BackgroundApathy, defined as a quantitative reduction in goal-directed activity, is a non-motor manifestation that can be present in Parkinson's disease (PD). It seems to be a risk factor for conversion to dementia (PDD) in this population. Amyloid-β deposition also predicts progression to PDD.ObjectiveWe aimed to investigate whether PD patients with apathy showed higher amyloid burden than those without, as well as how these features may influence the rate of progression to dementia.MethodsWe conducted an observational cross-sectional and longitudinal study. Forty-eight PD patients were recruited, including 20 with apathy and 28 without it according to the Starkstein Apathy Scale. They underwent clinical and cognitive evaluations and [18F]-Flutemetamol PET. The neuropsychological assessment was repeated after 3 years. The predictive value of apathy and amyloid burden for conversion was assessed via logistic regression. Longitudinal trajectories across neuropsychological tests were modeled with linear mixed-effects.ResultsPatients with apathy showed worse performance on several cognitive domains. Using disease duration and global cognition Z-score as covariates, amyloid burden was higher in apathetic vs. non-apathetic patients, mainly in the frontal and temporal cortices. Non-apathetic patients did not have regions with higher amyloid burden in comparison with apathetic patients. After 3 years' follow-up, the conversion rate to worse cognitive state was significantly higher in apathetic (47.4%) vs. non-apathetic (12.0%) patients (p < 0.05). Logistic regression showed that amyloid burden, but not apathy, predicted 3-year cognitive conversion (χ² = 9.95, p < 0.05).ConclusionsApathetic patients exhibit greater amyloid burden and higher cognitive deterioration over time than their non-apathetic counterparts.

Directly compare the brain glucose patterns seen with [F-18] fluorodeoxyglucose (FDG) positron emission tomography (PET) between 2 genetically determined forms of Alzheimer's disease: Down syndrome (DS) and autosomal dominant Alzheimer's disease (ADAD). Cross-sectional analyses of FDG were performed in individuals with DS (n = 76) from the Alzheimer Biomarker Consortium-Down Syndrome (ABC-DS), ADAD (n = 297), and neurotypical familial controls (n = 188) from the Dominantly Inherited Alzheimer Network (DIAN). Within-group linear regression models and generalized additive models were performed for select regional FDG uptake measures (isthmus cingulate and inferior parietal, precuneus, middle temporal gyrus, and precentral gyrus). Age, sex, apolipoprotein (APOE) ε4 carrier status, and cortical amyloid burden were included within these analyses. Even 20 years before expected onset of clinical symptoms, FDG uptake was lower for DS compared to neurotypical familial controls (p < 0.01). ADAD baseline FDG was similar to neurotypical familial controls until 7 years before expected symptom onset. Both symptomatic individuals with DS and ADAD had lower FDG compared to neurotypical familial controls (p < 0.01). A higher amyloid burden was associated with lower FDG for both genetic forms, with similar rates of decline in FDG uptake for DS and ADAD who were amyloid positive. Brain glucose metabolism is substantially lower for people with DS, even in individuals who are cognitively stable. The patterns of FDG decline are distinct in these 2 genetically determined forms of AD. The diagnostic utility of FDG-PET is specific to the genetic form of AD. ANN NEUROL 2025;98:1237-1248.

Blood-based biomarkers (BBMs) demonstrate high accuracy in detecting Alzheimer disease (AD) pathological changes in symptomatic individuals. In autosomal dominant AD and in individuals with Down syndrome, both populations with near-universal development of AD pathology, elevations in BBMs are detectable years before clinical onset, supporting their utility for identifying preclinical disease in these cases. Among BBMs, plasma phosphorylated tau 217 (p-tau217) exhibits strong concordance with established in vivo markers of AD pathology. However, its ability to identify older adults without cognitive impairment who are amyloid-positive remains variable across studies and settings. To assess the standardized effect size of mean differences and classification accuracy of p-tau217 for published studies that compared amyloid-positive and amyloid-negative older adults without cognitive impairment. PubMed, Embase, and EBSCOhost databases from inception to September 1, 2025. Observational studies or randomized clinical trials with baseline data on individuals without cognitive impairment who were classified as either amyloid positive or amyloid negative and reported numeric data for p-tau217 levels. The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) reporting guideline was used for this study. Two authors independently carried out literature searches to identify studies with older adults without cognitive impairment who were classified as either amyloid positive or amyloid negative where p-tau217 was quantified. The standardized mean difference (Hedges g) was used to characterize differences in mean p-tau217 levels. A pooled area under the curve (AUC) value was used to summarize the diagnostic accuracy of p-tau217 in identifying amyloid-positive individuals. Between-study heterogeneity was investigated using subgroup and sensitivity analyses. Publication bias was assessed using Egger tests. Data for 7834 participants (2533 amyloid positive, 5301 amyloid negative) from 18 publications were analyzed. A large effect size was observed for p-tau217 (Hedges g = 1.50; 95% CI, 1.33-1.68). Values for p-tau217 also demonstrated high accuracy for identifying amyloid-positive individuals without cognitive impairment (AUC = 0.87; 95% CI, 0.85-0.90). These findings demonstrate that plasma p-tau217 can reliably detect AD pathology in the preclinical stage. These findings support the clinical utility of plasma p-tau217 as a scalable, minimally invasive tool for early identification of AD, particularly in settings where timely intervention with disease-modifying therapies may offer the greatest benefit in slowing or preventing disease progression.

Subjective cognitive decline (SCD) serves as an initial symptom of preclinical Alzheimer's disease (AD). The accumulation of amyloid-beta (Aβ) is acknowledged as a critical risk factor for the eventual progression to mild cognitive impairment or dementia in individuals with SCD, highlighting the necessity for early detection and intervention. Previous studies have identified the retina and choriocapillaris as potential biomarkers for AD; however, these investigations have not thoroughly examined large and medium-sized choroidal vessels. Ultra-wide swept-source optical coherence tomography angiography (SS-OCTA), an innovative noninvasive imaging modality, facilitates rapid and precise quantitative assessment of retinal and choroidal boundaries and vasculature through dynamic scanning, encompassing large and medium-sized choroidal vessels. This study aims to characterize the outer retinal and choroidal vasculature and structure in individuals with SCD, examine the correlation between altered choroidal vasculature parameters and amyloid burden, and the presence of the apolipoprotein E (APOE) ε4 allele in SCD participants, to identify potential ocular biomarkers for high-risk SCD screening. In this study, 57 individuals with SCD and 45 matched normal controls were enrolled. Ultra-wide SS-OCTA was employed to assess the thickness of the outer retina and choroid and the blood flow within the choriocapillaris and large, medium-sized choroidal vessels. 18F-Florbetapir positron emission tomography scans were performed to classify amyloid-positive-SCD (Aβ + SCD) and amyloid-negative-SCD (Aβ-SCD) groups. Plasma Aβ42/40 and APOE ε4 genotypes were also measured. Compared with normal controls, individuals with SCD exhibited a significant increase in the choroidal vessel index and a reduction in outer retinal thickness. The Aβ + SCD group demonstrated an elevated choriocapillaris flow area relative to the Aβ- SCD group. Moreover, a negative correlation was observed between the choriocapillaris flow area and plasma Aβ42/40 levels in the SCD cohort. Among SCD participants, APOE ε4 carriers displayed increased choriocapillaris flow area and choroidal vessel volume compared to APOE ε4 non-carriers. Our findings provide intriguing insights into the relationship between amyloid pathology and changes in the choriocapillaris flow area. The choroid may serve as a potential biomarker for screening Aβ + SCD.

Transthyretin cardiac amyloidosis (ATTR-CM) is a progressive, underdiagnosed disease with high morbidity and mortality. While disease-modifying therapies (DMTs) slow progression, early treatment response markers remain scarce. This study assessed AI-quantified thoracic [99mTc]Tc-DPD SPECT/CT markers as potential non-invasive biomarkers for monitoring therapeutic efficacy. This longitudinal study included ATTR-CM patients receiving DMTs (transthyretin stabilizers, RNA interference, or antisense oligonucleotides). [99mTc]Tc-DPD SPECT/CT scans were acquired at baseline and after treatment (median interval 9 months, IQR 7-10). AI-driven segmentation and quantification extracted 26 markers (SUV metrics, retention index, amyloid-affected volume, and amyloid activity). Functional, clinical, and blood parameters, as well as clinical outcomes, were evaluated for their association with changes in imaging markers. In 45 patients (37 ATTRwt-CM, 8 ATTRv-CM), 65% (17/26) of AI-extracted SPECT/CT markers significantly decreased after treatment (all p < 0.001), including SUVmax reductions in the left ventricle (18.6 to 14.1) and myocardium (19.5 to 15.5). None of the markers significantly increased (p > 0.05). Six of the imaging markers, most notably SUVpeak (p = 0.007) of the myocardium and amyloid activity of the left ventricle (p = 0.009), were associated with reductions in NT-proBNP. Lower values for three markers, including amyloid activity of the myocardium, retention index, and SUVmean of the left atrium (all p = 0.016), were associated with improved NYHA class. An increase in amyloid-affected volume of the right ventricle (HR 3.19, 95% CI [1.29; 7.86], p = 0.005) and a decrease in right ventricular SUVmean (adjHR 0.15 95% CI [0.02;1.10], logrank p = 0.030) were associated with death or heart failure-associated hospitalization before and after multivariate adjustment. AI-driven analysis extracted imaging markers substantially faster and eliminated inter-rater variability. AI-driven [99mTc]Tc-DPD SPECT/CT analysis effectively detects treatment-induced reductions in cardiac amyloid burden, offering a non-invasive biomarker for early response assessment in ATTR-CM. AI-enabled imaging markers enhance reproducibility and efficiency, providing valuable support for personalized treatment strategies as new therapeutic options for ATTR-CM become available.

Proteins tend to misfold upon stressful events that alter their homeostasis, potentially leading to protein aggregation. A tight regulation of synthesis, folding and degradation, defined as proteostasis network (PN), is required to ensure the functionality of the cell. PN is of utmost importance in post-mitotic cells such as neurons, where protein quality must be preserved for their entire lifetime. Most neurodegenerative disorders are associated with dysregulation of this network. Here, we describe the alteration in key components of the PN during chronic stress and link them with the increase in the amyloid burden and with the aggregation of the protein TDP-43, a major player in Amyotrophic Lateral Sclerosis and other neurodegenerative diseases. Neuroblastoma SH-SY5Y cells were treated with a panel of environmental stressors and analyzed after 24 h and 72 h. Treatments resulted in altered PN functionality, including proteasome impairment, halted protein synthesis, engulfed bulk and selective autophagy, in the absence of overt cell death. Thioflavin staining showed increased amyloid burden throughout treatments, associated with phosphorylated TDP-43 (pTDP-43). Biochemical analyses further revealed the cleavage and increased insolubility of pTDP-43. Our results suggest that TDP-43 is a central player during the integrated stress response to chr onic insults and that increased amyloid burden may reflect the global wellfare of a cellular system, pointing toward the alteration of the PN as the main drive for the onset of sporadic neurodegenerative disorders.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00018-025-05884-6.

INTRODUCTIONShort‐chain fatty acids (SCFAs), produced by gut microbes, influence Alzheimer's disease (AD) pathology in animals. Less is known about SCFAs and AD in humans. We profiled feces of adults along the AD continuum to investigate gut microbiome and SCFA associations with AD pathology and cognition.METHODSWe measured SCFAs and bacterial abundances in fecal samples from 287 participants in the Wisconsin Alzheimer's Disease Research Center and Wisconsin Registry for Alzheimer's Prevention. We performed regressions examining associations between SCFAs or gut microbes and AD pathology and cognition.RESULTSFecal propionate, isovalerate, and propionate‐producing bacteria are inversely associated with amyloid status. Mediation analysis found that propionate mediates sex‐specific associations between SCFAs and cerebrospinal fluid biomarkers. SCFA levels are associated with slower cognitive decline.DISCUSSIONThese results link SCFAs and propionate‐producing bacteria with AD. This may inform efforts to leverage diet and specific bacteria to boost SCFA production and potentially ameliorate AD progression.HighlightsFecal SCFAs link to lower amyloid burden and microglial activation, notably in females.SCFA‐producing gut microbes have reduced abundance in amyloid‐positive participants.Fecal propionate mediates relationships between gut microbes and amyloid status.SCFAs are associated with slower plasma pTau217 accumulation in females.SCFAs are associated with slower cognitive decline.

INTRODUCTIONPlasma glial fibrillary acidic protein (GFAP), a marker of astrocytic activation, has been linked to Alzheimer's disease; however, its prognostic value in cognitively unimpaired (CU) individuals remains unclear.METHODSWe included 949 CU older adults from the A4 preclinical AD trial and its companion LEARN cohort. Baseline plasma GFAP was measured, and associations with cognitive decline (Preclinical Alzheimer's Cognitive Composite [PACC]), Clinical Dementia Rating (CDR) progression, and imaging biomarkers were assessed over 240 weeks.RESULTSBaseline plasma GFAP was higher in females and in A4 (amyloid‐positive) versus LEARN (amyloid‐negative) participants. Cross‐sectionally, elevated GFAP was associated with lower cognitive performance and greater amyloid burden. Longitudinally, higher GFAP predicted faster cognitive decline, increased risk of CDR progression, AD‐related cortical atrophy, and amyloid conversion, with stronger effects in females.DISCUSSIONPlasma GFAP is a prognostic biomarker in CU older adults, predicting cognitive and biological changes, with stronger associations observed in females, highlighting a possible sex‐specific vulnerability.HighlightsElevated plasma glial fibrillary acidic protein (GFAP) predicted faster cognitive decline measured by Preclinical Alzheimer's Cognitive Composite (PACC).GFAP was associated with increased risk of progression to mild cognitive impairment.GFAP predicted conversion to amyloid positivity in amyloid‐negative subjects.Higher baseline GFAP was associated with cortical atrophy in Alzheimer's disease (AD) ‐signature areas.Associations of GFAP with cognition and AD biomarkers were stronger in females.

There are 14 modifiable factors that are associated with a significantly lower risk of dementia. We tested the interactive effect of modifiable factors, genetic determinants, and initial pathologic burden on the spatial progression and local amplification of tau pathology. Methods: In total, 162 amyloid-positive individuals were included, for whom longitudinal [18F]AV-1451 PET scans, baseline information on global amyloid burden, ApoE4 status, body mass index (BMI), hypertension, education, neuropsychiatric symptom severity, and demographic information were available in the Alzheimer Disease Neuroimaging Initiative. All [18F]AV-1451 scans were intensity-standardized (reference: inferior cerebellum), z-transformed (control sample: 147 amyloid-negative subjects), thresholded (z score, >1.96), and converted to volume maps. Longitudinal tau changes were then assessed in terms of tau spatial extent (i.e., newly affected volume at follow-up) and tau level rise (i.e., tau increase in previously affected volume). These 2 measures were entered as dependent variables in linear mixed-effects models, including baseline modifiable risk factors (BMI, education, hypertension, neuropsychiatric symptom severity), global amyloid, tau volume or tau burden, ApoE4 status, clinical stage, sex, and age as predictors. Next, we tested the interactive effects between baseline amyloid or tau burden with the 4 modifiable factors on tau extent or tau level rise, respectively. Results: Greater tau extent was linked to higher BMI (β = 0.002; 95% CI, 0.0003-0.003), ApoE4 status (β = 0.024; 95% CI, 0.001-0.046), and baseline tau volume (β = 0.207; 95% CI, 0.107-0.308) across groups. In terms of tau level rise, we observed that absence of hypertension (β = 0.295; 95% CI, -0.477 to -0.114), dementia group (β = 0.305; 95% CI, 0.088-0.522), and BMI (β = 0.011; 95% CI, 0.00004-0.022) were linked to increased tau burden. A load-dependent effect of baseline amyloid and tau volume/burden was found for both tau extent (β = -0.005; 95% CI, -0.008 to -0.002) and tau level rise (β = -0.003; 95% CI, -0.005 to -0.001). Higher amyloid and BMI (β = 0.001; 95% CI, 0.0004-0.001) and lower education and higher tau burden (β = -0.035; 95% CI, -0.064 to -0.006) were linked to greater tau level rise. Conclusion: Education, BMI, and hypertension differentially influence tau's spatial extent and increase by its interaction with initial pathologic burden. Timely modification of these factors may overall slow tau progression.

Alzheimer’s disease (AD) is a neurodegenerative disorder with 58–79% heritability, yet known variants explain only a fraction of this risk. This meta-analysis synthesizes 60 studies (2015–2025) on GWAS, neuroimaging-genetics integration, and molecular therapeutics. A systematic PubMed search identified studies with &gt;1,000 samples, validated genetic findings, and relevance to AD pathology. Statistical analyses included meta-regression and pooled effect size calculations. Meta-analysis of 74 risk loci confirmed APOE, PSEN1, PSEN2, TREM2, CLU, and SORL1 as key contributors. APOE ε4 strongly correlated with amyloid burden (r = 0.62, p&lt;0.001). Novel loci (e.g., RBFOX1) and population-specific variants were identified. Amyloid immunotherapies (lecanemab, donanemab) reduced plaques but had modest cognitive benefits. Gene silencing (BIIB080) and CRISPR/Cas9 showed therapeutic potential. Integrating genomics with neuroimaging enhances risk prediction. Gene-based interventions and precision medicine offer future promise, but further research is needed to address missing heritability.

Clinical observations suggest that obstructive sleep apnea (OSA) and Alzheimer’s disease (AD) pathology may be linked; however, causal mechanisms and relationships are unclear. To investigate the potential interaction between amyloidosis and intermittent hypoxia (IH), a hallmark of OSA, starting at 4 months of age 5XFAD mice were exposed to chronic IH (CIH) consisting of 20 episodes per hour of hypoxia for 12 h/day, daily for 4 months (males) or 6 months (females). CIH did not induce significant changes in amyloid burden or the number of astrocytes in males or females, but there was a slight decrease in the number of microglia observed in the cortex of 5XFAD mice of both sexes. To further explore this effect, we performed bulk RNA sequencing on isolated microglia. In WT mice, the most robust gene changes induced by CIH were identified in male microglia, many of which were pro-inflammatory. In microglia from 5XFAD mice, compared to normoxia (NX), CIH exposure induced comparatively more DEGs in males. Further, in genes that were upregulated by CIH in WT vs 5XFAD mice of both sexes, there was an enrichment of pathways associated with oxidative phosphorylation, aerobic and cellular respiration, and ATP synthesis. These changes indicate that CIH has a more robust effect on the microglial transcriptome in 5XFAD mice than in WT mice, suggesting that the synergy between AD and OSA pathologies may be driven by metabolic changes in the microglial transcriptome. These observations are particularly interesting given the known sex differences in OSA and AD pathology in human disease.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12035-025-05390-7.

The A673T variant of the Amyloid Precursor Protein (APP), first identified in the Icelandic population, represents a paradigm-shifting discovery in Alzheimer’s Disease (AD) research. This protective mutation confers significant resistance against AD onset and age-related cognitive decline by modulating APP processing and reducing Amyloid-β (Aβ) aggregation. Remarkably, A673T not only mitigates amyloidogenic effects but also counteracts several pathogenic APP mutations implicated in familial AD. Recent in-vivo studies using knock-in mouse models have validated its neuroprotective effects, demonstrating substantial reductions in amyloid burden and preservation of synaptic function. Given its broad implications for understanding APP physiology, AD pathogenesis and the development of novel therapeutic strategies, this review comprehensively examines the physiological role of APP, its contribution to AD pathology, the impact of disease-related mutations and the unique protective mechanisms conferred by the A673T variant.

In addition to driving dependency and overdose, illicit use of opioids, such as fentanyl, is linked to the risk for cognitive decline and dementia. Growing evidence also indicates that opioid use is associated with pathological features, paralleled early in Alzheimer’s disease (AD), which raises the possibility of the involvement of mechanistic interactions between opioid use and AD progression. Here, we investigate how chronic fentanyl use (i.e., 20 days) influences the neuroimmune state, microglial activity, and amyloid burden in wildtype and APPPS1-21 mice, a transgenic model of AD. In wild-type mice, fentanyl use promoted a pro-inflammatory state without increasing the incidence of disease-associated microglia. In APPPS1-21 mice, chronic fentanyl use led to a shift favoring an anti-inflammatory state, which was associated with increased microglia clustering and activation at Aβ plaques, increased Aβ internalization in plaque-associated activated microglia, decreased soluble Aβ, and decreased plaque burden. Our findings indicate that chronic fentanyl use fundamentally changes the trajectory of neuroimmune activity and features characteristic of early AD by enabling microglia to enhance Aβ clearance. The interactions demonstrate how substance use can reshape the neuroimmune landscape in neurodegenerative disease, emphasizing the importance of tailored treatment strategies.

Background/Objective: Timely and successful treatments for Alzheimer's disease (AD) depend on early detection. The Multimer Detection System (MDS-OAβ) for quantifying plasma oligomeric amyloid-β (OAβ) has shown promise as a biomarker of amyloid disease. The theta-to-alpha ratio (TAR) and theta-to-beta ratio (TBR) are two examples of spectral power metrics that can be used in resting-state quantitative EEG (qEEG) to evaluate brain function non-invasively. This study used resting-state EEG (rEEG) recordings obtained while the subjects were both eyes-open (EO) and eyes-closed (EC) to investigate the relationship between regional qEEG power ratios and plasma MDS-OAβ levels in older adults. Methods: The analysis comprised 174 patients between the ages of 60 and 85, with 2 in the low-MDS-OAβ group and 82 in the high-MDS-OAβ group. The clinical plasma cutoff was 0.78 ng/mL. All participants underwent rEEG recordings and plasma OAβ quantification. EEG pre-processing included bandpass filtering (0.5-100 Hz), average re-referencing, artifact rejection using independent component analysis (ICA), and spectral power estimation using Welch's method. The TAR and TBR were calculated across five lobar regions (frontal, central, parietal, occipital, and temporal) during both EO and EC conditions. To normalize data distributions, EEG ratio variables were log-transformed prior to statistical analysis. Group comparisons and linear regression analyses were conducted to evaluate the associations between EEG power ratios and MDS-OAβ levels. Adjusted regression models included age, years of education, and neuropsychological test scores as covariates. Statistical significance was set at p < 0.05. Results: No significant associations were found between TAR and plasma MDS-OAβ levels across any lobar regions under either EO or EC conditions. In contrast, TBR exhibited consistent and significant negative associations with MDS-OAβ levels, particularly under EC conditions. Adjusted regression models revealed that higher MDS-OAβ levels were associated with lower TBR values in the central (β = -0.059, p = 0.015), parietal (β = -0.072, p = 0.006), occipital (β = -0.067, p = 0.040), and temporal (β = -0.053, p = 0.018) lobes, with the strongest inverse relationship observed in the parietal lobe. A similar, though slightly weaker, pattern was observed during EO conditions, with significant inverse associations in the frontal, central, and temporal lobes. Conclusions: Our findings indicate that, after adjusting for covariates, increased plasma MDS-OAβ levels are significantly associated with a reduced TBR, particularly in the parietal and central lobes, under both EO and EC resting-state conditions. In contrast, no significant associations were observed with TAR. These results suggest that a lower TBR may reflect an increased peripheral amyloid burden and highlight its potential as a sensitive qEEG biomarker for early amyloid-related brain changes in older adults.

Early and accurate diagnosis of Alzheimer’s disease (AD) is critical for patient outcomes yet presents a significant clinical challenge. This study evaluates the effectiveness of four machine learning models—Logistic Regression, Random Forest, Support Vector Machine, and a Feed-Forward Neural Network—for the five-class classification of AD stages. We systematically compare model performance under two conditions, one including cognitive assessment data and one without, to quantify the diagnostic value of these functional tests. To ensure transparency, we use SHapley Additive exPlanations (SHAPs) to interpret the model predictions. Results show that the inclusion of cognitive data is paramount for accuracy. The RF model performed best, achieving an accuracy of 84.4% with cognitive data included. Without this, performance for all models dropped significantly. SHAP analysis revealed that in the presence of cognitive data, models primarily rely on functional scores like the Clinical Dementia Rating—Sum of Boxes. In their absence, models correctly identify key biological markers, including PET (positron emission tomography) imaging of amyloid burden (FBB, AV45) and hippocampal atrophy, as the next-best predictors. This work underscores the indispensable role of cognitive assessments in AD classification and demonstrates that explainable AI can validate model behavior against clinical knowledge, fostering trust in computational diagnostic tools.

A 2-min digital clock-drawing test (DCTclock) captures more granular features of the clock-drawing process than the pencil-and-paper clock-drawing test, revealing more subtle deficits at the preclinical stage of Alzheimer's disease (AD). A previous cross-sectional study demonstrated that worse DCTclock performance was associated with higher Aβ and tau burden in older cognitively normal (CN) participants. This study investigates whether longitudinal changes in DCTclock performance are associated with amyloid-β (Aβ) and tau burden in preclinical AD. A total of 219 CN participants completed baseline and follow-up DCTclock assessments, baseline Aβ ([11C]PiB) and tau ([18F]Flortaucipir) PET imaging. Global Aβ and regional tau burden were estimated. Linear mixed models examined associations between longitudinal DCTclock and (1) Aβ, (2) tau, and (3) Aβ and tau burden, adjusted for age, sex, and education. Cognitive domain-specific performance and fine-grained features of DCTclock were analyzed. Elevated baseline Aβ or tau was most strongly associated with accelerated decline in DCTclock performance, particularly in the Information Processing cognitive domain, with stronger associations noted for tau burden. The associations were driven by pen-stroke latency-related features. Participants without elevated Aβ or tau burden demonstrated improved performance in these latency features, suggesting practice effects. Longitudinal declines in DCTclock performance, especially in Information Processing involving speed and executive function, were linked to early Aβ and tau burden in preclinical AD. These findings highlight the potential of digital cognitive assessment tools for tracking disease progression and assessing therapeutic efficacy in clinical trials.

Background: While the AMYLoidosis Index (AMYLI) has been extensively utilized for screening cardiac amyloidosis (CA). However, the relationship between this parameter and amyloid burden, as well as its prognostic value, remains elusive. Therefore, this study aimed to investigate the association between the AMYLI Score and amyloid burden and its prognostic value in patients with CA. Methods: This single-center, prospective, observational study was conducted at West China Hospital, Sichuan University, from November 2011 to September 2023. A total of 307 newly-diagnosed biopsy-proven AL amyloidosis patients who underwent both echocardiography and cardiac magnetic resonance (CMR) imaging were enrolled. The AMYLI score was calculated via transthoracic echocardiography as the product of relative wall thickness (RWT) and E/e′. Lastly, parameters reflecting amyloid burden, such as late gadolinium enhancement, and extracellular volume (ECV), were calculated via CMR. Results: The AMYLI score exhibited a moderately positive correlation with CMR parameters associated with amyloid burden (ECV; r = 0.57, P &lt; 0.001). During a median follow-up of 42 (interquartile range: 35-49) months, 173 patients died. Meanwhile, an AMYLI score ≥ 7.85 demonstrated a strong predictive value for all-cause mortality [hazard ratio (HR) 2.80, 95% confidence interval (CI): 1.80-4.35, P &lt; 0.001]. After adjusting for clinical (HR 2.01, 95% CI: 1.28-3,16, P = 0.001), biochemical (HR 1.64, 95% CI: 1.03-2.61, P = 0.026), echocardiographic (HR 1.99, 95% CI: 1.24-3.17, P = 0.002), CMR imaging-related (HR 1.92, 95% CI: 1.11-3.33, P = 0.014), and therapeutic (HR 1.79, 95% CI: 1.14-2.82, P = 0.007) factors, an AMYLI score ≥ 7.85 remained an independent prognostic factor. AMYLI score ≥ 7.85 added incremental prognostic value to conventional clinical and imaging risk factors. Conclusions: The AMYLI score is a reliable indicator of amyloid burden in patients with CA and possesses independent prognostic value, offering an alternative and convenient echocardiography-based imaging marker for the risk stratification of CA patients.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by extracellular deposition of amyloid in the heart. Vutrisiran, an RNA interference agent, rapidly suppresses hepatic production of TTR. The present analyses evaluate the impact of vutrisiran on cardiac structure, function and amyloid load measured by cardiovascular magnetic resonance (CMR) with extracellular volume (ECV) mapping. Purpose: To analyze the impact of vutrisiran vs placebo on cardiac structure, function and amyloid burden in HELIOS-B participants. Methods: In HELIOS-B ATTR-CM patients were randomized 1:1 to vutrisiran or placebo. The study population comprised HELIOS-B participants who underwent serial CMR assessments at the National Amyloidosis Centre as part of routine clinical care. CMRs were conducted at baseline, 1, 2, and 3-year timepoints during the HELIOS-B study. Image analysis was blinded to treatment allocation. Amyloid regression and progression were defined as an absolute reduction and increase in ECV of &gt; 5%, respectively. Changes in CMR parameters between baseline and follow-up were evaluated, and linear regression modelling was used to determine treatment effects. Results: Forty-three patients (mean (SD) age 75.0(5.67) years, 41/43male) underwent baseline CMR (21vutrisiran, 22placebo). Thirty-nine (21 vutrisiran, 18 placebo), 26 (14 vutrisiran, 12 placebo) and 17 (9 vutrisiran, 8 placebo) patients underwent 1, 2 and 3-year CMR, respectively. No patients received background tafamidis treatment. Baseline CMR characteristics were comparable between the treatment groups. At 3 years, vutrisiran led to significant increases in left and right ventricular ejection fractions (least square mean difference LVEF+20.5%, RVEF+21.1%; both p &lt; 0.001), stroke volumes (LVSV+27.4 mL, RVSV+25.7 mL; p = 0.005 and p = 0.026, respectively), significant reductions in LVmass (–30.8 g; p = 0.014), and cardiac amyloid load (ECV –6.7%; p = 0.009) compared to placebo. For all parameters noted above, vutrisiran led to improvements while placebo led to deterioration. Amyloid regression was observed in 22% of vutrisiran patients; no placebo patients regressed. Conversely, 63% of placebo patients demonstrated progression vs 11% for vutrisiran. Significant changes in cardiac structure and function were emergent as early as year two. Conclusion: In patients with ATTR-CM, treatment with vutrisiran was associated with improvements in cardiac structure, function and amyloid burden compared to placebo.

Background: Tafamidis has been shown to improve outcomes in patients with transthyretin cardiac amyloidosis (ATTR-CM). However, 41% of patients experience clinical deterioration despite treatment, which is associated with poor prognosis. Therefore, identifying Tafamidis responders early on may improve patient management and outcomes. Objective: To evaluate whether pre-treatment imaging and biomarker parameters can predict response to Tafamidis in patients with wild-type ATTR-CM using serial PiB PET imaging as a surrogate for treatment response. Methods: Twenty-five patients with wild-type ATTR-CM were prospectively enrolled and underwent PiB PET, cardiac MRI, echocardiography and laboratory testing (high-sensitivity troponin I, NT-proBNP and eGFR) prior to the initiation of Tafamidis treatment. PiB PET consisted of a 30-minute dynamic acquisition following intravenous injection. The retention index (RI) was calculated by dividing the mean myocardial PiB activity between 15 and 25 minutes by the arterial input function integral over 0 and 20 minutes. SUV images were derived from summed data between 10 and 20 minutes. Correlations were assessed between baseline parameters and changes in RI and SUV after one year of Tafamidis therapy. Results: Baseline RI (r = 0.58, p &lt; 0.005), interventricular septal thickness (r = 0.49, p &lt; 0.05) and LV mass index (r = 0.52, p &lt; 0.01) showed significant positive correlations with percent RI change over one year. However, baseline levels of high-sensitivity troponin I, NT-proBNP and eGFR did not significantly correlate with changes in RI or SUV. However, the percentage change in high-sensitivity troponin I correlated with SUV change (r = 0.54, p &lt; 0.05), while changes in NT-proBNP correlated with changes in left atrial volume index (LAVI) (r = 0.60, p &lt; 0.01) and patient age (r = 0.41, p &lt; 0.05). Conclusion: Higher baseline PiB uptake and greater left ventricular (LV) hypertrophy may predict an increase in amyloid burden despite Tafamidis therapy. Pre-treatment PiB PET scanning could be a useful method of identifying patients with wild-type ATTR-CM who will respond to tafamidis therapy.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive disease driven by amyloid accumulation in the myocardial extracellular space. CMR-derived extracellular volume (ECV) mapping provides a robust means of quantifying infiltration. While current therapies aim to halt deposition, agents targeting amyloid removal are in development. Understanding the infiltration spectrum, including early or subtle disease, may refine treatment strategies and trial endpoints. Aims: To characterise the spectrum of myocardial amyloid infiltration in ATTR-CM using CMR-derived ECV, assess its association with conventional markers and evaluate its prognostic significance. Methods: We retrospectively analysed 1408 patients undergoing CMR at a national centre (2011-2024). Patients were classified as asymptomatic carriers, non-cardiac ATTR, early or overt cardiomyopathy. For analysis, patients were stratified by ECV into five categories: no infiltration (0.20–0.29), mild (0.30–0.39), moderate (0.40–0.49), moderate-to-severe (0.50–0.59), and severe (≥0.60). Correlations between ECV and clinical markers (NAC stage, NT-proBNP, troponin, DPD grade, septal thickness, GLS) were assessed. Prognostic significance of ECV-categories was assessed using multivariable Cox models. Results: ECV increased progressively across the ATTR spectrum (median 0.28 in carriers to 0.57 in overt disease), showing moderate correlation with all clinical markers (ρ range=0.57-0.61). However, individual-level discordance was marked: 24% of patients with NT-proBNP &lt;500pg/mL and 49% of NAC stage I had at least moderate infiltration. In the lowest troponin and septal thickness tertiles, 32% and 34% had at least moderate infiltration. In multivariable analysis, ECV independently predicted all-cause mortality (HR per 0.10 increase: 1.14; 95% CI: 1.03–1.25; p=0.012), with risk rising notably above an ECV threshold of 0.43 on cubic spline modelling. Conclusion: CMR-derived ECV provides a direct, continuous, and quantitative measure of myocardial amyloid burden, enhancing risk stratification beyond conventional staging. Substantial infiltration was often present in patients with low symptom burden or biomarker levels, highlighting limitations of current clinical frameworks. These findings support integrating ECV into routine clinical assessment to guide treatment—particularly when weighing stabilisers vs amyloid-removal therapies—and highlight its potential as a surrogate endpoint for amyloid-clearing trials.