Microglia, the resident immune cells of the central nervous system, play a crucial role in the pathology of Alzheimer's disease (AD). Recent studies have highlighted their dual role in either exacerbating or alleviating disease progression. For instance, research has shown that microglia can slow tauopathy development by controlling the spread of phosphorylated tau (pTau) in both the central nervous system and blood (ref: Mason doi.org/10.1038/s41590-025-02198-4/). Additionally, boosting angiotensin-converting enzyme (ACE) expression specifically in microglia has been found to reduce amyloid-beta (Aβ) plaque load and preserve neuronal integrity in the 5xFAD mouse model of AD, suggesting a protective role of microglia when properly activated (ref: Gomez doi.org/10.1038/s43587-025-00879-1/). Furthermore, exercise has been shown to elicit distinct transcriptomic responses in microglia, particularly in the neurogenic stem-cell niche of the hippocampus, indicating that lifestyle factors can modulate microglial function and potentially mitigate AD pathology (ref: da Rocha doi.org/10.1038/s41593-025-01971-w/). The choroid plexus (ChP) has also emerged as a significant player in AD, with early transcriptional and cellular abnormalities observed in mouse models, suggesting that it may contribute to neuroinflammation and disease progression (ref: Yan doi.org/10.1186/s13024-025-00853-w/). In vitro studies have further elucidated the role of cytokines in reprogramming human macrophages toward AD-relevant phenotypes, emphasizing the importance of understanding microglial activation states (ref: Podleśny-Drabiniok doi.org/10.1016/j.celrep.2025.115909/). Overall, these findings underscore the complex interplay between microglial function and AD pathology, highlighting both protective and detrimental roles depending on the context of activation.

Genetic factors play a pivotal role in the susceptibility and progression of Alzheimer's disease (AD). The R136S mutation in the APOE3 gene has been identified as conferring resilience against tau pathology, inhibiting the cGAS-STING-IFN pathway, and thus protecting against cognitive decline despite the presence of other risk factors (ref: Naguib doi.org/10.1016/j.immuni.2025.05.023/). Conversely, the UNC5C T835M mutation has been linked to increased neurodegeneration and oxidative stress in aged mice, suggesting that certain genetic mutations can exacerbate AD pathology (ref: Karunakaran doi.org/10.1186/s13024-025-00850-z/). Furthermore, novel early-onset AD-associated genes have been identified that influence risk through the dysregulation of glutamate signaling and immune activation pathways, indicating that both late-onset and early-onset forms of AD may involve distinct genetic mechanisms (ref: Bradley doi.org/10.1002/alz.70377/). In addition to genetic mutations, therapeutic strategies targeting amyloid-beta (Aβ) have been explored. A peptide epitope vaccine targeting the Aβ1-10 sequence has shown promise in reducing Aβ-induced neuroinflammation in mouse models (ref: Park doi.org/10.1016/j.bbi.2025.06.001/). Moreover, the lipidomic analysis of 5xFAD mice has revealed significant alterations in lipid profiles associated with Aβ pathology, suggesting that lipid metabolism may be a critical area for therapeutic intervention (ref: Cha doi.org/10.1021/acs.jproteome.4c01133/). These findings collectively highlight the intricate genetic and molecular landscape of AD, emphasizing the need for targeted approaches in both understanding and treating the disease.

Neuroinflammation is a central feature of neurodegenerative diseases, particularly Alzheimer's disease (AD). Recent studies have demonstrated that depression can exacerbate AD pathology through mechanisms involving microglial activation and lactate-dependent signaling, leading to increased Aβ plaque deposition (ref: Liu doi.org/10.1186/s12974-025-03488-2/). Additionally, the presence of the APOE ε4 allele has been shown to exacerbate inflammation-induced lysosomal dysfunction in human iPSC-derived microglia, suggesting that genetic predispositions can influence immune responses in the context of AD (ref: Hellén doi.org/10.1186/s12974-025-03470-y/). Moreover, mitochondrial damage-associated molecular patterns (DAMPs) have been identified as key players in neuroimmune responses, acting as ligands for pattern recognition receptors on glial cells and influencing their reactivity (ref: Brooks doi.org/10.4103/NRR.NRR-D-24-01459/). Studies have also shown that blood serum from AD patients alters microglial phagocytosis, indicating that systemic factors can modulate local immune responses in the brain (ref: Altendorfer doi.org/10.4103/NRR.NRR-D-24-01287/). These findings underscore the complex interplay between neuroinflammation and immune responses in neurodegeneration, highlighting potential therapeutic targets for modulating these pathways.

The search for effective therapeutic strategies for Alzheimer's disease (AD) has led to various innovative approaches targeting neuroinflammation and oxidative stress. One promising avenue involves the modulation of Sirt1, which has been shown to regulate inflammatory cytokines and oxidative stress, potentially influencing the transition from depressive disorders to AD (ref: Zou doi.org/10.1007/s12035-025-05084-0/). Additionally, Ciliatoside A has demonstrated efficacy in attenuating neuroinflammation by activating mitophagy and inhibiting NLRP3 inflammasome activation in microglial cells, highlighting the potential of targeting mitochondrial health in AD therapy (ref: Guo doi.org/10.1016/j.phymed.2025.156928/). Short-term inhibition of NOX2 has also shown promise in preventing Aβ-induced pathology in mice, suggesting that oxidative stress pathways may be viable targets for intervention (ref: Mukhina doi.org/10.3390/antiox14060663/). Furthermore, the design of multitarget compounds that act as dual GPR40 agonists and HDAC6 inhibitors represents a novel strategy to modulate neuroinflammation in AD (ref: Pinheiro doi.org/10.1016/j.ejmech.2025.117868/). Collectively, these studies underscore the multifaceted nature of AD and the importance of developing targeted therapies that address the underlying mechanisms of the disease.

Neurodegenerative mechanisms in Alzheimer's disease (AD) are complex and multifactorial, involving various pathways that contribute to disease progression. One significant area of research focuses on blood-brain barrier (BBB) dysfunction, which has been implicated in the pathogenesis of cerebral small vessel disease and AD. Studies have shown that BBB permeability increases alongside white and gray matter lesions, correlating with cognitive decline (ref: Shal doi.org/10.1161/STROKEAHA.124.050452/). This highlights the critical role of vascular health in neurodegeneration and suggests that interventions targeting BBB integrity may be beneficial. Additionally, neuroinflammation has been identified as a key contributor to neurodegenerative processes. For instance, targeting neuroinflammation with compounds like 3-monothiopomalidomide has shown promise in mitigating traumatic brain injury and subsequent neurodegeneration (ref: Hsueh doi.org/10.1186/s12929-025-01150-w/). Furthermore, the role of mitochondrial damage-associated molecular patterns in modulating neuroimmune responses has been emphasized, indicating that mitochondrial health is crucial for maintaining neuroinflammatory balance (ref: Brooks doi.org/10.4103/NRR.NRR-D-24-01459/). These findings collectively underscore the importance of understanding the intricate mechanisms underlying neurodegeneration to develop effective therapeutic strategies.

Environmental and lifestyle factors significantly influence the risk and progression of Alzheimer's disease (AD). Recent studies have explored the impact of dietary components, such as medium-chain triglycerides (MCT) derived from coconut oil, which have been shown to ameliorate memory deficits and promote neurite outgrowth in AD mouse models (ref: Chen doi.org/10.3389/fnut.2025.1585640/). This suggests that dietary interventions may play a role in cognitive health and neuroprotection. Moreover, the effects of systemic factors, such as blood serum from AD patients, have been shown to alter microglial phagocytosis, indicating that environmental influences can modulate immune responses in the brain (ref: Altendorfer doi.org/10.4103/NRR.NRR-D-24-01287/). Additionally, short-term inhibition of NOX2 has been demonstrated to prevent Aβ-induced pathology, suggesting that lifestyle modifications that reduce oxidative stress may also be beneficial (ref: Mukhina doi.org/10.3390/antiox14060663/). These findings highlight the importance of considering environmental and lifestyle factors in the context of AD, emphasizing the potential for preventive strategies that incorporate dietary and lifestyle changes.

Synaptic function is critically linked to cognitive decline in Alzheimer's disease (AD), with recent studies revealing the importance of synaptic pruning and neurogenesis in maintaining cognitive health. Research has shown that synaptic pruning genes are correlated with AD pathology and cognitive decline, with sex-specific patterns observed in the associations between complement genes and AD pathology (ref: Sanfilippo doi.org/10.1007/s11357-025-01740-4/). This suggests that understanding the molecular mechanisms underlying synaptic pruning may provide insights into cognitive deficits associated with AD. Furthermore, the role of microglia in promoting a pro-neurogenic niche for neuronal progenitors has been highlighted, indicating that microglial activity can influence neurogenesis and cognitive outcomes in neurodegenerative diseases (ref: Pecoraro doi.org/10.1016/j.bbi.2025.06.017/). These findings underscore the importance of synaptic health and neurogenesis in cognitive function, suggesting that therapeutic strategies aimed at enhancing synaptic integrity and promoting neurogenesis may be beneficial in mitigating cognitive decline in AD.

Microglial activation and neuroinflammation are central to the pathophysiology of Alzheimer's disease (AD). Recent research has demonstrated that exposure to blood serum from AD patients can significantly alter microglial phagocytosis, leading to impaired clearance of amyloid-beta (Aβ) and exacerbated neuroinflammation (ref: Altendorfer doi.org/10.4103/NRR.NRR-D-24-01287/). This highlights the potential impact of systemic factors on local immune responses in the brain. Additionally, mitochondrial damage-associated molecular patterns have been identified as key modulators of microglial reactivity, suggesting that targeting these pathways may provide therapeutic opportunities for modulating neuroinflammation (ref: Brooks doi.org/10.4103/NRR.NRR-D-24-01459/). Moreover, the interplay between neuroinflammation and cognitive decline has been underscored by findings that depression can exacerbate AD pathology through lactate-dependent activation of microglial Kv1.3 channels, promoting Aβ deposition (ref: Liu doi.org/10.1186/s12974-025-03488-2/). This suggests that addressing neuroinflammatory processes may be crucial in developing effective interventions for AD. Overall, these studies emphasize the complex role of microglial activation in neuroinflammation and its implications for AD pathology.