To better characterize the genetic architecture underlying Alzheimer's disease (AD) and related dementias (ADRD), we performed a meta-analysis of European-ancestry genome-wide association studies in 128,681 cases or proxy cases of ADRD and 849,833 (proxy) controls. We identified 91 genetic loci associated with ADRD risk, of which 16 are new and 56 are specifically detected in clinically diagnosed AD cases. We also provide a list of 18 loci (15 new) requiring further external validation. A polygenic score combining the effects of ADRD loci other than APOE was primarily associated with AD rather than non-AD pathology. Individuals in the tenth decile of the score exhibited a twofold increased risk of presenting with Braak neurofibrillary tangles stage of >4 and moderate-to-severe neuritic amyloid plaque pathology at death compared to individuals in the median score group. In conclusion, our study validated a large number of loci associated with the risk of clinically diagnosed AD, while further investigations are required to confirm the impact of the other loci on AD clinical diagnosis and of each locus on AD pathology.

Alzheimer's disease (AD), the leading cause of dementia, is characterized by early synaptic dysfunction that precedes overt cognitive decline. While amyloid-β and Tau remain central to AD pathogenesis, molecular triggers of synapse weakening remain unclear. Here, we investigated AETA, a novel brain-secreted peptide derived from amyloid precursor protein (APP), as a potential mediator of synapse dysfunction in AD. We previously identified AETA as a unique modulator of NMDA receptor activity in the healthy brain; however, its role in AD etiology was yet to be explored. Post-mortem analyses of human hippocampal and prefrontal cortex tissues revealed significantly elevated AETA levels in AD patients, particularly in females. To further explore the contribution of AETA to AD synaptic pathology, we analyzed a new mouse model, the AETA-m mouse, exhibiting chronically increased brain AETA expression. Hippocampi of female AETA-m mice displayed an increase in the number of astrocyte and microglia, but no overt neuroinflammation. RNA sequencing of female AETA-m hippocampi revealed alterations in synaptic gene expression that closely paralleled those observed in vulnerable human AD brain regions, most notably in the hippocampus. These two phenotypes were absent in males. Functionally, hippocampal neurons from AETA-m mice displayed impaired NMDA receptor signaling, dendritic spine loss, and memory deficits especially in females, mirroring early AD-associated synaptic dysfunction. Together, these findings identify AETA as a novel key contributor of synaptic vulnerability in AD and associated memory processing, especially in females. Targeting AETA signaling may therefore offer new therapeutic avenues for preventing or mitigating synaptic and cognitive decline in AD.

Predicting spatial transcriptomics from histology images offers cost-effective insights but faces privacy barriers preventing cross-institutional data sharing. To address this, we present privateST, a homomorphic-encryption-optimized framework that substantiates the feasibility of secure spatial transcriptomics prediction. To accommodate the computational constraints of homomorphic encryption, we downsampled the input images using bilinear interpolation. To improve prediction accuracy for the 100 target genes, we incorporated predictions for an auxiliary set of 150 highly expressed genes. This approach enables the model to learn from a more diverse genomic context, thereby refining the feature representations for the high-priority target genes. To adapt the architecture for homomorphic encryption, we replaced Max-Pooling and ReLU with Average-Pooling and polynomial approximation, respectively. These modifications eliminate non-linear comparison operations, significantly reducing the multiplicative depth. We also implemented multiplexed packing to optimize the efficiency of encrypted data processing. Remarkably, our results demonstrate that despite the reduced input resolution, this proposed approach achieves accuracy comparable to the original ResNet-18 configurations without downsampling.

Objective Neurobehavioral symptoms of dementia substantially impair the quality of life (QOL) of caregivers. However, most caregiver burden instruments are ordinal and lack empirically derived symptom-specific weighting, limiting quantitative interpretation. This study aimed to develop a utility-weighted scale to quantitatively assess caregiver QOL impairment across the dementia severity levels. Methods Eleven dementia-related neurobehavioral symptoms were identified through a literature review and interviews with 115 dementia care professionals. Utility weights were estimated using a conjoint analysis based on the rankings of 27 hypothetical dementia profiles. The resulting Caregiver Quality of Life (CgQOL) scale was evaluated for reliability and validated in individuals with Alzheimer's disease using the Zarit Burden Interview (ZBI), Functional Assessment Staging Tool (FAST), and Mini-Mental State Examination (MMSE). Results A conjoint analysis revealed a clear hierarchy of symptom importance, with agitation having the highest relative importance (15.5%), followed by difficulties with toileting (12.1%) and sleep disturbances (11.7%). The total CgQOL scores ranged from 0 to 36.3. The scale demonstrated excellent inter-rater reliability (weighted κ=0.86) and internal consistency (Cronbach's α=0.998). CgQOL scores increased monotonically with advancing FAST stage and were negatively correlated with the MMSE scores. Moderate convergent validity was observed with the ZBI scores, thus indicating that the two instruments captured related but distinct aspects of the caregiver burden. Conclusion The CgQOL scale is a novel parametric utility-weighted instrument that quantitatively captures caregiver QOL impairment associated with dementia-related neurobehavioral symptoms and complements existing caregiver burden measures. This framework enables a more nuanced and quantitative evaluation of caregiver burden and may serve as a complementary tool to conventional scales in both clinical and research settings.

Alzheimer's disease (AD) represents a continuum progressing from preclinical stages through prodromal mild cognitive impairment (MCI) to dementia. The stage-specific relationships between amyloid-β (Aβ) pathology, hippocampal subfield atrophy, and cognitive decline remain poorly understood, particularly whether network-level hippocampal degeneration mediates Aβ-cognition relationships and whether preserved subfield volumes are associated with preserved cognitive function. We investigated 465 participants from the Chinese Preclinical Alzheimer's Disease Study, stratified into cognitively normal Aβ-negative (n=132), MCI Aβ-negative (MCI-, n=128), MCI Aβ-positive (MCI+, n=93), and AD dementia (n=112) groups. Participants underwent neuropsychological assessments, T1-weighted MRI, APOE genotyping, and amyloid imaging. We employed elastic net regression, mediation, moderation, and structural covariance network analyses to investigate stage-specific associations between hippocampal subfields and cognition. We further evaluated the clinical utility of subfield volumes for discriminating Aβ status in MCI patients. Progressive hippocampal atrophy emerged prominently at the MCI+ stage. Mediation analyses revealed that Aβ-associated subfield atrophy statistically mediated cognitive decline exclusively in MCI+, affecting global cognition, memory, and attention. These mediating subfields were organized into three domain-specific structural covariance networks with bootstrap-confirmed stable morphological covariances, showing coordinated degeneration patterns that statistically mediated Aβ-cognition associations. Preserved right subiculum volume was associated with better memory function in MCI+ (β=0.358, 95%CI: 0.205-0.511). Incorporating right subiculum volume improved discrimination of amyloid-positive status in MCI, with significant Net Reclassification Improvement and Integrated Discrimination Improvement (both P <0.01), providing incremental improvement beyond conventional demographic and cognitive measures. In conclusion, MCI+ represents a pivotal phase where Aβ is linked to the emergence of coordinated hippocampal network deterioration. The right subiculum demonstrates dual significance: as a critical structural substrate supporting memory maintenance in the presence of amyloid pathology and as a potential MRI-based marker for identifying amyloid-positive MCI patients.

Frailty and its subtypes including physical, cognitive, multidimensional and social frailty have been reported to be associated with a wide range of adverse outcomes in older adults. However, little effort has been made to collate and assess the credibility of this evidence. The aim of this umbrella review was to systematically evaluate the certainty of associations between frailty subtypes and adverse health outcomes across community, nursing home and hospital settings. We registered an a priori protocol with PROSPERO (CRD420251123204) and searched five databases from inception to August 2025. We included 37 systematic reviews and meta-analyses. Methodological quality was assessed using a measurement tool to assess systematic reviews (AMSTAR) 2. Evidence credibility was evaluated using predefined statistical criteria. Non-pooled outcomes were judged by the grading of recommendations assessment, development, and evaluation (GRADE) approach. A total of 31 frailty-related outcomes and 11 prefrailty-related outcomes were identified, with a corrected covered area of 0.98%. Pooled analyses showed suggestive evidence for associations of frailty with mortality (pooled relative risk (RR) 2.07) and prefrailty with mortality (pooled RR 1.38). Frailty was also associated with higher risks of hospitalisation, institutionalisation, falls, fractures, cognitive decline and depression. Cognitive frailty showed a markedly elevated risk of dementia (pooled RR 3.75). Multidimensional frailty had the highest mortality risk. Social frailty was associated with mortality and functional decline. Hospital-based evidence indicated that frailty predicted delirium, in-hospital death and post-discharge mortality. Although most non-pooled outcomes presented low to moderate certainty, the direction of effects was consistent. These findings support early detection and multidimensional management of frailty, particularly cognitive and social frailty.