Alzheimer's disease (AD) is a progressive neurological disease that gradually impairs cognitive function and ultimately results in death. It represents the most prevalent cause of dementia in the elderly people [1]. The molecular hallmarks of AD are the build-up of tau-associated neurofibrillary tangles and β-amyloid plaques (Aβ) [2]. It can cause neurodegeneration in both sporadic and genetic types. While non-amnestic cognitive decline is a less prevalent form of AD, amnestic cognitive impairment is the predominant expression. It is a leading contributor to cognitive impairment during midlife and later stages of life, with its clinical presentation often influenced by coexisting neurodegenerative and cerebrovascular pathologies [3].

It is commonly acknowledged that Aβ, which may take many different forms and have different consequences, is a major contributing factor to AD. The initial line of defence of body against infection and disease is the innate immune system, which recognizes pathogen and cellular stresses [4]. Innate immune sensors recognize pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) which triggers a number of downstream signalling events, such as the inflammatory cytokines and interferons (IFN) and the activation of programmed cell death (PCD). In order to eliminate the replicative niche of pathogen and eliminate undesirable cells and preserve homeostasis, PCD is the crucial part of innate immune response. The PCD pathways are classified as lytic and non-lytic. The best characterised lytic mechanisms are necroptosis and pyroptosis while apoptosis is basically a non-lytic pathway [5]. Although these pathways were formerly thought to be autonomous but later significant molecular crosstalk between these pathways has been discovered, helping to conceptualize PANoptosis. Multiprotein PANoptosome complexes that incorporate elements form existing cell death pathways regulate PANoptosis, a distinct innate immunological lytic, inflammatory PCD mechanism that is triggered by caspases and receptor interacting protein kinases (RIPKs). Four PANoptosome complexes have been molecularly described so far are RIPK1-PANoptosome, NLRP12 (NLR family, pyrin domain containing 12) PANoptosome, AIM2 (absent in melanoma-2)- PANoptosome and Z-DNA binding protein −1 (ZBP1) PANoptosome [6].

PANoptosis represents a central mechanism contributing to the progression of AD by integrating the molecular pathways of pyroptosis, apoptosis and necroptosis into a unified form of programmed inflammatory cell death. Driven by Aβ accumulation, tau pathology, mitochondrial dysfunction and neuroinflammation, PANoptosis amplifies neuronal injury and accelerates cognitive decline. Aβ and NFT activates inflammasomes, caspases and RIP kinases, promoting a cascade of mitochondrial damage, oxidative stress and synaptic loss. Mitochondrial dysfunction and the release of DAMPs further enhance inflammasome activation and cell death. Glial cell-mediated neuroinflammation sustains this destructive cycle by releasing cytokines that reinforces PANoptotic signalling. The convergence of these processes leads to widespread neurodegeneration and highlights PANoptosis as a key pathological features of AD. Importantly, therapeutic targeting of upstream regulators like NLRP3, RIPK1 and caspase-1 may interrupt this cycle, offering novel strategies to slow disease progression [7,8].

In AD, multiple signalling pathways converge to activate PANoptosis. The cGAS-STING pathway is triggered by mitochondrial dysfunction, activating inflammasomes (NLRP3, AIM2) and leading to pyroptosis and neuroinflammation [9,10]. The PI3K/AKT pathway, typically protective against cell death, is suppressed by Aβ-induced insulin resistance, removing it inhibitory effects on caspases, RIPK1/3 and inflammasomes thus promoting PANoptosis and BBB damage [11]. The JAK/STAT/IRF1 axis, activated by chronic cytokine signalling, drives the transcription of PANoptotic components like ZBP1, AIM2 and NLRP3, contributing to neurodegeneration [12]. Moreover, the MAPK pathway (p38/ERK/JNK), activated by oxidative stress, amplifies inflammation and cell death by promoting PANoptosome assembly and mitochondrial dysfunction [13]. Together, these pathways orchestrate widespread neuronal loss and chronic inflammation, linking AD pathology with PANoptotic signalling. This review also highlights the preclinical studies of the drugs such as Celasterol [14], Magnoflorine [15], Scutellaria baicalensis [16], Alizaregon [17], Calycosin [18], Liproxstatin-1 [19] targeting PANoptosis. Therapeutic intervention of AD which are in different phases of clinical trials including Nicotinamide riboside (NR), Barcitinib, MW150, Metformin, Astragalus, Dexmeditomidine, Semaglutide has been observed to ameliorate the pathologies of AD by modulating PANoptotic pathways.