The genetic landscape of Alzheimer's disease (AD) is significantly influenced by the apolipoprotein E (APOE) gene, particularly the APOE4 variant, which is the strongest genetic risk factor for the disease. Research has demonstrated that the local haplotype of APOE4, rather than merely the presence of a single risk allele, plays a crucial role in increasing the risk of AD. Tcw et al. utilized human brain cell models derived from both population and isogenic induced pluripotent stem cells to elucidate the cellular impacts of APOE4, revealing that it induces specific changes in astrocytes and microglia that may contribute to AD pathology (ref: Tcw doi.org/10.1016/j.cell.2022.05.017/). Furthermore, Le Guen et al. conducted a large-scale analysis involving over 475,000 participants to assess the association of rare missense variants in APOE with AD risk, employing logistic regression models to establish significant correlations (ref: Le Guen doi.org/10.1001/jamaneurol.2022.1166/). These findings underscore the complexity of genetic contributions to AD, highlighting the need for further exploration of APOE's role in neurodegeneration and cognitive decline. In addition to APOE, other studies have investigated the pathological mechanisms associated with AD. Lee et al. focused on autophagy dysregulation in AD mouse models, revealing that impaired autolysosome acidification leads to the accumulation of amyloid-beta (Aβ) within neurons, a precursor to senile plaques (ref: Lee doi.org/10.1038/s41593-022-01084-8/). This suggests that the interplay between genetic factors and cellular processes is critical in understanding AD progression. Moreover, the exploration of tau pathology, as demonstrated by Teng et al., indicates that neurofibrillary tangles correlate with clinical severity, emphasizing the multifaceted nature of AD pathology (ref: Teng doi.org/10.1001/jamaneurol.2022.1375/). Collectively, these studies illustrate the intricate relationship between genetic predispositions and the biological mechanisms underlying Alzheimer's disease.

Neuroinflammation plays a pivotal role in the pathogenesis of Alzheimer's disease, with recent studies highlighting the involvement of specific immune signaling pathways. Puntambekar et al. investigated the effects of CX3CR1 deficiency on microglial function in the context of amyloid pathology, demonstrating that loss of CX3CR1 exacerbates neurodegeneration and cognitive decline by impairing microglial responses to Aβ accumulation (ref: Puntambekar doi.org/10.1186/s13024-022-00545-9/). This finding underscores the importance of microglial activation in modulating neuroinflammatory responses and suggests that targeting CX3CR1 signaling may offer therapeutic potential in AD. Additionally, Kenigsbuch et al. utilized single-cell transcriptomics to identify a disease-associated oligodendrocyte signature in AD models, revealing that these oligodendrocytes are linked to neuroinflammatory processes (ref: Kenigsbuch doi.org/10.1038/s41593-022-01104-7/). The study suggests that oligodendrocytes may contribute to the neuroinflammatory milieu in AD, further complicating the interplay between neuronal and non-neuronal cell populations. Furthermore, the role of RIPK1 in mediating inflammatory responses was explored by Li et al., who found that nuclear RIPK1 promotes chromatin remodeling to facilitate the transcription of pro-inflammatory genes (ref: Li doi.org/10.1038/s41422-022-00673-3/). These findings collectively highlight the multifaceted nature of neuroinflammation in AD and its potential as a therapeutic target.

The pathological mechanisms underlying Alzheimer's disease are characterized by the accumulation of amyloid-beta and tau proteins, which serve as critical biomarkers for disease progression. Lee et al. demonstrated that faulty autolysosome acidification in AD mouse models leads to the autophagic build-up of Aβ, contributing to the formation of senile plaques (ref: Lee doi.org/10.1038/s41593-022-01084-8/). This study emphasizes the importance of autophagy in maintaining neuronal health and suggests that autophagic dysregulation may be a key factor in AD pathology. Moreover, the relationship between tau pathology and cognitive decline was further elucidated by Rabin et al., who found that cerebral amyloid angiopathy interacts with neuritic plaques to accelerate tau burden and cognitive decline (ref: Rabin doi.org/10.1093/brain/). This interaction highlights the complex interplay between different pathological features of AD and their cumulative effects on cognitive function. Additionally, Tanner et al. explored the correlations between PET imaging biomarkers and cognitive performance in early and late-onset AD, revealing that tau and neurodegeneration, rather than amyloid, were significantly associated with cognitive decline across age groups (ref: Tanner doi.org/10.1093/brain/). These findings collectively underscore the need for a comprehensive understanding of the pathological mechanisms and biomarkers associated with Alzheimer's disease to inform future therapeutic strategies.

Cognitive decline in Alzheimer's disease is often assessed through various clinical measures, with recent studies emphasizing the importance of dual decline in gait speed and cognition as a significant predictor of dementia risk. Collyer et al. reported that individuals exhibiting both cognitive and gait speed decline had the strongest association with increased dementia risk, highlighting the need for integrated assessments in clinical settings (ref: Collyer doi.org/10.1001/jamanetworkopen.2022.14647/). This finding suggests that monitoring gait speed may serve as a valuable clinical marker for early detection of cognitive decline. Additionally, the role of genetic factors in cognitive decline was explored by Le Guen et al., who investigated the association of rare APOE missense variants with AD risk across a large cohort (ref: Le Guen doi.org/10.1001/jamaneurol.2022.1166/). Their findings indicate that specific genetic variants may influence the trajectory of cognitive decline in affected individuals. Furthermore, the study by Teng et al. on the safety and efficacy of semorinemab in individuals with prodromal to mild AD revealed that neurofibrillary tangles correlate with clinical severity, reinforcing the link between pathological features and cognitive outcomes (ref: Teng doi.org/10.1001/jamaneurol.2022.1375/). Collectively, these studies highlight the multifactorial nature of cognitive decline in Alzheimer's disease, emphasizing the interplay between genetic, pathological, and clinical factors.

Recent clinical trials and therapeutic approaches for Alzheimer's disease have focused on targeting the underlying pathological mechanisms associated with the disease. Teng et al. conducted a randomized clinical trial to assess the safety and efficacy of semorinemab, a monoclonal antibody targeting aggregated tau protein, in individuals with prodromal to mild AD. The study found that while both the treatment and placebo groups experienced similar increases in clinical dementia rating scores, the trial provided valuable insights into the potential of tau-targeting therapies (ref: Teng doi.org/10.1001/jamaneurol.2022.1375/). This highlights the ongoing challenges in developing effective treatments that can significantly alter disease progression. In addition to tau-targeting strategies, Chou et al. explored the structural mechanisms of NMDA receptor channel blockers, which hold promise for treating various neurological disorders, including Alzheimer's disease (ref: Chou doi.org/10.1038/s41594-022-00772-0/). Understanding the binding mechanisms of these therapeutic agents is crucial for optimizing their efficacy and minimizing side effects. Furthermore, Lee et al.'s investigation into autophagy dysregulation in AD mouse models underscores the potential for autophagy-enhancing therapies to mitigate Aβ accumulation and improve neuronal health (ref: Lee doi.org/10.1038/s41593-022-01084-8/). Collectively, these studies reflect a growing interest in diverse therapeutic strategies aimed at addressing the complex pathology of Alzheimer's disease.

Neuroimaging and biomarker studies have become essential in understanding the progression of Alzheimer's disease and informing clinical practice. Recent research by Tanner et al. utilized PET imaging to investigate the relationships between amyloid, tau, and metabolic markers with cognitive performance in both early and late-onset AD. Their findings revealed that tau and neurodegeneration were significantly associated with cognitive decline, while amyloid levels did not show the same correlation, suggesting that tau pathology may be a more reliable biomarker for cognitive impairment (ref: Tanner doi.org/10.1093/brain/). Additionally, Rabin et al. examined the interaction between cerebral amyloid angiopathy and neuritic plaques, finding that this interaction exacerbates tau burden and cognitive decline (ref: Rabin doi.org/10.1093/brain/). This highlights the importance of considering multiple pathological features when assessing cognitive outcomes in AD. Furthermore, Lee et al. provided insights into the mechanisms of autophagy dysregulation in AD, which may serve as a potential biomarker for disease progression (ref: Lee doi.org/10.1038/s41593-022-01084-8/). Together, these studies underscore the critical role of neuroimaging and biomarker research in advancing our understanding of Alzheimer's disease and guiding therapeutic interventions.

Lifestyle and environmental factors are increasingly recognized as significant contributors to the risk of developing Alzheimer's disease. Recent studies have explored the interplay between genetic predispositions and lifestyle choices, with Le Guen et al. highlighting the association of rare APOE missense variants with AD risk, suggesting that genetic factors may interact with environmental influences to modulate disease onset (ref: Le Guen doi.org/10.1001/jamaneurol.2022.1166/). This emphasizes the need for a holistic approach to understanding AD, considering both genetic and lifestyle factors. Moreover, Collyer et al. investigated the dual decline in gait speed and cognition as a predictor of dementia risk, suggesting that physical activity and mobility may serve as critical lifestyle factors influencing cognitive health (ref: Collyer doi.org/10.1001/jamanetworkopen.2022.14647/). The findings indicate that maintaining physical activity could be a protective factor against cognitive decline. Additionally, studies on circadian rhythms and sleep patterns, such as those by Shafer and Mofrad, suggest that disruptions in these areas may also impact cognitive function and contribute to AD risk (ref: Shafer doi.org/10.7554/eLife.79139/; ref: Mofrad doi.org/10.7554/eLife.75769/). Collectively, these studies highlight the importance of integrating lifestyle and environmental factors into the broader context of Alzheimer's disease research.