Emerging approaches to bridging discovery science with clinical care in Alzheimer's disease

Alzheimer's disease (AD), first identified over a century ago, remains a devastating neurodegenerative disorder affecting millions of people worldwide. Despite decades of research, therapeutic progress has been limited, with over 99 ​% of clinical trials failing to yield effective treatments. However, recent breakthroughs, such as the FDA approval of anti-amyloid monoclonal antibodies (MABs), signal a turning point in the field. This progress underscores the critical importance of integrating innovative scientific discoveries with clinical practice to address the urgent global health crisis posed by AD. As aging populations grow, the projected surge in AD cases demands not only optimized current therapies but also transformative strategies that target the disease's complex pathophysiology. Collaborative, multidisciplinary efforts are now unlocking unprecedented opportunities to redefine AD treatment, offering hope for meaningful advances in the years ahead.

AD pathology is marked by intricate mechanisms beyond amyloid plaques and tau tangles, including, but not limited to, neuroinflammation, impaired protein aggregate clearance, mitochondrial dysfunction, oxidative stress, cellular senescence, dysregulation of non-neuronal brain cells, and disrupted hippocampal neurogenesis. This special issue of Neurotherapeutics highlights cutting-edge research illuminating these pathways and their therapeutic potential. A landmark development is the advent of MABs, which reduce amyloid burden and represent the first disease-targeted therapies for AD. While challenges such as amyloid-related imaging abnormalities (ARIA), particularly edema (ARIA-E) and microhemorrhages (ARIA-H), represent significant risks, these therapies also lay the groundwork for future multimodal approaches. Innovations in biomarker-guided protocols and safety monitoring, as reviewed by Cummings [1], are enhancing the clinical utility of MABs, emphasizing their role in a growing and broader therapeutic arsenal.

Central to AD progression is impaired protein clearance that also leads to cerebral amyloid angiopathy (CAA) and glymphatic dysfunction, which represent major risk factors for ARIA. Bonnar et al. [2] explore interventions to restore glymphatic flow, such as sensory stimulation and sleep optimization, that may reduce amyloid accumulation while mitigating ARIA risks. Similarly, targeting innate immune pathways holds promise. Specifically, Kehs et al. [3] identify interferon-induced transmembrane protein 3 (IFITM3) as a nexus between infection, inflammation, and Aβ overproduction. Inhibiting IFITM3 could curb amyloidogenesis, while Alarcón-Espósito et al. [4] highlight the cGAS-STING pathway as a driver of neuroinflammation and tauopathy. Advances in cGAS inhibitors, developed through inspiring academic-industry collaborations, exemplify how immune modulation is merging with precision drug design to disrupt AD pathogenesis.

Beyond amyloid, novel strategies to degrade pathological aggregates are emerging. Kuriyama et al. [5] review proteolysis targeting chimeras (PROTACs) and photo-oxygenation, which target intracellular proteins. PROTACs utilizes bifunctional molecules that recruit E3 ubiquitin ligases to tag intracellular proteins for proteasomal degradation, while photo-oxygenation utilizes light-activated photocatalysts (typically flavin and Thioflavin T derivatives) to selectively oxygenate amyloid structure proteins, disrupting their ability to form pathological β-sheets that lead to their accumulation. Recent advances in near-infrared light, ultrasound, and chemiluminescence are also improving tissue penetration of the activating signal for this strategy. These approaches, combined with additional tau-specific degraders such as autophagy-targeting chimeras (AUTOTACs), TRIM21-dependent degraders and intrabodies, and lysosome-targeting chimeras (LYTACs), reviewed by Sandhoff et al. [6], underscore the potential of personalized, conformation-specific therapies that selectively eliminate disease-causing species while sparing the native forms needed for normal function. Furthermore, cryogenic-electron microscopy (cryo-EM), which enables macromolecular structure determination without the need for crystallization, has revealed structural heterogeneity in Aβ and tau aggregates, enabling therapies tailored to toxic polymorphs, a leap toward precision medicine that is described by Sun and Mok [7].

Mitochondrial dysfunction and oxidative stress further exemplify AD's complexity, with the brain's high metabolic activity and significant oxygen consumption rendering it particularly susceptible to oxidative damage. Percy et al. [8] outline strategies to restore mitochondrial health, including antioxidants and fission/fusion modulators, while Soni et al. [9] introduce HPPE, a dual nuclear factor erythroid 2-related factor 2 (Nrf2) activator and BTB and CNC homology 1 (Bach1) inhibitor. Nrf2 is well-known for its role in orchestrating antioxidant, anti-inflammatory, and proteostatic pathways critical for neuronal survival, and diminished Nrf2 activity is a driver of Aβ deposition, tau hyperphosphorylation, mitochondrial dysfunction, and neuroinflammation in AD. Moreover, Nrf2 activation, through agents such as sulforaphane, combats this pathology. However, excessive activation of the Nrf2 pathway causes reductive stress, which can prove deleterious, and the electrophilic nature of sulforaphane can also cause dangerous side effects when administered in high doses. In addition, prolonged Nrf2 activation leads to an upregulation of Bach1, which transcriptionally represses Nrf2 levels. HPPE serves as a non-electrophilic Nrf2 activator and BACH1 inhibitor that safely elevates Nrf2 to augment protection from oxidative stress while avoiding reductive stress or electrophilic off-target effects. These innovations, described by Percy et al. [8] and Soni et al. [9], highlight a shift away from singular targets to multi-pathway modulation.

Glial dysfunction is also an increasingly recognized therapeutic frontier in AD. Ziar et al. [10] describe how astrocyte and oligodendrocyte pathology promote AD through neuroinflammation, synaptic dysfunction, and myelin degeneration. For example, APOE4 disrupts oligodendrocyte cholesterol homeostasis, impairing myelination and accelerating Aβ deposition by diverting microglial clearance activity away from pathological Aβ in order to meet the need for removal of myelin debris, revealing a vicious cycle between myelin integrity and amyloidosis. The authors review how remyelination strategies (leucine-rich repeat and immunoglobulin domain-containing protein 1 (LINGO-1) antibodies or clemastine) and glial-targeted therapies (Nrf2 activators or glucagon-like peptide 1 receptor (GLP-1R) agonists) can restore brain homeostasis.

Another emerging cellular target in AD is that of cellular senescence, which is a state of irreversible cell cycle arrest driven by aging and stress. Hudson et al. [11] review the novel roles of senescent neurons, oligodendrocyte precursor cells (OPCs), microglia, and blood-brain barrier (BBB) cells in driving neuroinflammation, synaptic dysfunction, and protein aggregation in AD. Each of these cell types inflicts unique contributions to the progression of AD, which synergize to promote neurodegeneration. Senolytic strategies, which selectively clear senescent cells (senolytics) or suppress their toxicity (senomorphics), are showing significant promise in preclinical AD models. These agents include dasatinib ​+ ​quercetin (D ​+ ​Q) (reduces senescent OPCs and neurofibrillary tangles, restores cerebral blood flow, and alleviates plaque burden, and currently in Phase II clinical trials), fisetin (clears senescent neurons, mitigates oxidative stress, and exhibits anti-inflammatory effects), and navitoclax (attenuate microglial/astrocyte senescence).

The final cellular target for AD addressed in this special issue is therapeutic modulation of postnatal hippocampal neurogenesis. This process, critical for synaptic plasticity, learning, and memory, is impaired early in AD and mild cognitive impairment (MCI). Mostafa et al. [12] present cutting-edge insights into the regulation of neurogenesis and its potential modulation to counteract cognitive decline by rejuvenating hippocampal plasticity in AD. Robust efforts in the field have been devoted to generating various small drug-like molecules that enhance hippocampal neurogenesis, as well as identifying existing medications and lifestyle interventions that augment this process. While currently at the preclinical developmental stage, there is considerable confidence and optimism in the field that augmenting hippocampal neurogenesis in AD patients will help restore brain function.

Lastly, Ren et al. [13] envision a future where digital twin (DT) technology accelerates drug discovery and personalizes treatment. By integrating multi-omics data with AI, DTs can predict disease trajectories and biomarker efficacy, optimize clinical trials, and tailor therapies, further revolutionizing AD care through precision medicine.

In conclusion, the fight against AD is entering an era of unprecedented innovation. From immune modulators and protein degraders to senolytics and digital twins, the convergence of diverse scientific disciplines is illuminating pathways once deemed intractable. While challenges remain, such as ensuring therapeutic safety, accessibility, and equitable implementation, the collaborative spirit driving these advances inspires optimism. By bridging discovery science with clinical translation, the field is poised to transform AD from a terminal diagnosis to a manageable condition. As research continues to unravel the interplay of aging, genetics, and pathophysiology, the promise of therapies that halt or prevent AD grows ever more tangible. Together, these efforts herald a future where the profound burden of Alzheimer's is alleviated, restoring hope for patients, families, and societies worldwide.