Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is mostly prevalent in people older than 65 years. The hippocampus is a widely studied region of interest (ROI) for a number of reasons, such as memory function analysis, stress development observation and neurological disorder investigation. Moreover, hippocampal volume atrophy is known to be linked with Alzheimer's disease. On the other hand, several biomarkers, such as amyloid beta (aß ₄₂ ) protein, tau, phosphorylated tau and hippocampal volume atrophy, are being used to diagnose AD. In this research work, we have proposed a method to diagnose AD based on slice-wise volumetric features extracted from the left and right hippocampi of structural magnetic resonance imaging (sMRI) data. The proposed method is an aggregation of a convolutional neural network (CNN) model with a deep neural network (DNN) model. The left and right hippocampi have been localized automatically using a two-stage ensemble Hough-CNN. The localized hippocampal positions are used to extract (80 × 80x80 voxels) 3-D patches. The 2-D slices are then separated from the 3-D patches along axial, sagittal, and coronal views. The pre-processed 2-D patches are used to extract volumetric features from each slice by using a discrete volume estimation convolutional neural network (DVE-CNN) model. The extracted volumetric features have been used to train and test the classification network. The proposed approach has achieved average weighted classification accuracies of 94.82% and 94.02% based on the extracted volumetric features attributed to the left and right hippocampi, respectively. In addition, it has achieved area under the curve (AUC) values of 92.54% and 90.62% for the left and right hippocampi, respectively. Our method has outperformed the other methods by a certain margin in the same dataset.

The transcription factor CLOCK–BMAL1 is a core component of the molecular clock machinery that drives circadian gene expression and physiology in mammals. Recently, we reported that this heterodimeric transcription factor functions as a signaling molecule in response to the resetting stimuli via the Ca²⁺-dependent protein kinase C pathway. Here, we demonstrate that the CREB-binding protein (CBP) plays a key role in rapid activation of the CLOCK–BMAL1 heterodimer that leads to phase resetting of the circadian clock. Under physiological conditions, a bimolecular fluorescence complementation (BiFC) assay revealed that CLOCK and BMAL1 dimerize in the cytoplasm and subsequently translocate into the nucleus in response to serum stimuli (mean time duration was 29.2 minutes and mean velocity 0.7 μm/minute). Concomitantly, BMAL1 rapidly recruited CBP on Per1 promoter E-box, but not p300 (a functional analog of CBP), in the discrete nuclear foci. However, recruitment of CBP by cAMP/Ca²⁺ response element-binding (CREB) protein on CRE was not markedly increased upon delivery of the resetting stimuli. Furthermore, overexpression of CBP greatly potentiated the CLOCK–BMAL1-mediated Per1 transcription, and this effect was completely abolished by site-directed mutation of E-box elements, but not by the mutation of CRE in the Per1 promoter. Furthermore, molecular knockdown of CBP severely dampened circadian oscillation of clock gene expression triggered by the resetting stimuli. These findings suggest that CBP recruitment by BMAL1 mediates acute transactivation of CLOCK–BMAL1, thereby inducing immediate-early Per1 transcription and phase resetting of the circadian clock.

Amyloid-β (Aβ) oligomers are implicated in the onset of Alzheimer’s disease (AD). Herein, quinoline-derived half-curcumin-dioxaborine (Q-OB) fluorescent probe was designed for detecting Aβ oligomers by finely tailoring the hydrophobicity of the biannulate donor motifs in donor-π-acceptor structure. Q-OB shows a great sensing potency in dynamically monitoring oligomerization of Aβ during amyloid fibrillogenesis in vitro. In addition, we applied this strategy to fluorometrically analyze Aβ self-assembly kinetics in the cerebrospinal fluids (CSF) of AD patients. The fluorescence intensity of Q-OB in AD patients’ CSF revealed a marked change of log (I/I₀) value of 0.34 ± 0.13 (cognitive normal), 0.15 ± 0.12 (mild cognitive impairment), and 0.14 ± 0.10 (AD dementia), guiding to distinguish a state of AD continuum for early diagnosis of AD. These studies demonstrate the potential of our approach can expand the currently available preclinical diagnostic platform for the early stages of AD, aiding in the disruption of pathological progression and the development of appropriate treatment strategies.

Genome-wide association studies (GWAS) of Alzheimer’s disease are predominantly carried out in European ancestry individuals despite the known variation in genetic architecture and disease prevalence across global populations. We leveraged published GWAS summary statistics from European, East Asian, and African American populations, and an additional GWAS from a Caribbean Hispanic population using previously reported genotype data to perform the largest multi-ancestry GWAS meta-analysis of Alzheimer’s disease and related dementias to date. This method allowed us to identify two independent novel disease-associated loci on chromosome 3. We also leveraged diverse haplotype structures to fine-map nine loci with a posterior probability >0.8 and globally assessed the heterogeneity of known risk factors across populations. Additionally, we compared the generalizability of multi-ancestry- and single-ancestry-derived polygenic risk scores in a three-way admixed Colombian population. Our findings highlight the importance of multi-ancestry representation in uncovering and understanding putative factors that contribute to risk of Alzheimer’s disease and related dementias.