.000), outperforming any single-feature model. Based on SHAP and SFS analyses, six potential EEG indicators were identified: central region delta frequency band, central region theta frequency band, temporal region beta frequency band, microstate mean duration, microstate C duration, and the transition probability from microstate C to A. Mediation analysis revealed a significant negative correlation between central region theta frequency band and CSF Aβ₁₋₄₂ levels (r = - 0.31, p = 0.015), and the central region theta frequency band mediated the relationship between Aβ₁₋₄₂ levels and Mini-Mental State Examination (MMSE) scores (indirect effect = 0.0007, 95% CI: 0.0001-0.0013).

Conclusion: The combined application of EEG and ML enables efficient classification diagnosis of early-stage AD, and EEG is correlated with intracerebral pathological biomarkers and cognitive impairment.