Neuroinflammation plays a critical role in the pathogenesis of Alzheimer's disease (AD), with microglia being central to this process. Recent studies have highlighted the regulatory mechanisms governing microglial activation and their inflammatory responses. For instance, Ndoja et al. demonstrated that the ubiquitin ligase COP1 suppresses neuroinflammation by degrading the transcription factor c/EBPβ in microglia, which is known to regulate pro-inflammatory genes that are upregulated in AD (ref: Ndoja doi.org/10.1016/j.cell.2020.07.011/). This finding underscores the potential of targeting COP1 as a therapeutic strategy to modulate microglial function and reduce neuroinflammation in AD. Additionally, Nguyen et al. utilized single-nucleus RNA sequencing to identify distinct microglial subpopulations in postmortem human brains, revealing that genetic risk factors such as APOE and TREM2 are associated with a depletion of CD163-positive amyloid-responsive microglia, which may contribute to the inflammatory milieu in AD (ref: Nguyen doi.org/10.1007/s00401-020-02200-3/). These insights into microglial heterogeneity and their response to amyloid pathology provide a deeper understanding of the neuroinflammatory landscape in AD. Moreover, the interplay between genetic factors and microglial function is further illustrated by Davis et al., who found that the presence of a second X chromosome in a mouse model conferred resilience against AD-related deficits, suggesting that sex chromosomes may influence microglial responses and neuroinflammation (ref: Davis doi.org/10.1126/scitranslmed.aaz5677/). This highlights the complexity of microglial involvement in AD, where both genetic predispositions and inflammatory responses are intricately linked. Furthermore, the study by Ruan et al. on the P2RX7 inhibitor indicates that targeting specific pathways in microglia can suppress exosome secretion and mitigate disease phenotypes in tau transgenic mice, suggesting a therapeutic avenue for early-stage tauopathies (ref: Ruan doi.org/10.1186/s13024-020-00396-2/). Collectively, these studies emphasize the critical role of microglial function and neuroinflammation in AD, presenting potential targets for therapeutic intervention.

Tau pathology is a hallmark of neurodegenerative diseases, particularly Alzheimer's disease, where hyperphosphorylated tau accumulates and disrupts neuronal function. Park et al. explored the neurovascular dysfunction associated with tau, revealing that mutated tau in mice leads to impaired cerebral blood flow responses to neural activity, indicating that tau may contribute to vascular dysfunction independent of neurodegeneration (ref: Park doi.org/10.1038/s41593-020-0686-7/). This finding suggests that tau's impact on neurovascular health may precede cognitive decline, highlighting its role in the early stages of AD pathology. Additionally, Drummond et al. provided insights into the interactome of phosphorylated tau, identifying a network of proteins that interact with tau and contribute to its pathological effects, thereby expanding our understanding of tau's role in neurodegeneration (ref: Drummond doi.org/10.1093/brain/). Furthermore, the study by Steiner et al. on TREM2 emphasizes the importance of microglial signaling in tau pathology, as TREM2 variants are linked to altered tau processing and clearance (ref: Steiner doi.org/10.15252/embj.2019104247/). This connection between tau and microglial function suggests that therapeutic strategies targeting tau pathology may need to consider the role of microglial activation and signaling pathways. The findings from Heckmann et al. also support this notion, as they demonstrated that the noncanonical function of the autophagy protein Atg16L is crucial for preventing spontaneous AD in mice, indicating that autophagy and tau pathology are interconnected (ref: Heckmann doi.org/10.1126/sciadv.abb9036/). Overall, these studies underscore the multifaceted nature of tau pathology in neurodegeneration, revealing its implications for vascular health, microglial function, and potential therapeutic targets.

Genetic factors and biomarkers play a pivotal role in understanding Alzheimer's disease (AD) and its progression. Dumitrescu et al. conducted a genome-wide association study (GWAS) to identify genetic variants associated with cognitive resilience in individuals exhibiting neuropathological features of AD without cognitive impairment. Their findings suggest that certain genetic pathways may confer protection against cognitive decline despite the presence of AD pathology, highlighting the potential for personalized therapeutic strategies (ref: Dumitrescu doi.org/10.1093/brain/). Additionally, Mengel et al. identified plasma NT1 tau as an early and specific biomarker for AD, demonstrating that elevated levels of NT1 tau in individuals with mild cognitive impairment (MCI) can predict progression to AD dementia (ref: Mengel doi.org/10.1002/ana.25885/). This discovery emphasizes the importance of early detection and monitoring of tau pathology in clinical settings. Moreover, Tang et al. introduced the PSCAN approach, which leverages protein structures to enhance gene discovery related to complex diseases, including AD. Their validation of PSCAN on real datasets underscores its potential utility in identifying novel genetic associations and signal variants that may contribute to AD risk (ref: Tang doi.org/10.1186/s13059-020-02121-0/). The integration of genetic insights with biomarker discovery is further supported by Haenig et al., who presented an interactome map connecting neurodegenerative disease proteins, revealing extensive interconnectivity among known AD-related proteins and those previously unassociated with neurodegeneration (ref: Haenig doi.org/10.1016/j.celrep.2020.108050/). Collectively, these studies highlight the critical interplay between genetic factors and biomarkers in advancing our understanding of AD, paving the way for targeted interventions and improved diagnostic tools.

Cerebrovascular dysfunction is increasingly recognized as a significant contributor to the pathophysiology of Alzheimer's disease (AD). Grill et al. investigated the psychological outcomes of disclosing amyloid imaging results to research participants, revealing that individuals with elevated amyloid levels did not experience short-term negative psychological effects, suggesting that awareness of amyloid status may not adversely impact mental health (ref: Grill doi.org/10.1001/jamaneurol.2020.2734/). This finding is crucial as it underscores the importance of transparency in clinical research and its implications for patient care. Additionally, Beckmann et al. constructed multiscale causal networks from a large multi-omics dataset, identifying VGF as a key regulator in AD, which may influence cerebrovascular health and cognitive outcomes (ref: Beckmann doi.org/10.1038/s41467-020-17405-z/). Furthermore, Anatürk et al. examined the longitudinal trajectories of cognitive and social activities, finding associations with brain health indicators in older adults. Their study suggests that engagement in cognitive and social activities may mitigate the effects of aging on brain structure and function, highlighting the potential for lifestyle interventions to support cerebrovascular health in aging populations (ref: Anatürk doi.org/10.1001/jamanetworkopen.2020.13793/). These findings collectively emphasize the intricate relationship between cerebrovascular function, cognitive health, and psychological outcomes in AD, suggesting that both biological and lifestyle factors play critical roles in disease progression and patient well-being.

The psychological and cognitive outcomes of individuals with Alzheimer's disease (AD) are critical areas of research, particularly in understanding the impact of disease progression on mental health. Grill et al. explored the short-term psychological effects of disclosing amyloid imaging results to participants without cognitive impairment, finding that those with elevated amyloid levels reported increased concern about AD, yet did not experience significant negative psychological sequelae (ref: Grill doi.org/10.1001/jamaneurol.2020.2734/). This study highlights the importance of communication strategies in clinical settings, as understanding one's risk may influence psychological well-being. Additionally, Avila et al. examined the role of educational attainment in contributing to cognitive reserve across different racial and ethnic groups, revealing that education may differentially impact cognitive trajectories and brain integrity indicators, such as hippocampal volume and cortical thickness (ref: Avila doi.org/10.1002/alz.12176/). Moreover, Szigeti et al. investigated the role of the CHRFAM7A gene, a human-specific fusion gene that negatively regulates cholinergic signaling, in the context of AD. Their findings suggest that this gene may account for the translational gap observed in cholinergic therapies, emphasizing the need for tailored approaches in treatment strategies (ref: Szigeti doi.org/10.1016/j.ebiom.2020.102892/). Collectively, these studies underscore the complex interplay between psychological factors, cognitive reserve, and genetic influences in AD, highlighting the necessity for comprehensive approaches to address both cognitive and emotional aspects of the disease.

Identifying therapeutic targets and treatment strategies for Alzheimer's disease (AD) is a critical focus of current research. Flagmeier et al. investigated the aggregation of the Aβ42 peptide, demonstrating that the disruption of lipid membranes correlates with the kinetics of oligomer formation, suggesting that targeting membrane interactions may be a viable therapeutic strategy (ref: Flagmeier doi.org/10.1038/s41594-020-0471-z/). This study highlights the importance of understanding the biophysical properties of amyloid peptides in developing effective treatments. Additionally, Heckmann et al. explored the noncanonical functions of the autophagy protein Atg16L, revealing that its loss drives spontaneous AD in mice, indicating that autophagy modulation could be a potential therapeutic avenue for neurodegeneration (ref: Heckmann doi.org/10.1126/sciadv.abb9036/). Furthermore, Kalar et al. conducted a registry study examining the effects of calcium channel blockers (CCBs) on mortality and stroke risk in dementia patients, finding that amlodipine was associated with reduced mortality risk in Alzheimer's dementia patients (ref: Kalar doi.org/10.1111/joim.13170/). This suggests that existing medications may offer unexpected benefits in managing AD-related symptoms. Ates et al. also reported that CMS121, a fatty acid synthase inhibitor, alleviates cognitive loss and modulates lipid metabolism in transgenic AD mice, reinforcing the role of lipid metabolism in AD pathophysiology (ref: Ates doi.org/10.1016/j.redox.2020.101648/). Together, these studies emphasize the need for innovative therapeutic strategies that target various aspects of AD pathology, from amyloid aggregation to metabolic dysregulation and existing pharmacological agents.

Environmental and lifestyle factors significantly influence the risk and progression of Alzheimer's disease (AD). Casares et al. highlighted the role of oxidative stress and inflammation in neurodegenerative diseases, proposing that pharmacological activation of NRF2 or inhibition of BACH1 could provide neuroprotective effects (ref: Casares doi.org/10.1016/j.redox.2020.101689/). This suggests that lifestyle interventions aimed at reducing oxidative stress may be beneficial in mitigating AD risk. Additionally, Lumsden et al. conducted a phenome-wide association study to explore the disease risks associated with different APOE genotypes, revealing that the APOE ε4 allele is linked to increased risks for various conditions, including AD (ref: Lumsden doi.org/10.1016/j.ebiom.2020.102954/). Understanding these genetic predispositions can inform lifestyle modifications to reduce disease risk. Moreover, Avila et al. examined the differential contributions of education to cognitive reserve across racial and ethnic groups, indicating that higher educational attainment may provide protective effects against cognitive decline (ref: Avila doi.org/10.1002/alz.12176/). This underscores the importance of educational opportunities and cognitive engagement in promoting brain health. Furthermore, Ma et al. investigated the burden of mortality attributable to extreme temperatures, finding associations with increased risks of mortality from various causes, including AD (ref: Ma doi.org/10.1016/j.envint.2020.105994/). These findings collectively emphasize the multifaceted impact of environmental and lifestyle factors on AD, suggesting that comprehensive public health strategies should address both genetic and modifiable risk factors to reduce the burden of the disease.

Amyloid pathology is a central feature of Alzheimer's disease (AD), with amyloid-β (Aβ) accumulation being implicated in neurotoxicity and cognitive decline. Darling et al. elucidated the atomic structures of Aβ oligomers, revealing how they form lipid-stabilized pores that disrupt neuronal membranes, thereby providing insights into the neurotoxic mechanisms of Aβ (ref: Darling doi.org/10.1016/j.tins.2020.07.006/). This structural understanding is crucial for developing targeted therapies aimed at preventing Aβ aggregation and its deleterious effects on neuronal function. Additionally, Jia et al. investigated the potential of exosomal synaptic proteins as biomarkers for predicting AD at asymptomatic stages, demonstrating that specific protein profiles can indicate early pathological changes (ref: Jia doi.org/10.1002/alz.12166/). Moreover, Ledo et al. examined the role of presenilin 1 phosphorylation in regulating Aβ degradation by microglia, highlighting the importance of microglial function in Aβ clearance and its implications for AD pathology (ref: Ledo doi.org/10.1038/s41380-020-0856-8/). This emphasizes the need for therapeutic strategies that enhance microglial activity to promote Aβ clearance. Furthermore, Mengel et al. identified plasma NT1 tau as a specific and early marker of AD, reinforcing the significance of tau pathology in conjunction with amyloid pathology in disease progression (ref: Mengel doi.org/10.1002/ana.25885/). Collectively, these studies underscore the critical role of amyloid pathology in AD and its implications for early diagnosis and therapeutic interventions.