Background/Objectives: This study explored the heterogeneous distribution pattern of translocator protein 18kDa (TSPO)-PET/MRI using radioligand [18F] DPA-714 in temporal lobe epilepsy patients and identified clinical factors influencing imaging outcomes. Methods: The TSPO imaging in individual patient was evaluated with both visual reading and quantitative assessment using an asymmetry index based on cerebellum-normalized standardized uptake values. The association between clinical factors and TSPO imaging outcomes was assessed. Pathological evaluation was conducted in three patients. Results: Twenty-nine TLE patients and ten healthy controls were enrolled. Visual evaluation revealed increased [18F] DPA-714 uptake in twenty patients as compared to controls, predominantly in a unilateral regional brain, while the remaining nine patients showed visually undetectable uptake of [18F] DPA-714. Consistently, quantitative analysis revealed that 69% (20/29) patients exhibited at least one brain area with significant asymmetry index, notably in the temporal lobe (85%, 17/20). A high asymmetry index could also be observed in the parietal (13.8%, 4/29) and occipital lobe (17.2%, 5/29). Significant associations were identified between the asymmetry index and seizure frequency (p = 0.045, OR = 7.994), and the interval from last seizure to PET scan (p = 0.033, OR = 6.712). Moreover, we confirmed the pathology in three patients via immunohistochemistry, which underscored the potential of TSPO-PET in detecting minor lesion. Conclusions: TSPO-PET reveals patient-specific and network-level neuroinflammatory heterogeneity in MRI-negative TLE, supporting its potential role as a complementary tool for presurgical evaluation.

Synaptic loss is a major pathological cause of cognitive impairment in Alzheimer's disease (AD). We integrated in vivo synaptic density imaging using synaptic vesicle glycoprotein 2A positron emission tomography (PET) from a prospective AD cohort with brain transcriptomic data. Partial least squares analysis identified 1,233 genes associated with synaptic loss, enriched for synaptic organization, Tau phosphorylation, cytoskeletal integrity, and ubiquitin-mediated protein degradation. Cell-type enrichment showed downregulation in glutamatergic and GABAergic neurons and upregulation in oligodendrocytes and endothelial cells. Stratification by Tau Braak staging suggested stage-dependent transcriptional programs involved in myelination and inflammation. These associations were supported by retest PET data and longitudinal analyses, which further linked progressive synaptic decline to DNA repair and telomere pathways. Proteomic profiling further highlighted mitochondrial dysfunction. Together, these findings delineate transcriptional signatures underlying synaptic decline in AD with consistency evidence across cross-sectional, retest, longitudinal, and proteomic analyses underscoring their mechanistic relevance and biomarker potential.

68Ga-pentixafor PET/MRI, which targets the C-X-C chemokine receptor type 4 (CXCR4), has been shown to significantly enhance lesion localization accuracy in Cushing’s disease (CD). However, a subgroup of CD tumors exhibits both reduced 68Ga-pentixafor uptake and low CXCR4 expression. In this study, we propose a CXCR4-based stratification of CD patients to evaluate the utility of this stratification for improving lesion localization accuracy, delineating clinical characteristics, predicting survival outcomes, and characterizing mutational features. This retrospective study analyzed 138 patients with surgically and pathologically confirmed CD. Patient subsets underwent 68Ga-Pentixafor PET/MRI (n = 78), CXCR4 immunohistochemistry (n = 116), and targeted gene sequencing (n = 129). Follow-up data were available for 115 patients. The localization sensitivity and diagnostic accuracy of 68Ga-pentixafor PET/MRI reached 98.7

Parkinson's disease (PD) exhibits a characteristic posterior-to-anterior gradient of striatal dopamine loss, yet the underlying upstream mechanisms remain unclear. We combined in vivo ¹⁸F-FPCIT dopamine transporter (DaT) PET/MRI, quantitative susceptibility mapping, and diffusion MRI tractography in 48 PD patients and 10 healthy controls to test whether substantia nigra pars compacta (SNc) iron and microstructural disruption mediate posterior putaminal vulnerability. PD patients showed marked posterior putamen (pPut) DaT reduction (~60%) and elevated SNc iron. SNc iron negatively correlated with striatal DaT availability, and nigrostriatal pathways to the pPut exhibited higher axial diffusivity. Serial mediation analyses demonstrated that SNc iron indirectly impaired striatal DaT function via reduced SNc DaT binding. Putaminal DaT-SBR robustly discriminated PD from controls (AUC 0.93-0.96), exceeding caudate performance. Transgenic and α-synuclein preformed fibril mouse models provided qualitative anatomical support. These findings identify SNc iron-related degeneration as a key driver of posterior striatal vulnerability in PD.

Background:The Centiloid (CL) value offers a standardized metric for quantifying amyloid-β (Aβ) levels in the brain. We aimed to investigate the associations of plasma phosphorylated tau 217 (P-tau217) and glial fibrillary acidic protein (GFAP) with Aβ (A) deposition, Tau (T) accumulation, cortical atrophy (N), and cognitive decline across varying CL scales. Methods:This study involved 1346 participants who underwent [18F]florbetapir PET, plasma P-tau217 and GFAP measurements, structural MRI (sMRI), and cognitive assessments. A subset of 604 participants additionally completed [18F]MK6240 PET. CL values were stratified into three scales: CL ≤ 10, 10 < CL ≤ 30, and CL > 30. ROC analyses assessed the discriminative abilities of plasma P-tau217 and GFAP across various CL scales. Adjusted regression models examined their associations with Aβ/Tau burden, cortical atrophy, and cognitive decline among different CL scales. Findings:Plasma levels of P-tau217 and GFAP exhibited a progressive increase across the groups of CL ≤ 10, 10 < CL ≤ 30, and CL > 30 (P < 0.0001), and were most positively associated with CL values within the 10 < CL ≤ 30 range (β = 0.236, P = 0.016; β = 0.206, P = 0.027, respectively). Plasma P-tau217 effectively differentiated between CL > 30 and CL ≤ 30 in cognitively normal (CN) and mild cognitive impairment (MCI) participants (AUC = 0.919 and 0.926, respectively), whereas in dementia participants, it more effectively separated CL > 10 from CL ≤ 10 (AUC = 0.959). A sequential mediation model indicated that CL values influenced the MK6240-SUVR (temporal-meta-ROI) through plasma GFAP, followed by P-tau217, with the most significant effects observed within the 10 < CL ≤ 30 range. Elevated GFAP levels were correlated with reduced cortical thickness and poorer cognitive performance in the CL ≤ 10 group, while increased P-tau217 levels were associated with atrophy and non-executive cognitive deficits in the CL > 10 group. Interpretation:Plasma P-tau217 and GFAP track early Aβ accumulation, downstream Tau pathology, neurodegeneration, and cognitive deterioration across different CL scales. These biomarkers may provide valuable information for risk stratification and therapeutic targeting of AD within specific CL contexts. Funding:National Natural Science Foundation of China (Grant No. 82171198, 82501892), Shanghai Municipal Commission of Health Research Project (Grant No. 202440009, 202440010), Shanghai Municipal Science Technology Major Project (Grant No. 2018SHZDZX01), STI2030-Major Projects (Grant No. 2022ZD0213800), and Shanghai Medical Innovation and Development Foundation "Brain Health Youth Fund-Precision Diagnosis and Treatment Research on Alzheimer's Disease" (Grant No. SMIDF-150-2025A30).

Apolipoprotein E (APOE) and ethnicity were proved to have strong effect on Alzheimer's disease. However, study on APOE effect on amyloid-PET in East Asians was limited. Here, we assess the effects of APOE and race/ethnicity interaction effects on amyloid-positivity and amyloid-PET among East Asian and Not Hispanic and Latino White people. Linear regression model was used to estimate the APOE and APOE/ethnicity interaction on amyloid-PET among East Asians ( N  = 1529) and Not Hispanic and Latino White (ADNI, N  = 1259). Logistic generalized estimating equations were used to estimate the APOE/ethnicity interaction effect on frequency of amyloid-positivity (using cohort-specific visual check). For estimation of APOE and APOE/ethnicity effect, the APOE ε3/ε3 was used as reference group. Both models were adjusted for age, sex and years of education. APOE ε4 alleles were ascociated with higher risk amyloid deposition compared with ε3/ε3 group (ε2/ε4: β=37.68, p  <0.001, ε3/ε4: β=20.96, p  <0.001, ε4/ε4: β=36.27, p  <0.001) among East Asians. However, ε2 alleles showed no protective effect on amyloid deposition in East Asians. For APOE/ethnicity interaction effect (Figure 2), ε4 alleles in East Asians were associated with less amyloid deposition and amyloid positivity risk than Not Hispanic and Latino White population. In contrast, ε2 alleles were associated with higher risk of amyloid deposition and positivity in East Asians than Not Hispanic and Latino White people. Moreover, APOE ε2/ε4 showed similar effect between East Asians and White people on amyloid deposition and positivity. Through recent advances in AD-related genetic cohorts, this study provided the largest-to-date overview of the association of APOE with amyloid-PET risk in East Asians. APOE ε4 alleles were associated with less amyloid deposition risk and APOE ε2 alleles were associated with higher risk than White people. These novel insights are critical to guide AD clinical trial design and research.

INTRODUCTION:White matter hyperintensities (WMHs) are common in both Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA), yet their spatial tissue characteristics and microstructural differences remain poorly understood. METHODS:We analyzed 351 participants: 184 amyloid beta (Aβ)-positive AD and mild cognitive impairment (MCI), 139 Aβ-negative cognitively normal controls (CN), and 28 probable CAA. Multimodal magnetic resonance imaging metrics were used to estimate spatial gradient parameters for periventricular WMHs (pWMH) and deep WMHs (dWMH). RESULTS:CAA demonstrated distinctive free-water fraction (FWF), fractional anisotropy (FA), mean diffusivity (MD), and plasma volume within pWMH, as well as spatial gradient parameters of pWMH. These pWMH spatial gradient parameters produced area under the curve (AUC) values of 0.71 (FWF), 0.72 (MD), and 0.79 (FA) when distinguishing CAA from AD/MCI. We retested a subset of the cohort after 1 to 2 years (AUCs: FWF = 0.89, MD = 0.79, FA = 0.85). DISCUSSION:Spatial gradient parameters reflect disease-specific microstructural and vascular changes, providing insights into CAA and AD pathology.

The 18 kDa translocator protein (TSPO) has been a central molecular target for imaging inflammation in the preclinical and clinical research settings across a plethora of applications, including neuroinflammation, cardiovascular inflammation and cancer. Recently, we reported the development of [18F]LW223 as a third-generation TSPO positron emission tomography (PET) radiotracer with binding to human TSPO independent of the rs6971 genetic polymorphism. This study reports the first whole-body human analysis, including biodistribution and dosimetry calculations, following intravenous administration of [18F]LW223. Whole-body PET images were acquired over 250 min after intravenous bolus injection of 184.3 ± 20.2 MBq of [18F]LW223 in healthy adult human volunteers. Volumes of interest (VOIs) in different source organs were manually delineated by three independent observers, then time-activity curves were generated for residency times calculations for subsequent quantification of radiation equivalent and effective doses using OLINDA/EXM 2.2 software. The radiotracer biodistribution in humans recapitulated known TSPO expression in various tissues. The main elimination route was found to be hepatobiliary, and the critical organ was the intestine. The cumulated radioactivity excreted by the kidneys was < 10

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaques, tau neurofibrillary tangles, and synaptic dysfunction. Cellular prion protein mediates Aβ oligomer neurotoxicity through metabotropic glutamate receptor 5 (mGluR5), leading to synaptic impairment and loss. However, the longitudinal trajectory of mGluR5 and its relationship with amyloid pathology remain poorly understood in vivo. We performed baseline dual-tracer PET imaging in 38 participants and longitudinal [ 18 F] PSS232PET/MR in 23 cognitively impaired patients over a mean follow-up of 14.3 months. Longitudinal analyses revealed widespread reductions in mGluR5 availability among Aβ-positive individuals, whereas Aβ-negative participants exhibited more restricted declines. Baseline amyloid pathology predicted accelerated mGluR5 decline in parahippocampus and hippocampus. Higher baseline hippocampal mGluR5 availability was associated with accelerated subsequent cognitive decline, suggesting that preserved or compensatorily elevated mGluR5 may identify individuals at increased risk of future deterioration. These findings indicate that longitudinal mGluR5 decline follows an amyloid-dependent spatiotemporal pattern, with selective medial temporal vulnerability in Aβ-positive individuals. This study provides in vivo evidence linking amyloid pathology to progressive mGluR5 dysfunction and supports the development of mGluR5-targeted therapeutic strategies for amyloid-positive AD.

To evaluate a HER2-targeted theranostic strategy using [68Ga]Ga-NOTA-5F7 PET/CT and [131I]SGMIB-5F7 SPECT/CT in breast cancer. Twenty female patients underwent [68Ga]Ga-NOTA-5F7 PET/CT. Among them, 10 patients also underwent paired [18F]FDG PET/CT, and 12 had follow-up evaluations. Additionally, four patients underwent [131I]SGMIB-5F7 SPECT/CT imaging at 1, 4, and 24 h post-injection for dosimetric analysis. Semi-quantitative assessments were conducted using the maximum standardized uptake values (SUVmax), metabolic tumor volume (MTV), and target-to-background ratios (TBR). [68Ga]Ga-NOTA-5F7 PET/CT showed a significant correlation between HER2 expression and SUVmax in both primary and metastatic lesions (r = 0.9408, p < 0.0001), whereas [18F]FDG PET/CT showed no significant correlation (r = 0.2243, p = 0.2706). The sensitivity, specificity, and accuracy of [68Ga]Ga-NOTA-5F7 were all higher than that of [18F]FDG PET/CT (95

Fibrillar tau is a defining hallmark of Alzheimer’s disease, gradually accumulating and spreading throughout the brain. The synapse plays a key role in this process—both by facilitating the spread of tau between neurons and by serving as a direct target of tau-induced neurotoxicity. However, few studies in humans have explored synaptic density both as a facilitating factor and as a target of tau pathology. In this dual PET tracer study, we used 18F-SynVesT-1 synaptic vesicle glycoprotein 2A (SV2A) PET to assess synaptic density and 18F-MK6240 tau-PET to assess fibrillar tau in 59 amyloid-PET-positive patients and 25 amyloid-PET-negative cognitively normal individuals from the Chinese Preclinical Alzheimer’s Disease Study (CPAS). Spatial correlation analyses revealed that brain regions with higher SV2A tracer uptake in cognitively normal individuals exhibited higher 18F-MK6240 uptake in Alzheimer’s disease. These findings were independently replicated in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), where normal SV2A-PET maps from CPAS were correlated with tau-PET data from 372 Aβ+ participants, including longitudinal follow-up in 204 cases. In both cohorts, regions with higher normal synaptic density showed greater tau burden, and in ADNI, higher synaptic density in normal brain also predicted faster tau accumulation over time. Gene-set enrichment analyses of transcriptomic data mapped onto regional tau-PET uptake further showed that areas of high 18F-MK6240 uptake were enriched in genes encoding synapse-related proteins. Together, these findings suggest that synapse-rich regions are especially prone to tau accumulation. We also investigated the downstream impact of tau on synaptic integrity. Notably, regions with higher 18F-MK6240 uptake showed reduced SV2A tracer uptake, indicating synaptic loss, not only in the same regions but also in areas connected to those with high tau. Stronger loss of SV2A tracer uptake was observed in the regions with stronger resting-state functional connectivity to epicenters of high 18F-MK6240 uptake in the Alzheimer’s disease group. The connectivity-dependent synaptic loss could not be fully explained by tau levels in the connected target regions but was found to be partially mediated by them. These findings suggest that tau pathology contributes to synaptic loss both locally and in distant, connected brain regions. Overall, our results highlight the central importance of the synapse in Alzheimer’s disease: synapses appear to both facilitate fibrillar tau accumulation and become impaired through its toxic effects. Understanding the synapse’s role in tau pathology may open new avenues for therapeutic interventions aimed at slowing down tau progression and neurodegeneration.

Introduction We hypothesize that specific cognitive assessments and plasma biomarkers may exhibit heightened sensitivity during the stage of subjective cognitive decline (SCD). The integration of these plasma biomarkers and cognitive assessments could enhance the ability to predict beta-amyloid (Aβ) pathology in individuals with SCD. Methods A total of 231 participants, including 74 normal controls (NC) and 157 SCD, underwent Aβ and tau PET scans and blood testing for Aβ40, Aβ42, p-tau181, p-tau217, NfL, and GFAP. Cognitive assessments, plasma biomarkers, tau PET SUVr, and demographics were compared between Aβ+ and Aβ− groups within NC and SCD. The least absolute shrinkage and selection operator (LASSO) and logistic regression were employed to perform variable selection and develop predictive models. Results We observed significantly worse global cognition, visuospatial memory performance, executive function, and metamemory, as well as higher tau PET SUVr, elevated levels of p-tau217, p-tau181, and GFAP, and lower Aβ42/Aβ40 ratios in SCD Aβ+ compared to SCD Aβ-. The model incorporating BVMT-LD and p-tau217 achieved a slightly higher AUC than the model using p-tau217 and Aβ42/Aβ40 (0.94 vs. 0.93). Partial correlation analyses indicated that both auditory verbal memory (AVLT-LD) and visuospatial memory (BVMT-LD) were significantly negatively associated with p-tau217, whereas only AVLT-LD demonstrated a significant negative association with tau pathology severity. Conclusion Visuospatial memory deficit and plasma p-tau217 are powerful biomarkers for identifying Aβ+ in SCD. Auditory verbal memory links to tau pathology severity, while visuospatial memory is more sensitive to Aβ deposition, supporting early intervention to prevent AD progression.

Background: Lecanemab lowers amyloid-β (Aβ) in early Alzheimer’s disease, but whether amyloid clearance modifies downstream tau, synaptic, plasma biomarker, and cognitive trajectories in real-world treated patients remains uncertain. Methods: In this observational longitudinal study, 188 Aβ-positive participants were enrolled from Shanghai memory clinics: 128 received lecanemab and 60 untreated participants served as a comparison group. Aβ positivity was established by visual [18F]florbetapir positron emission tomography (PET) reads. Participants underwent cognitive follow-up, Aβ PET, [18F]MK6240 tau PET, [18F]SynVesT-1 synaptic vesicle glycoprotein 2A (SV2A) PET, and Nucleic Acid Linked Immuno-Sandwich Assay sequencing (NULISAseq) central nervous system (CNS) plasma proteomics; longitudinal Aβ/tau/SV2A PET was available in 77/36/20 treated and 50/25/15 comparison participants, respectively. Findings: Baseline sex, education, apolipoprotein E (APOE) ε4 status, amyloid burden, tau PET meta-temporal standardised uptake value ratio (SUVR), and Mini-Mental State Examination (MMSE) were not significantly different between groups; treated participants were younger and had lower baseline SV2A. At 12 months, Centiloid change differed between treated and comparison participants (mean difference −62·3 Centiloid; p<0·001). Treated participants showed decreased Braak II tau but increased Braak V–VI and global cortical tau; relative to controls, tau accumulation was attenuated in Braak II and synaptic loss in Braak I. Plasma apolipoprotein E-related NULISA Protein Quantification (NPQ) changes were associated with meta-temporal and Braak IV tau accumulation. Baseline tau and SV2A burden, and longitudinal SV2A change, were associated with MMSE trajectories. Interpretation: Amyloid clearance during lecanemab treatment was accompanied by regionally restricted downstream effects rather than uniform tau or synaptic recovery. Baseline tau burden and synaptic loss was associated with future cognitive declines during treatment, Synaptic integrity may represent a proximal correlate of clinical benefit, but these exploratory multimodal markers require prospective validation.

INTRODUCTION:We investigated the relationship between metabotropic glutamate receptor subtype 5 (mGluR5) availability and plasma biomarkers in individuals with cognitive impairment. METHODS:Seventy-one subjects were included (17 cognitively unimpaired [CU], 10 early-onset cognitive impairment [EOCI], and 44 late-onset cognitive impairment [LOCI]). Amyloid beta (Aβ) pathology was quantified using 18F-Florbetapir, and mGluR5 availability by 18F-PSS232. The associations of mGluR5 availability, plasma biomarkers, and age were explored using partial correlation, mediation, and interaction analyses. RESULTS:In individuals aged over 65 years and the LOCI group, mGluR5 availability was positively associated with plasma glial fibrillar acidic protein (GFAP). This positive relationship of mGluR5 with plasma GFAP in LOCI only survived in the Aβ-positive subgroup (r = 0.475, p = 0.011). DISCUSSION:Increased mGluR5 availability is significantly associated with elevated plasma GFAP levels dependent on age in individuals aged over 65 years and the LOCI group.

Purpose Alzheimer’s disease is characterized by progressive accumulation of hyperphosphorylated tau protein, which propagates in a prion-like manner along connected neuronal pathways. However, it remains unclear whether functional connectivity between gray and white matter (FCGW) can predict tau spread. This study aimed to determine the association between FCGW and tau deposition and to evaluate its value in predicting longitudinal tau spread. Methods We integrated resting-state fMRI with cross-sectional and longitudinal tau-PET data from two independent cohorts. We assessed baseline associations between FCGW and tau deposition and then constructed an individual-level spreading model to predict longitudinal tau accumulation. Results In both cohorts, FCGW showed a positive correlation with tau deposition. Model-simulated white-matter tau deposition was associated with clinical scales and predicted cognitive decline. The spreading model, which incorporated baseline tau-PET and the top 10% of gray and white matter, yielded the highest predictive performance for future tau accumulation. Conclusion FCGW captures key network pathways underlying tau spread in AD and improves prediction of future tau accumulation. These findings highlight the importance of FCGW in understanding tau propagation and support development of network-targeted therapeutic strategies.

With the rapid aging of the population, Alzheimer's disease (AD) presents an increasingly severe challenge to public health in China. Early diagnosis and treatment are critical strategies for slowing the progression of the disease. The development of positron emission tomography (PET) has made it possible to visualize the key pathological mechanisms of AD, significantly advancing research in this field. This review examines the current landscape of PET imaging applications in AD in China, highlighting advancements in molecular probes, diagnostic frameworks, and translational research. 18 F-fluorodeoxyglucose ( 18 F-FDG) PET serves as a foundational tool for assessing cerebral glucose metabolism and has established itself as an early method for detecting the characteristic hypometabolic patterns associated with AD. The subsequent advent and clinical integration of amyloid-β (Aβ) PET ligands marked a transformative shift, enabling the in vivo detection of core AD neuropathology and significantly enhancing diagnostic accuracy. More recently, the introduction of tau PET tracers has facilitated the precise mapping of neurofibrillary tangle deposition, providing a more comprehensive pathological picture. This review also emphasizes the increasing importance of multimodal imaging approaches, which integrate PET data with magnetic resonance imaging (MRI) and other modalities to bolster diagnostic confidence and prognostic evaluation. This synergy is encapsulated in the A/T/(N) (Aβ, tau, and neurodegeneration) framework, a biomarker-based classification system that is increasingly guiding clinical research and trial enrollment in China. Finally, exploration of PET imaging with novel radiotracers targeting emerging pathological processes in China, holds immense promise for uncovering deeper insights into disease mechanisms and monitoring therapeutic efficacy.

Background:Gait slowing and cognitive impairment often coexist in older adults, yet their relationship with core Alzheimer's disease (AD) biomarkers remains incompletely understood. Objective:To investigate the associations of isolated and combined slow gait (SG) and cognitive impairment subtypes with cerebral amyloid-β (Aβ) deposition and the apolipoprotein E ε4 (APOE ε4) allele in Chinese older adults. Methods:This cross-sectional study included 1,753 participants (mean age 65.9 years). Based on gait speed and cognitive status, participants were classified into six groups: normal, slow gait alone (SG-A), subjective cognitive decline alone (SCD-A), mild cognitive impairment alone (MCI-A), SCD with slow gait (SCD-SG), and MCI with slow gait (MCI-SG). 687 individuals underwent 18F-florbetapir positron emission tomography (PET) scans, 654 participants were examined for Apolipoprotein E (APOE) genotyping, and 618 participants had all relevant information recorded. Results:The MCI-SG group exhibited the most pronounced physical decline (slowest gait speed and weakest handgrip strength) and the highest burden of AD pathology, with a significantly higher prevalence of Aβ positivity (38%) and APOE ε4 carriage (32%) compared with other groups. While overall Aβ positivity rates across the six groups were not significantly different, logistic regression analyses revealed specific, strong associations. Aβ positivity was significantly associated with both SCD-SG (OR = 1.78, 95% CI: 1.03-3.08) and MCI-SG (OR = 1.85, 95% CI: 1.07-3.21) compared with the normal group. In contrast, APOE ε4 carriage was specifically and more strongly linked to MCI-SG (OR = 3.21, 95% CI: 1.41-7.31) compared with the SCD-A group. These combined gait-cognitive impairment phenotypes showed consistently stronger associations with AD biomarkers than isolated impairments across multiple reference groups. The risk was greatest for MCI-SG in individuals who were both Aβ positive and APOE ε4 carriers (OR = 2.27, 95% CI: 1.19-5.15). Conclusion:The co-occurrence of slow gait and mild cognitive impairment (MCI-SG) represents a distinct high-risk clinical phenotype strongly linked to AD pathology. Aβ and APOE ε4 show differential associations across the gait-cognitive spectrum. Integrated assessment of gait and cognition improves risk stratification in older adults and may guide early intervention strategies.

Importance:Amyloid positron emission tomography (PET) is increasingly used in research and clinical settings to determine the etiology of cognitive decline and eligibility for amyloid-targeting therapies. To assist with amyloid PET evaluation and to guide clinical decision-making, images can be quantified in a standardized unit called Centiloid, the interpretation of which can vary according to the method and threshold used. Objective:To collect Centiloid values from available studies and determine robust positivity cutoffs using data-driven methods and correspondence with visual reads. Data Sources:PubMed search (October 2024) identified studies with Centiloid values. Corresponding authors were invited to share individual participant data. Additional data were obtained through access-controlled repositories and conference outreach (July 2024-July 2025). Study Selection:Studies were included if they provided Centiloids, radiotracer, age, and sex. Data Extraction and Synthesis:Each study was analyzed using a unified statistical pipeline; study estimates were pooled using random-effects meta-analysis. Main Outcomes and Measures:Gaussian mixture models (GMMs) were fitted to Centiloid values for each study. In studies with a bimodal distribution (per integrated completed likelihood), single cutoffs for positivity were set as mean plus 2 SDs of the lower gaussian component. Using GMMs, a double-cutoff approach defined a lower certainty range using a 90% posterior probability cutoff for assignment to the low (amyloid-negative) vs high (amyloid-positive) component. An alternative Centiloid cutoff was derived from maximizing the correspondence (Cohen κ) with the binary visual reads when available. Results:This meta-analysis included cross-sectional amyloid PET scans acquired with 5 radiotracers from 49 227 participants across 53 studies from 15 countries (mean age, 71 years; 54% female, 62% cognitively impaired). The data-driven GMM approach identified a bimodal distribution in 51 studies (n = 48 786), resulting in a single cutoff for positivity of 18 Centiloids (95% CI,16-19; I2 = 97%). The double-cutoff approach revealed high confidence for interpreting scans as negative when Centiloid values were lower than 11 (95% CI, 9-13; I2 = 95%) and interpreting scans as positive if Centiloid values were higher than 26 (95% CI, 24-28; I2 = 95%). In analyses of correspondence with binary (positive or negative) visual reads of amyloid PET scans (n = 35 045; 36 studies), Centiloids were highly predictive of visual positivity (Cohen κ, 0.86; 95% CI, 0.83-0.89; I2 = 96%) with a cutoff of 27 Centiloids (95% CI, 24-30; I2 = 80%). Conclusions and Relevance:In this individual participant data meta-analysis, positivity cutoffs converged around 18 Centiloids (data-driven) and 27 Centiloids (visual reads). Findings from a double-cutoff analysis suggest that scans in the 11 to 26 Centiloid range should be interpreted with caution depending on the context of use.

White matter microstructural changes play a crucial role in cognitive decline in aging and neurodegenerative disorders including Alzheimer’s disease (AD). However, the processes underlying white matter microstructural changes and the molecular pathways leading to these changes in AD remain largely unknown. AD involves cortical and juxtacortical microstructural changes, with free water fraction (FWF) as a potential imaging marker. We measured FWF using diffusion magnetic resonance imaging in 68 juxtacortical regions of 153 cognitively normal controls and 194 patients with AD as evidenced by elevated amyloid PET. We estimated the expression of 15,633 genes in the same regions using transcriptomic data from the Allen Human Brain Atlas. The biological processes and cell types associated with the linked genes were evaluated. Mediation analysis was used to examine whether FWF mediates the association between APOE ε4 status and cognitive performance. Gene ontological analyses revealed that these genes were enriched for biological processes relating to lipid metabolic process, ensheathment of neurons, and synaptic signaling and were predominantly expressed in oligodendrocytes, GABAergic neurons, and pyramidal neurons from the hippocampus CA region. These ontological enrichment results were replicated in two additional datasets. Furthermore, mediation analyses revealed a domain-specific role of FWF in the association between APOE ε4 status and cognitive performance. Our findings provide mechanistic insights into regional juxtacortical microstructural changes in AD, particularly the processes involving lipid metabolism, offering potential therapeutic targets.