The genetic and molecular underpinnings of Alzheimer's disease (AD) have been extensively explored, revealing complex interactions between genetic variants and lipid metabolism. A study by Guo et al. highlights how lipidated apolipoprotein E (ApoE) isoforms interact differently with low-density lipoprotein receptors, with ApoE2 showing protective effects against neurodegeneration compared to ApoE3 and ApoE4. This study emphasizes the role of polyunsaturated fatty acids in modulating these interactions, linking lipid peroxidation to age-related lysosomal pathologies (ref: Guo doi.org/10.1016/j.cell.2024.10.027/). Furthermore, Wu et al. critique the methodology of proxy genome-wide association studies (GWAS) in AD, pointing out significant biases that misrepresent genetic correlations with educational attainment and cognitive outcomes, thereby questioning the validity of proxy-based genetic assessments (ref: Wu doi.org/10.1038/s41588-024-01963-9/). In a complementary approach, Wang et al. conducted a genome-wide association study identifying numerous associations between cerebrospinal fluid metabolites and genetic traits, revealing new loci that may contribute to AD pathology (ref: Wang doi.org/10.1038/s41588-024-01973-7/). This genetic architecture is further supported by Western et al., who created a cerebrospinal fluid proteogenomic atlas, identifying key proteins that may serve as biomarkers for AD (ref: Western doi.org/10.1038/s41588-024-01972-8/). The interplay between genetic predisposition and metabolic pathways is further illustrated by Zha et al., who demonstrated how microbiota-derived lysophosphatidylcholine can mitigate AD pathology through ferroptosis suppression, highlighting the gut-brain axis as a potential therapeutic target (ref: Zha doi.org/10.1016/j.cmet.2024.10.006/). Koskeridis et al. expanded this narrative by identifying shared genetic loci between AD and cardiovascular traits, suggesting a common pathological framework that may inform future therapeutic strategies (ref: Koskeridis doi.org/10.1038/s41467-024-53452-6/). Lastly, Wang et al. explored circRNA dysregulation in AD progression, revealing novel molecular mechanisms that could be targeted for intervention (ref: Wang doi.org/10.1186/s13073-024-01404-6/).

The pathophysiology of Alzheimer's disease encompasses a range of molecular and cellular changes that contribute to its clinical manifestations. Miyoshi et al. utilized spatial and single-nucleus transcriptomic analyses to differentiate between genetic and sporadic forms of AD, providing insights into the transcriptomic landscape of the disease and its potential links to Down syndrome (ref: Miyoshi doi.org/10.1038/s41588-024-01961-x/). This study underscores the importance of understanding the molecular etiology of AD, particularly in genetically predisposed populations. In a related investigation, Schworer et al. tracked the progression of amyloid and tau pathology in individuals with Down syndrome, revealing that tau deposition typically begins several years after amyloid positivity, which could inform early intervention strategies (ref: Schworer doi.org/10.1016/S1474-4422(24)00426-5/). The neuropathological landscape is further complicated by findings from Mayà et al., who examined post-mortem brain tissues from individuals with rapid eye movement sleep behavior disorder, highlighting the presence of α-synuclein pathology and its relationship with AD (ref: Mayà doi.org/10.1016/S1474-4422(24)00402-2/). Additionally, Ghetti et al. investigated Biondi bodies in ependymal cells, linking their formation to various neurodegenerative conditions, including AD, thus expanding the understanding of amyloid inclusions in the disease context (ref: Ghetti doi.org/10.1007/s00401-024-02807-w/). The multiplexed expansion revealing technique developed by Kang et al. allows for enhanced imaging of multiprotein nanostructures, providing a powerful tool for studying the complex protein interactions in AD (ref: Kang doi.org/10.1038/s41467-024-53729-w/). Collectively, these studies illustrate the multifaceted nature of AD pathology and the need for integrated approaches to unravel its complexities.

The identification of reliable biomarkers for Alzheimer's disease is crucial for early diagnosis and treatment. Therriault et al. demonstrated that plasma p-tau217 levels could effectively rule in or out amyloid-β pathology in individuals with probable AD dementia, achieving a positive predictive value exceeding 95% (ref: Therriault doi.org/10.1038/s43587-024-00731-y/). This finding underscores the potential of plasma biomarkers in clinical settings, particularly as new anti-amyloid therapies emerge. In a related study, Salloway et al. analyzed data from clinical trials of gantenerumab, revealing insights into amyloid-related imaging abnormalities (ARIA) and their long-term implications for patient management (ref: Salloway doi.org/10.1001/jamaneurol.2024.3937/). The exploration of novel therapeutic candidates is also highlighted by Panek et al., who introduced a multifunctional modulator of cholinergic and GABAergic neurotransmission, proposing it as a potential palliative treatment for AD (ref: Panek doi.org/10.1002/anie.202420510/). Furthermore, Balcomb et al. investigated the interaction of SMOC1 with amyloid and tau aggregates, suggesting its role in modulating AD pathology (ref: Balcomb doi.org/10.1007/s00401-024-02819-6/). These studies collectively emphasize the importance of integrating biomarker discovery with therapeutic development to enhance diagnostic accuracy and treatment efficacy in AD.

Therapeutic strategies for Alzheimer's disease are evolving, focusing on both pharmacological and non-pharmacological interventions. Ward et al. explored frailty trajectories as potential predictors of dementia onset, suggesting that understanding these trajectories could inform preventive strategies (ref: Ward doi.org/10.1001/jamaneurol.2024.3774/). This highlights the need for accessible markers that can indicate biological age and dementia risk. Rossi et al. raised the question of oligodendrocytes' role in AD, proposing that these cells may be critical in understanding the disease's pathology and warranting further research into their therapeutic potential (ref: Rossi doi.org/10.1186/s13024-024-00760-6/). Liu et al. conducted a comprehensive morphometric analysis of mouse brains, providing valuable insights into neuronal diversity and potential targets for intervention (ref: Liu doi.org/10.1038/s41467-024-54745-6/). Kokkali et al. reported on the multimodal effects of BNN27, a synthetic nerve growth factor mimetic, in a mouse model of AD, demonstrating its potential to ameliorate various aspects of the disease (ref: Kokkali doi.org/10.1038/s41380-024-02833-w/). Additionally, Blankenship et al. examined the hyperexcitability of dopamine neurons in AD models, linking this dysregulation to cognitive deficits and suggesting new avenues for therapeutic exploration (ref: Blankenship doi.org/10.1038/s41467-024-53891-1/). These findings collectively underscore the multifaceted approach required for effective AD treatment, integrating insights from various biological systems.

Environmental and lifestyle factors play a significant role in the risk and progression of Alzheimer's disease. Wang et al. conducted a large longitudinal study that demonstrated a strong association between cardiorespiratory fitness (CRF) and reduced dementia risk, particularly among individuals with a genetic predisposition to the disease (ref: Wang doi.org/10.1136/bjsports-2023-108048/). Their findings suggest that higher CRF is linked to better cognitive function and delayed onset of dementia, emphasizing the importance of physical fitness in mitigating AD risk. Zha et al. further explored the gut-brain axis, revealing that microbiota-derived lysophosphatidylcholine can alleviate AD pathology by suppressing ferroptosis, thus highlighting the potential of dietary and microbiome interventions in AD prevention (ref: Zha doi.org/10.1016/j.cmet.2024.10.006/). Vockert et al. examined the cognitive reserve hypothesis, demonstrating that personalized fMRI-based scores can moderate the impact of AD pathology on cognitive performance, suggesting that educational and lifestyle factors may enhance cognitive resilience (ref: Vockert doi.org/10.1038/s41467-024-53360-9/). The interplay between genetic predisposition and lifestyle factors is crucial, as evidenced by the findings of Chen et al., who investigated the pathogenic effects of the APP N-terminal mutation, linking genetic factors to synaptic damage (ref: Chen doi.org/10.1038/s41380-024-02837-6/). These studies collectively emphasize the need for a holistic approach to AD, integrating lifestyle modifications with genetic and environmental considerations.

Neuroinflammation and the immune response are critical components of Alzheimer's disease pathology. Lobanova et al. introduced ASC specks as a novel biomarker for inflammation in neurodegenerative diseases, utilizing advanced imaging techniques to quantify these inflammatory markers in human brain samples (ref: Lobanova doi.org/10.1038/s41467-024-53547-0/). This innovative approach could enhance the understanding of inflammatory processes in AD and inform therapeutic strategies targeting neuroinflammation. Welikovitch et al. developed a transgenic mouse model to investigate the interplay between amyloid-β and tau pathology, revealing how these neuropathologies contribute to synapse loss and glial activation (ref: Welikovitch doi.org/10.1093/brain/). This model provides a valuable platform for testing anti-inflammatory therapies. Arber et al. focused on the role of microglia in familial British dementia, demonstrating their contribution to the production of amyloidogenic peptides, thus linking immune responses to amyloid pathology (ref: Arber doi.org/10.1007/s00401-024-02820-z/). Garland et al. characterized the microglial translocator protein (TSPO) as a marker of neuroinflammation, providing insights into the phagocytic phenotype of microglia in AD (ref: Garland doi.org/10.1007/s00401-024-02822-x/). These findings collectively highlight the importance of neuroinflammatory processes in AD and the potential for targeting these pathways in therapeutic interventions.

Cognitive and behavioral aspects of Alzheimer's disease are critical for understanding its impact on patients and developing effective interventions. Vockert et al. explored the cognitive reserve hypothesis, demonstrating that higher personalized fMRI-based cognitive reserve scores can mitigate the effects of AD pathology on cognitive decline, suggesting that educational and lifestyle factors play a significant role in cognitive resilience (ref: Vockert doi.org/10.1038/s41467-024-53360-9/). This highlights the potential for cognitive training and educational interventions to enhance cognitive function in at-risk populations. Gleason et al. investigated the long-term cognitive effects of menopausal hormone therapy, finding no significant impact on cognitive performance over a decade, which raises questions about the efficacy of hormonal interventions in cognitive health (ref: Gleason doi.org/10.1371/journal.pmed.1004435/). Khodadadi Arpanahi et al. conducted a comprehensive study on the progression of Alzheimer's disease using resting-state fMRI, revealing dynamic changes in brain connectivity that correlate with disease stages (ref: Khodadadi Arpanahi doi.org/10.1016/j.arr.2024.102590/). Additionally, Mackin et al. examined cortico-limbic volume abnormalities in late-life depression, finding distinct patterns compared to amyloid pathology, which could inform differential diagnosis and treatment strategies (ref: Mackin doi.org/10.1038/s41380-024-02677-4/). These studies collectively underscore the importance of understanding cognitive and behavioral dimensions of AD to inform clinical practice and improve patient outcomes.

Translational research in Alzheimer's disease focuses on bridging the gap between laboratory findings and clinical applications. Zha et al. elucidated the gut-microbiome-brain axis, demonstrating how microbiota-derived lysophosphatidylcholine can alleviate AD pathology, suggesting dietary interventions as a potential therapeutic avenue (ref: Zha doi.org/10.1016/j.cmet.2024.10.006/). This highlights the importance of integrating microbiome research into AD treatment strategies. Guo et al. investigated the role of lipidated ApoE in AD, revealing how specific isoforms interact with receptors to influence neurodegeneration, which could inform targeted therapies aimed at modulating lipid metabolism (ref: Guo doi.org/10.1016/j.cell.2024.10.027/). Salloway et al. provided insights into amyloid-related imaging abnormalities (ARIA) in clinical trials, emphasizing the need for careful monitoring of these effects in patients undergoing treatment with anti-amyloid therapies (ref: Salloway doi.org/10.1001/jamaneurol.2024.3937/). Panek et al. introduced a novel drug candidate that modulates cholinergic and GABAergic neurotransmission, representing a promising approach for palliative treatment in AD (ref: Panek doi.org/10.1002/anie.202420510/). These studies collectively illustrate the critical role of translational research in developing effective interventions for Alzheimer's disease, emphasizing the need for a multidisciplinary approach that incorporates genetic, environmental, and therapeutic factors.