Authors: Jin-Hui Chen, Tsen-Fang Tsai
Categories: Review, Psoriasis, Psoriatic arthritis, Alzheimer’s disease, Skin–brain axis, Neuroinflammation, Dementia
Source: Dermatology and Therapy
Authors: Jin-Hui Chen, Tsen-Fang Tsai
Various comorbidities have been associated with psoriasis. Most clinical studies support the hypothesis that psoriasis may be a risk factor for dementia. Meanwhile, some evidence indicates that certain immunomodulatory agents, many of which are widely used in psoriatic disease management, exert neuroprotective effects and may attenuate dementia progression. In view of the lack of existing studies that specifically investigate the effects of systemic treatments for psoriatic disease on dementia or cognitive impairment, in this narrative review, we focus on Alzheimer’s disease, as a model to explore whether systemic psoriasis treatments influence dementia risk and severity. Our findings suggest that some systemic treatments for psoriasis may also provide potential neuroprotective benefits.
Systemic drugs used in psoriatic disease are related to decreased risk of Alzheimer’s disease.The neuroprotective effect of dermatological treatment brought out further evidence of skin–brain axis.Immune modulation that targets chronic systemic inflammation, microglial and astrocytic activation, or the formation of amyloid-β plaques and neurofibrillary tangles are the key mechanisms bridge systemic psoriasis therapies and the beneficial effect on Alzheimer’s disease.Improved understanding of the shared immune dysregulation of psoriatic disease and Alzheimer’s disease may support more precise treatment selection and potentially lower long-term neurological comorbidity risk.
Psoriasis is an immune-mediated disease primarily driven by immune dysregulation and cytokine cascades within the self-amplifying IL-23/IL-17 signaling pathway. Due to the close association between psoriasis and psoriatic arthritis, psoriatic disease is a unified term to include both conditions in clinical practice. Psoriatic disease is a systemic inflammatory disorder associated with multiple comorbidities, including cardiovascular disease, metabolic syndrome, and chronic kidney disease [1, 2].
Recent studies have highlighted important associations between psoriasis and brain-related disorders. Patients with psoriasis show an increased risk of developing mild cognitive impairment and subsequent dementia [3], as well as higher prevalence of neuropsychiatric disorders such as depression, anxiety [4, 5] and multiple sclerosis [6]. These findings suggest a potential bidirectional communication between the brain and the skin under chronic inflammatory conditions. More recently, the roles of interleukin (IL), including IL17 and IL-22, are proposed [7, 8].
The link between psoriasis and dementia was initially proposed on the basis of shared pro-inflammatory molecules, such as angiotensin II [9], and elevated homocysteine levels [10, 11]. These findings suggested that interventions such as ACE inhibitors and folic acid supplementation, which lower homocysteine, could potentially benefit both conditions. Later, inhibition of TNF-α was shown to improve symptoms of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS)-associated dementia while also treating rheumatic diseases and psoriasis [12], thereby reinforcing the hypothesis of a shared inflammatory pathway.
Among neurological comorbidities of psoriasis, dementia represents one of the most urgent challenges in aging societies. Notably, some studies suggest that systemic therapy for psoriasis may reduce the risk of dementia [13, 14], implying that both disease severity and treatment strategies could influence the observed outcomes.
A meta-analysis of nine studies published in 2000 involving 3,638,487 participants demonstrated that psoriasis and psoriatic arthritis were associated with increased risks of both non-vascular dementia and vascular dementia [15]. Based on these findings, brief cognitive assessments and early dementia screening have been recommended for older patients with psoriasis [13, 15].
However, some subsequent large-scale observational studies [3, 16] did not confirm a direct link after adjustment for comorbidities. Long-term systemic therapy, particularly biologics, has been associated with a reduced incidence of dementia [17, 18]. Recent systemic reviews and meta-analyses have suggested a modestly increased risk of dementia among patients with psoriasis; however, this association is substantially attenuated after adjustment for comorbidities [19], highlighting the likelihood that shared risk factors and overlapping inflammatory mechanisms, rather than a direct causal relationship. Thus, stratified analyses by psoriasis severity and treatment exposure are essential to clarify whether the increased dementia risk is attributable to psoriasis itself, systemic inflammation, or the effects of therapy [20, 21].
Genome-wide association studies (GWASs) have suggested that inflammation may play a role in the development of AD, and that a potential genetic link exists between psoriasis and AD [14]. Traditionally, extracellular amyloid β (Aβ) deposition and intracellular neurofibrillary tangles (NFTs) [22, 23] are considered as central to AD pathogenesis. However, growing evidence has revealed that neuroinflammation, cholinergic dysfunction, mitochondrial dysfunction, and oxidative stress—primarily driven by immune cell activation in response to accumulated proteins—are key contributors to AD progression. Sustained activation of microglia and astrocytes leads to chronic neuroinflammation, synaptic loss, and neuronal death, which are recognized hallmarks of many neurodegenerative diseases, especially AD [24–26]. In particular, dysfunction of immune-cell-mediated pathways accelerates neuroinflammation and neurodegeneration in AD [27]. As a result, immunomodulation has emerged as a potential therapeutic strategy.
The role of systemic antipsoriatic treatment in dementia was first highlighted by Kim et al. [28], who analyzed 535,927 patients with psoriasis. They reported that patients who did not receive systemic therapy showed a higher risk of AD compared with those treated systemically.
Further evidence supports this possibility that antipsoriastic treatment may have potential neuroprotective effect. For example, nonsteroidal anti-inflammatory drugs (NSAIDs) were found to have a protective effect against dementia in several epidemiological studies. Acitretin, a first-line treatment for psoriasis, has been shown to enhance sAPPα production and restore functional brain connectivity in early AD models [29, 30]. Other systemic agents, including PDE4 inhibitors [31] and biologics such as TNF-α inhibitors [32] and ustekinumab [33], have also demonstrated potential neuroprotective effects and improvement in cognitive function. In this narrative review, we investigate whether systemic psoriasis therapies influence dementia risk through immunologic, inflammatory, or neuroprotective pathways. A comprehensive summary of these therapeutic agents, their molecular mechanisms, and their corresponding Alzheimer’s disease intervention targets is provided in Table 1. Mechanistic findings from preclinical models, categorized as Level 5 evidence, are detailed in Table 2. A structured summary of key observational cohort and case–control studies, including adjusted effect estimates and evidence quality (Level 3–4), is presented in Table 3. Finally, current randomized controlled trials (RCTs) and interventional studies assessing the cognitive impact of shared treatments are summarized as Level 1–2 evidence in Table 4.Table 1Summary of drug mechanisms for psoriatic disease and corresponding Alzheimer’s disease intervention targetsDrug mechanism classSpecific drug(s)Target AD pathology intervention pointPotential mechanism of actionCurrent evidence citationsConventional therapyNSAIDsIndomethacin, naproxen, celecoxibSystemic chronic inflammationAnti-inflammatory properties.May be protective against AD during early stages but potentially adverse in later stages.Indomethacin slowed cognitive deterioration in patients with mild-to-moderate dementia [35].ADAPT trial suggested NSAID use was associated with a reduced incidence of AD in healthy individuals [36].MTXMTXSystemic chronic inflammationMay cross the BBB at low doses to confer protection.Associated with a reduced risk of dementia.UK CPRD study reported MTX had the strongest effect in reducing dementia risk among csDMARDs [38].CaN inhibitorsCyclosporin, tacrolimus (FK506)CaN/NFAT signaling/Aβ neurotoxicityNormalization of CaN/NFAT activity. Inhibition of CaN/NFAT signaling reduces Aβ neurotoxicity and neuroinflammation.Aberrant CaN/NFAT signaling is implicated in neuronal apoptosis and synaptic deficits in AD.Experimental approaches using classical CaN/NFAT inhibitors alleviated AD-related symptoms [44, 45].Targeting astrocytic CaN/NFAT signaling alleviated cerebrovascular and synaptic function deficits in mouse models of small cerebral vessel disease [43].RetinoidsAcitretin, isotretinoinUpregulate α-secretase (ADAM10)Cholinergic functionModulates retinoic acid (RA) signaling. Increases α-secretase ADAM10 activity, promoting non-amyloidogenic processing and reducing Aβ formation. Also supports cholinergic neurotransmission.Acitretin reverses early functional network degradation in familial AD mouse models [29, 30].A phase 2 clinical trial showed enhanced cerebrospinal fluid (CSF) sAPPα levels in patients with AD following oral acitretin administration [30].Targeted synthetic DMARDs (tsDMARDs)PDE4 inhibitorsApremilast, rolipram, roflumilastcAMP/PKA/CREB pathwayNeuroinflammationInhibition of PDE4 elevates intracellular cAMP, regulating inflammatory responses.The cAMP/PKA/CREB pathway is essential for memory formation.Attenuates neuroinflammation, reduces oxidative stress, and enhances neural plasticity.Rolipram (a BBB-permeable PDE4 inhibitor) demonstrated efficacy in AD animal models [56].JAK/STAT inhibitorsTofacitinib, upadacitinibMicroglia/astrocyte activationNeuroinflammationTargets the JAK/STAT pathway, orchestrating immune responses.Tofacitinib is capable of penetrating the BBB. May modulate astrocyte and microglia activation.A meta-analysis demonstrated improved mental health outcomes in patients with RA treated with Jakinibs. [42].Tofacitinib has been proposed as a treatment for refractory autoimmune encephalitis [63].Upadacitinib downregulates BDNF expression and modulates pain-related and neuroinflammatory pathways in human monocyte-derived microglial-like cells [64].TYK2 inhibitorsDeucravacitinibImmune signalingModulates pathogenic immune signaling.Experimental evidence shows that TYK2 activity promotes tau aggregation, disrupts autophagic clearance, and accelerates neurodegeneration in tauopathy models [69, 70].TYK2 inhibition has been shown to mitigate TDP-43 pathology by suppressing dsRNA-induced neuroinflammation [71].Biologic agentsTNF-α inhibitorsInfliximab, etanercept, adalimumab, golimumab, certolizumabTNF-α (key neuroinflammation initiator)Pharmacological blockade of TNF-α reduces neurotoxic cascades, Aβ accumulation, tau hyperphosphorylation, and neuronal death.Infliximab reduced tau phosphorylation and Aβ deposition in AD mouse models [32].Observational studies found that RA and patients with psoriasis treated with these inhibitors had a significantly reduced risk of AD [79].Etanercept has been associated with cognitive improvement in patients with AD [78].IL-17 inhibitorsSecukinumab, ixekizumab, brodalumab, bimekizumabIL-17 activityBBB integrityBlocks IL-17 activityIL-17 recruits neutrophils, disrupts the BBB, enhances oxidative stress, and promotes neuronal damage. Blockade may attenuate neuroinflammation by interfering with neutrophil trafficking.Animal studies demonstrate that anti-IL-17 antibodies mitigate Aβ-induced cognitive decline [100].IL-17 overexpression in animal models was shown to improve glucose metabolism, reduce soluble Aβ in the hippocampus and CSF, relieve anxiety, and improve learning deficits [105].IL-12/23 and IL-23 InhibitorsUstekinumab, briakinumab, guselkumab, risankizumab, tildrakizumabIL-23/IL-17A axisp40 subunitTargets the IL-23/IL-17A axis, which is implicated in chronic neuroinflammation in AD pathogenesis.Inhibition of IL-12/23 p40 reduces Aβ deposition.Vom Berg et al. found that p40 blockade reduced Aβ deposition and improved cognitive performance in APP/PS1 mice [91].Elevated serum IL-23 and p40 concentrations correlate with Aβ burden [92, 93].Aβ amyloid-beta, AD Alzheimer’s disease, BBB blood–brain barrier, BDNF brain-derived neurotrophic factor, CaN calcineurin, cAMP cyclic adenosine monophosphate, CREB cAMP response element-binding protein, csDMARDs conventional synthetic disease-modifying anti-rheumatic drugs, dsRNA double-stranded RNA, IL interleukin, JAK Janus kinase, NFAT nuclear factor of activated T cells, NSAIDs nonsteroidal anti-inflammatory drugs, PDE4 phosphodiesterase 4, PKA protein kinase A, RA retinoic acid, ROS reactive oxygen species, STAT signal transducer and activator of transcription, TNF-α tumor necrosis factor alpha, TYK2 tyrosine kinase 2, TDP-43 TAR DNA-binding protein 43, tsDMARD targeted synthetic disease-modifying antirheumatic drug, MTX methotrexate, CSF cerebrospinal fluidTable 2Mechanistic evidence from preclinical models (animal models and in vitro)Study (year)Model/subjectsExposure (drug/class)Mechanism/main findingsShi et al. (2011)APP/PS1 transgenic miceInfliximab (TNF-α inhibitor)Reduced Aβ plaques and tau phosphorylation; induced CD11c-positive cellsSompol et al. (2023)Mouse model of small cerebral vessel diseaseCaN/NFAT inhibitorsAlleviated cerebrovascular and synaptic function deficits by reducing Aβ neurotoxicityRosales Jubal et al. (2021)Familial AD mouse modelAcitretin (retinoid)Reversed early functional network degradation in the brainGarcía-Osta et al. (2012)AD animal modelsRolipram (PDE4 inhibitor)Demonstrated efficacy in improving cognitive targets via cAMP pathwayLiu et al. (2023)Human monocyte-derived microglial-like cellsUpadacitinib (JAK1 inhibitor)Downregulated BDNF expression and modulated neuroinflammatory pathways (in vitro)Kim et al. (2024)/Fröhlich et al. (2025)Tauopathy mouse modelTYK2 inhibitionRegulated tau levels, phosphorylation, and aggregation; improved tau clearanceKönig et al. (2024)AD models with TDP-43 inclusionsTYK2 inhibitorMitigated TDP-43 pathology by inhibiting dsRNA-induced neuroinflammationCristiano et al. (2019)Aβ-induced memory-impaired miceIL-17 neutralizing antibodyRescued neuroinflammation and memory impairment; reduced cytokine releaseYang et al. (2017)AD mouse modelIL-17A overexpressionDecreased cerebral amyloid angiopathy (noted as potentially context-dependent/protective)Vom Berg et al. (2012)APP/PS1 micep40 blockade (IL-12/23)Reduced Aβ deposition and improved cognitive performanceAβ amyloid-beta, AD Alzheimer’s disease, APP amyloid precursor protein, BDNF brain-derived neurotrophic factor, CaN calcineurin, cAMP cyclic adenosine monophosphate, dsRNA double-stranded RNA, IL interleukin, JAK1 Janus kinase 1, NFAT nuclear factor of activated T cells, PDE4 phosphodiesterase 4, TNF-α tumor necrosis factor alpha, TYK2 tyrosine kinase 2, TDP-43 TAR DNA-binding protein 43Table 3Observational cohorts (human studies) assessing immune-modulatory therapies and dementia-related outcomesStudy (year)DesignPopulation (N)Exposure (drug)Covariates adjustedMain effect (estimate)Judge et al. (2017)Retrospective population study (UK CPRD)Patients with RAMTXNot specified in excerptStrongest protective effect against dementia among csDMARDsChou et al. (2016)Nested case–control study (US database)41,109 (patients with RA)TNF inhibitorsComorbidities, APOE statusSignificant AD risk reduction (adjusted OR 0.45)Chou et al. (2017)Propensity score-matched case–controlPatients with RAcsDMARDs (MTX, HCQ, etc.)Propensity score matching1.63-fold higher risk of dementia (contradictory finding)Mohammadi Shahrokhi (2018)Biomarker studyPatients with ADIL-17A/IL-23 levelsAge-associated inflammationIdentified as plausible risk factors for ADPedrini et al. (2017)Blood-based biomarker panelAD cohortIL-12/23p40Aβ loadJointly associated as predictors of Aβ burdenAD Alzheimer’s disease, APOE apolipoprotein E, Aβ amyloid-beta, CPRD Clinical Practice Research Datalink, csDMARDs conventional synthetic disease-modifying antirheumatic drugs, HCQ hydroxychloroquine, IL interleukin, MTX methotrexate, OR odds ratio, RA rheumatoid arthritis, TNF tumor necrosis factorTable 4RCTs and clinical evidence assessing immune-modulatory therapies and dementia-related outcomesStudy (year)DesignPopulation (N)Exposure (drug)Main clinical outcomesImbimbo (2010)6-month randomized trialPatients with dementiaIndomethacin (NSAID)Slowed cognitive deterioration (P < 0.003)ADAPT trial (2013)Multi-center randomized trial2529 (healthy older patients)Naproxen/celecoxib (NSAID)Reduced AD incidence in healthy users; potentially harmful in later stagesEndres et al. (2014)Phase 2 clinical trialPatients with ADAcitretinIncreased CSF sAPPα levels (suggesting neuroprotection)Camargo et al. (2015)Case reportPatient with AD with RAEtanercept (TNF inhibitor)Cognitive improvement observed during treatmentAD Alzheimer’s disease, ADAPT Alzheimer’s Disease Anti-inflammatory Prevention Trial, CSF cerebrospinal fluid, NSAID nonsteroidal anti-inflammatory drug, RA rheumatoid arthritis, RCTs randomized controlled trials, sAPPα soluble amyloid precursor protein-alpha, TNF tumor necrosis factor
Original research articles, clinical trials, observational studies, or translational/preclinical studies published in PubMed (MEDLINE) from 2015 to 2025 were included.
For each therapeutic class, relevant studies were identified by combining drug-specific terms with outcome-related keywords, including dementia, Alzheimer’s disease, cognitive impairment, neuroinflammation, and neurologic or psychologic adverse effects. Search strings incorporated Boolean operators to ensure comprehensive coverage of potential associations between psoriasis therapies and dementia-related outcomes.
Titles and abstracts were screened for eligibility, and articles were included if they examined any aspect of the relationship between systemic psoriasis treatments and dementia, cognitive function, or neuroinflammatory mechanisms. Both preclinical and clinical studies were considered, given the limited evidence in this field. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Inclusion criteria were the Studies involving patients with psoriasis or psoriatic arthritis, or experimental models relevant to psoriatic disease–related immune pathways.Studies examining outcomes related to Alzheimer’s disease, dementia, cognitive impairment, or AD-associated pathological mechanisms (e.g., amyloid-β deposition, tau pathology, neuroinflammation).Studies evaluating systemic anti-inflammatory or immunomodulatory therapies commonly used in psoriatic disease.
Exclusion criteria were the Case reports with insufficient mechanistic or clinical relevance.Studies focusing exclusively on non-Alzheimer’s dementia without relevance to shared inflammatory or immune mechanisms.Articles without accessible full text or lacking sufficient methodological detail.Non-English publications.
As this study is a narrative review, no formal Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram, risk-of-bias assessment, or quantitative synthesis was performed. The purpose of this review was to integrate emerging clinical and mechanistic evidence and to generate hypotheses regarding the potential neuroprotective effects of systemic psoriasis therapies.
The figure was first created with BioRender.com (https://BioRender.com/0yacnud). We used ChatGPT (OpenAI, GPT-5.1) to assist in enhancing the fluency of the academic text. No content, data interpretation, or scientific conclusions were generated by the tool.
NSAIDs are the first-line treatment of psoriatic arthritis. Initial observations indicated that patients with rheumatoid arthritis using NSAIDs exhibited an unexpectedly lower prevalence of dementia [34], prompting several epidemiological studies to investigate the potential protective effect of NSAIDs against cognitive decline. One study reported that regular administration of indomethacin over 6 months slowed down and showed less cognitive deterioration in participants with mild-to-moderate dementia compared with placebo (P < 0.003) [35]. In the ADAPT trial, 2529 healthy volunteers with a family history of AD were randomized to receive naproxen, celecoxib, or placebo [36]. However, the trial was terminated after 2 years due to increased cardiovascular and cerebrovascular adverse events in the treatment arms, reaching statistical significance in the naproxen group. Extended analyses suggested that NSAID use was associated with a reduced incidence of AD in healthy individuals, whereas in participants already diagnosed with AD, NSAIDs appeared to have adverse effects. This indicates that the impact of NSAIDs on dementia may vary across disease stages, being potentially protective during early stages but harmful in later stages [37].
In a retrospective, population-based study using data from the UK Clinical Practice Research Datalink (CPRD), Judge et al. (2017) [38] reported that conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) were associated with a reduced risk of dementia, with the strongest effect observed for MTX. This therapeutic effect may be related to the lower doses used in this context, which are sufficient to cross the blood–brain barrier and potentially confer protection against AD. Additional studies have suggested an association between MTX use and lower AD risk, supporting its potential as a therapeutic candidate [39, 40]. However, a systematic review published in 2024 [41] concluded that hydroxychloroquine, rather than MTX, may be the more promising candidate based on existing observational evidence. In contrast, another population-based study [42] found a 1.63-fold higher risk of dementia in patients with RA treated with csDMARDs—including hydroxychloroquine, MTX, sulfasalazine, and leflunomide—especially when multiple csDMARDs were used in combination.
Normally, phosphatase calcineurin (CaN) dephosphorylates nuclear factor of activated T-cells (NFAT), promoting its transcriptional activity, including the expression of interleukin-2 and other cytokines in T helper lymphocytes. Aberrant CaN/NFAT signaling has been implicated in several AD pathologies, including neuronal apoptosis, synaptic deficits, and glial activation. Once activated, CaN/NFAT amplifies inflammation by driving expression of multiple inflammatory factors, many of which are elevated in AD. Normalization of CaN/NFAT activity can be achieved with immunosuppressants such as cyclosporin A or tacrolimus(FK506). A recent study showed that aberrant astrocytic Ca2^+^/CaN/NFAT signaling contributes to vascular pathology associated with cognitive decline and dementia [43]. Experimental approaches using classical CaN/NFAT inhibitors or astrocyte-specific NFAT suppression have alleviated AD-related symptoms by reducing amyloid-β neurotoxicity and neuroinflammation. However, clinical use of long-term cyclosporin is limited by potential adverse effects, especially nephrotoxicity [44, 45].
Retinoids, including isotretinoin and acitretin, exert neuroprotective effects through modulation of retinoic acid (RA) signaling. The brain efficiently converts vitamin A to RA, which activates retinoic acid receptors (RARs) essential for synaptic plasticity in memory-related regions such as the hippocampus. Impaired RA signaling has been observed in early-stage AD animal models [46], and RA reduces Aβ formation via α-secretase ADAM10, promoting non-amyloidogenic APP processing [10, 47]. Acitretin, a selective RAR agonist, increases α-secretase activity and reduces Aβ40/Aβ42 levels in AD mouse models [48], and a phase 2 clinical trial showed enhanced cerebrospinal fluid (CSF) sAPPα levels in patients with AD after 4 weeks of oral acitretin administration [30]. RA also mitigates neuroinflammation by inhibiting IL-6 and TNF-α production in microglia and astrocytes, reducing astrocytosis and shifting microglia to a resting state [49]. Additionally, RA supports cholinergic neurotransmission by upregulating ChAT and VAChT, enhancing acetylcholine synthesis and availability, which may improve cognitive function in AD [50–52].
Collectively, these findings indicate that NSAIDs, MTX, calcineurin inhibitors, and retinoids may modulate dementia risk or AD pathology through anti-inflammatory, amyloid-modifying, or neurotransmitter-regulating mechanisms. However, their effects appear context-dependent, highlighting the need for careful evaluation of stage-specific risks and benefits in potential therapeutic applications.
Inhibition of PDE4 elevates intracellular cyclic adenosine monophosphate (cAMP), thereby regulating inflammatory responses and offering therapeutic benefits in conditions such as psoriasis and neuroinflammation [31]. PDE4 is highly expressed in the brain, where it selectively hydrolyzes cAMP, a second messenger essential for learning, memory, and cognitive function [53]. Genetic studies, through PDE4D mutations in acrodysostosis (ACRDY2), highlight the critical role of the cAMP/PKA/CREB pathway in long-term memory formation [54]. PDE4 inhibitors improve psychological symptoms by attenuating neuroinflammation, reducing oxidative stress, and enhancing neural plasticity [55]. Apremilast is the only PDE4 inhibitor currently approved for psoriasis treatment but has limited penetration to the BBB. Rolipram, the first BBB permeable PDE4 inhibitor, demonstrated efficacy in animal models of AD [56]. However, its severe behavioral and other side effects limit clinical use. Orismilast is a potent and selective PDE4B/D inhibitor that showed efficacy in a randomized, double-blinded, placebo-controlled, dose-finding phase 2b trial in psoriasis [57]. However, its ability to cross BBB is unknown. Roflumilast can be given either orally or topically. Preclinical data show brain penetration in animal models under certain condition, and it is found to enhance cognition [58]. Although currently it is only approved for topical use in psoriasis, oral roflumilast has been reported successful for psoriasis in a real-world 24-week prospective cohort study [59].
Microglia and astrocytes are key mediators of central nervous system (CNS) inflammation. Overactivation of these cells influences JAK/STAT signaling, which orchestrates innate and adaptive immune responses and contributes to neuroinflammatory cascades. Targeting the JAK/STAT pathway is considered a promising neuroprotective strategy. STAT proteins differentially regulate microglial STAT1 promotes the pro-inflammatory M1 state, whereas STAT6 facilitates differentiation toward the anti-inflammatory M2 state, indicating resolution of neuroinflammation [60]. The JAK2/STAT5/NF-κB pathway further integrates microglial activation and Th17 cell involvement in autoimmune neuroinflammatory responses. Nicotinic acetylcholine receptors can reduce Aβ neurotoxicity via JAK2/STAT3 activation, although whether this requires STAT3-mediated gene regulation remains unclear; humanin and its derivatives similarly mitigate Aβ neurotoxicity through JAK2/STAT3 while preserving cholinergic function [61].
Despite modest CNS expression, JAK/STAT signaling is critical in the cortex, hippocampus, and cerebellum, and influences serotonergic and phospholipase C pathways relevant to stress and mood disorders. Emerging evidence indicates broader therapeutic potential for JAK inhibitors (“Jakinibs”) beyond immunological diseases. A 2021 meta-analysis demonstrated improved mental health outcomes in patients with RA treated with Jakinibs alone or with MTX [62].
Tofacitinib is an orally administered JAK1/3 inhibitor approved for psoriatic arthritis and psoriasis (in Russia) and is capable of penetrating the BBB. While no studies have directly examined its effects in dementia or AD, tofacitinib has been proposed as a treatment for refractory autoimmune encephalitis, highlighting its potential to modulate neuroinflammation in the CNS [63]. Upadacitinib, a selective JAK1 inhibitor, showed a potential for modulating microglial activity and pain-related neuroimmune pathways in chronic inflammatory diseases in an in vitro model of human microglia-like cells derived from monocytes under pro-inflammatory conditions. By modulating the P2X4 receptor pathway, it downregulates the expression and secretion of brain-derived neurotrophic factor (BDNF), a key mediator in microglia-driven neuroinflammation and pain signaling [64]. Although there is no study investigating the effects of upadacitinib on Alzheimer’s disease, it showed a strong connection with microglia activation and neuroinflammation.
Extensive research has implicated genetic alterations in TYK2 as potential drivers of inflammatory diseases [65, 66], prompting the development of small-molecule TYK2 inhibitors for the treatment of autoimmune disorders. Deucravacitinib is currently the only TKY2 inhibitor approved for the treatment of psoriasis [67]. Furthermore, a recent study has ensured the key role of TYK2 as a key neuroimmune modulator. Tyler et al. reported that central TYK2 inhibition reduced clinical disease severity, lymphoid cell infiltration, and microglial activation, and attenuated the activation of interferon-responsive reactive astrocytes (IRRA) by using brain-penetrant TYK2 inhibitors (cTYK2i) in experimental autoimmune encephalomyelitis (EAE) [68].
As for AD, TYK2 has been implicated in signaling pathways that contribute to neuroinflammation, glial activation, and neuronal death in AD. Experimental evidence indicates that TYK2 activity enhances tau phosphorylation and aggregation, impairs autophagic tau clearance, and aggravates neurodegeneration in tauopathy models [69, 70]. TYK2 inhibition has also been shown to target TDP-43-pathology, which is observed in up to 57% of patients with AD, and is the most prominent proteinopathy after Aβ and tau pathology, by inhibiting cdsRNA-induced neuroinflammation [71]. In summary, inhibition of TYK2 may mitigate tau and TDP-43 pathology, suppress neuroinflammation, and enhance neuronal and glial function in AD, thereby supporting further exploration of TYK2-targeted therapeutic strategies.
Food and Drug Administration (FDA)-approved biologics for psoriasis include tumor necrosis factor-alpha (TNF-α) inhibitors, interleukins IL-12/IL-23 inhibitor, IL-17 inhibitors, and IL-23 inhibitors, in time sequence [72]. A recent propensity score-matched, population-based cohort study included 1766 patients (883 per group) showed that biologic therapy for psoriasis was associated with a 53% reduced risk of incident dementia compared to systemic therapy alone, promising the potential link between the biologics used for psoriasis and dementia [73]. However, the effects of different classes of biologics were not analyzed separately.
Tumor necrosis factor-α (TNF-α), produced by neuronal cells, microglia, and astrocytes, is a pivotal cytokine initiating and regulating neuroinflammation in AD. In AD, activated microglia secrete TNF-α along with IL-1, IL-6, and other neurotoxic mediators, driving a cascade of inflammatory responses that amplify neuronal injury [74, 75]. TNF-α signals through two TNFR1, broadly expressed on all cells, and TNFR2, mainly expressed on immune and endothelial cells. Soluble TNF preferentially binds TNFR1, which mediates pro-inflammatory and pro-apoptotic pathways via caspase activation, whereas transmembrane TNF interacts with TNFR2, promoting neuroprotective signaling through PI3K/Akt, NF-κB, and MAPK pathways [76, 77]. In AD, TNF-α and TNFR1 expression are elevated, while TNFR2 is downregulated, tipping the balance toward neurodegeneration. Pharmacological blockade of this axis, such as with atrosimab—a TNFR1-specific antagonist—has been shown to attenuate inflammation and neuronal apoptosis in AD models [77]. Collectively, elevated TNF-α contributes to BBB disruption, amyloid-β accumulation, tau hyperphosphorylation, and neuronal death, positioning it as both a biomarker and therapeutic target in AD.
Therapeutically, TNF-α inhibitors have shown neuroprotective potential in AD. Infliximab, a chimeric monoclonal antibody against TNF-α, reduced tau phosphorylation, amyloid-β deposition, and TNF levels in AD mouse models [32].
Etanercept, a fusion protein combining the extracellular domain of TNFR2 with human IgG1 Fc, has been associated with cognitive improvement in patients with AD with concomitant rheumatoid arthritis [78]. Observational studies further support this an analysis of 41,109 rheumatoid arthritis patients in a US insurance database found that those treated with TNF inhibitors had a significantly reduced risk of AD (adjusted odds ratio [OR] 0.45, 95% confidence interval [CI] 0.23–0.90; P = 0.02) after adjusting for comorbidities and apolipoprotein E (APOE) status [79]. A larger retrospective study involving 56 million electronic health records confirmed that patients with RA treated with etanercept, adalimumab, or infliximab had markedly lower risks of AD (ORs 0.34, 0.28, and 0.52, respectively; all P < 0.0001). Similar reduction of AD risk was also observed in patients with psoriasis treated with etanercept or adalimumab [80]. Animal studies and systematic reviews illustrated that TNF-α inhibition, is a biologically plausible and potentially effective strategy for preserving cognition and slowing AD progression [81].
Currently, there are no clinical studies investigating golimumab or certolizumab in relation to AD. However, experimental evidence has shown that certolizumab promotes functional recovery after spinal cord injury in rats by inhibiting the TNF-α/NF-κB signaling pathway, thereby reducing neuroinflammation and neuronal apoptosis [82]. Although individual TNF inhibitors have not been extensively studied and compared, their therapeutic potential in neurodegeneration is promising.
The IL-23/IL-17A axis is increasingly recognized as a pivotal pathway in age-associated inflammation, and it has been implicated in the pathogenesis of AD. A key question concerns the sites of inflammation that stimulate IL-23/IL-17A signaling within the brain. Several descriptive and experimental studies have explored the role of IL-12/23 p40 and IL-23 and its down-stream IL-17/IL-22 signaling in AD in recent years [83, 84].
IL-23 is a heterodimeric proinflammatory cytokine composed of IL-23A (also known as p19) and IL-12B, with the p40 subunit shared with IL-12 [85]. Its receptor, IL-23R, contains IL-12Rβ1 as a common subunit with the IL-12 receptor [86]. Activation of IL-23R triggers retinoic-acid receptor (RAR)-related orphan receptor gamma t (RORγt) and RORα, transcription factors critical for Th17 differentiation [87]. Given its role in promoting Th17 differentiation and IL-17A expression, IL-23 signaling has been proposed as a key contributor to AD pathogenesis.
Chen et al. (2014) reported elevated serum levels of IL-17A and IL-23 in Chinese patients with AD, with IL-23—though not IL-17A—significantly increased in female patients [88]. Similarly, vom Berg et al. identified increased p40 expression in microglia of APP/PS1 mice and elevated cerebrospinal fluid levels of p40 in patients with AD. Importantly, p40 blockade with monoclonal antibodies in mice reduced amyloid-β (Aβ) deposition and improved cognitive performance [89]. Other experimental studies further demonstrated that suppression of IL-23 signaling (via inhibition of the p40 subunit) attenuates AD-like pathology [90, 91].
Moreover, it is suggested that the IL-17A/IL-23 axis be activated in patients with AD, with higher serum IL-23 levels and p40 concentrations correlating with Aβ burden, indicating its potential as a predictive biomarker [92, 93]. Experiments in bone-marrow-chimeric mice further revealed that microglial-derived, but not myeloid-derived, IL-12/23 p40 drives Aβ plaque accumulation, underscoring the central role of microglia in p40-mediated neuroinflammation [89]. While IL-23 inhibitors have currently no direct evidence that these agents are associated AD pathology or improve cognitive outcomes, these abovementioned findings showed molecular changes in neurological environment linked to AD. They also emphasized the need for further research to determine whether neuroinflammation in AD is primarily mediated by IL-12/23 p40, IL-23, or IL-12, and to elucidate their respective roles in neuroinflammatory mechanisms.
IL-17, a pro-inflammatory cytokine secreted primarily by Th17 cells, plays a crucial role in host defense. However, uncontrolled IL-17 activity is associated with immunopathological conditions [94]. In AD, accumulating evidence indicates that IL-17 contributes to neuroinflammation and neurodegeneration through multiple mechanisms. Aβ aggregates in the CNS can activate complement and stimulate microglia to produce pro-inflammatory mediators, leading to Th17 cell activation and IL-17 secretion [95]. IL-17 subsequently recruits and activates neutrophils, disrupts the BBB, enhances oxidative stress, and promotes neuronal damage. In vitro data further suggest that IL-17 may induce autophagy in neurons, accelerating neurodegeneration [96]. Consistently, higher proportions of circulating Th17 cells and elevated IL-17 concentrations in both plasma and cerebrospinal fluid have been observed in patients with AD compared with cognitively healthy controls [97, 98], supporting its role as a potential biomarker [99].
The key study of the IL-17 inhibitor modulating AD was published in 2019, showing IL-17Ab reduced neuroinflammation and behavioral symptoms induced by Aβ [100]. Animal studies demonstrate that anti-IL-17 antibodies mitigate Aβ-induced cognitive decline and reduce glial fibrillary acidic protein (GFAP), S100 proteins, cytokine release, and neutrophil infiltration [100], highlighting its therapeutic promise. Moreover, IL-17/IL-23 pathway blockade may attenuate neuroinflammation by interfering with neutrophil trafficking [101]. Neutralization of IL-17 in the ventricles of 3xTg-AD mice prevented short-term memory and synaptic plasticity deficits at early stages of disease, indicating a modulatory effect of IL-17 inhibition on Alzheimer’s pathology [102]. Additionally, IL-17 neutralizing antibodies were reported to ameliorate amyloid-β-induced neuroinflammation and cognitive decline in animal models [64].
Mechanistically, Aβ exposure was found to significantly increase IL-17 expression in the hippocampus and cortex, primarily derived from activated Th17 cells and astrocytes. Downregulation of IL-17 leading to suppression of IL-17, NF-κB–mediated neuroinflammation and oxidative damage, which supports neuronal survival and synaptic integrity [64].
No studies to date have used FDA-approved anti-IL-17 monoclonal antibodies in these animal models of amyloid-β-induced neurotoxicity. Among currently available IL-17 inhibitors, secukinumab has the most extensive supporting evidence with neurological diseases. In a rat model study of germinal matrix hemorrhage (GMH), secukinumab treatment significantly reduced inflammatory markers, attenuated microglial activation and neutrophil infiltration by suppression of the PKCβ/ERK/NF-κB pathway, and improved both short- and long-term neurobehavioral outcomes [103]. Another study also demonstrated that secukinumab significantly improved spatial learning and memory, reduced neuronal apoptosis, and decreased oxidative stress markers, thereby mitigating sepsis-induced neuronal injury in a rat model [104].
However, contradictory findings suggest a protective role of IL-17A under certain contexts, as IL-17 overexpression in animal models was shown to improve glucose metabolism, reduce soluble Aβ in the hippocampus and CSF, relieve anxiety, and improve learning deficits [105]. These observations indicate that the effect of IL-17 on AD pathology may shift from protective to pathogenic depending on disease stage and inflammatory milieu. Despite the established efficacy of IL-17A blockade in reducing systemic inflammation and pain [106, 107], IL-17 inhibition represents a promising but complex therapeutic target in AD, warranting further mechanistic and clinical investigation.
Several drugs have been approved for AD treatment; these include cholinesterase inhibitors and new disease-modifying treatments, such as lecanemab and donanemab. However, the efficacies are only moderate, and adverse events such as brain swelling or bleeding may occur. Psoriasis and psoriatic arthritis are both systemic inflammatory diseases with comorbidities including AD. Thus, it will be interesting to study whether systemic drugs used in the treatment of psoriatic disease can affect AD. Three key aspects warrant further (1) the potential protective effect against AD from antipsoriatic treatments (Fig. 1), (2) the major factors that predispose patients with psoriasis to AD, and (3) future directions for research in this emerging field.Fig. 1Proposed mechanisms linking psoriasis and Alzheimer’s disease and potential therapeutic interventions targeting the skin–brain axis. From chronic systemic inflammation, blood–brain barrier disruption driven by activated microglia and reactive astrocytes to the formation of amyloid-β plaques and neurofibrillary tangles, these key pathogenic processes represent mechanistic bridges between psoriasis and Alzheimer’s disease. Systemic treatments for psoriasis may modulate these pathogenic processes through these pathways, thereby offering theoretical benefits in slowing or interrupting AD progression. Created in BioRender. Chen, A. (2025) https://BioRender.com/0yacnud. Aβ amyloid-beta, BBB blood–brain barrier, CaN calcineurin, CREB cAMP response element-binding protein, IL interleukin, JAK Janus kinase, NF-κB nuclear factor kappa B, NFAT nuclear factor of activated T cells, NSAIDs nonsteroidal anti-inflammatory drugs, PDE4 phosphodiesterase 4, PKA protein kinase A, ROS reactive oxygen species, STAT signal transducer and activator of transcription, TNF-α tumor necrosis factor alpha, TYK2 tyrosine kinase 2, MTX methotrexate
Our review highlights that antipsoriatic treatments—including conventional therapies such as NSAIDs, small-molecule agents, and biologics—may exert differential impacts on the risk and progression of AD and other types of dementia or neurological diseases. By modulating the shared inflammatory pathways, antipsoriatic treatments may reduce neurotoxic cascades and neuronal apoptosis.
Activation of microglia and reactive astrocytes is considered the key initiating event in neuroinflammation, driving subsequent pathological changes within the central nervous system. Consequently, small-molecules agents such as JAK/STAT and TYK2 inhibitors, as well as biologic therapies targeting the TNF-α, IL-17, and IL-23 pathways of psoriatic disease have demonstrated potential in reducing not only systemic but also central inflammation. Conventional therapies, including NSAIDs, have been historically investigated for AD prevention due to their anti-inflammatory properties.
The expression of Fas ligand (FASL) on Th17 cells and its interaction with Fas receptors on neurons can induce apoptosis, while chronic neuroinflammation recruits neutrophils, microglia, and other immune cells that release proinflammatory mediators leading to synaptic dysfunction and neuronal loss. By targeting these immune circuits, antipsoriatic therapies may exert neuroprotective effects that go beyond cutaneous disease control. High-impact clinical evidence from Barak Levitt et al. [73] reinforces this biological framework, demonstrating that biologic therapy is associated with a 53% reduction in incident dementia risk compared with conventional systemic therapy alone. Through this study, we have anchored the “hypothetical” neuroprotective mechanisms (such as IL-17 and TNF-α inhibition) previously derived from animal models into a clearer clinical context. In conclusion, our review reinforces the strong connection between skin and brain, providing another strong evidence of the existence of the skin–brain axis.
Patients with psoriasis may be predisposed to AD through multiple interrelated pathways.
First, both disorders share common pathophysiological mechanisms. Persistent systemic inflammation and elevated levels of circulating cytokines that can cross the BBB represent key biological links, potentially explaining the higher prevalence of various neurological and psychiatric comorbidities observed in psoriasis.
Second, psoriasis is frequently accompanied by metabolic syndrome and cardiovascular comorbidities [1], which are all conditions already recognized as established risk factors for dementia [3]. Consequently, psoriasis itself may act as an indirect predisposing factor for AD through these associated systemic disorders.
Lastly, genetic susceptibility may underlie both diseases, connecting immune dysregulation with neurodegenerative vulnerability. According to a recent study, despite the overall genetic correlation being low, large-scale GWAS and cross-trait analyses revealed meaningful genetic overlap between Alzheimer’s disease and immune-mediated conditions such as psoriasis and psoriatic arthritis [108].
Although most of the studies support the positive correlation between AD and psoriasis, these findings must be interpreted with caution given the heterogeneity of evidence and the potential for residual confounding.
Disease severity represents another important confounder. Severe psoriasis is characterized by a higher systemic inflammatory burden, which itself may contribute to neurodegenerative processes. Furthermore, concomitant medications, healthcare use patterns, and survivor bias may further influence observed associations in observational studies. A structured summary of key observational cohort and case–control studies, including adjusted effect estimates and evidence quality, is presented in Table 3.
Importantly, much of the mechanistic evidence supporting a “skin–brain axis” is derived from preclinical models, which demonstrate biologically plausible links between immune modulation, microglial activation, astrocytic reactivity, and Alzheimer-related pathology. These mechanistic findings are detailed in Table 2. However, extrapolation of these findings to clinical benefit in humans remains speculative in the absence of a sufficient number of adequately powered randomized controlled trials. Current randomized controlled trials (RCTs) and interventional studies assessing the cognitive impact of shared treatments are summarized as Level 1–2 evidence in Table 4, though these trials currently provide only preliminary insights into stage-specific efficacy. Therefore, while preclinical and observational data collectively support a potential neuroprotective role of systemic psoriasis therapies, these findings should be viewed as hypothesis-generating rather than confirmatory.
Large-scale, longitudinal cohort studies and registry-based analyses are essential to establish the causes and to quantify how different therapeutic modalities, particularly biologics and small-molecule inhibitors, may influence cognitive outcomes.
Moreover, basic mechanistic studies are warranted to delineate the molecular and cellular pathways that bridge systemic inflammation and neurodegeneration, including the roles of Th17-mediated immune responses, microglial activation, and astrocyte dysfunction in mediating neuroinflammatory cascades.
In summary, the convergence of dermatologic and neuroinflammatory research may pave the way for dual-purpose interventions, offering hope that patients with psoriasis and AD can derive substantial benefit from integrated, inflammation-targeted therapies.
This comprehensive review highlights the potential neuroprotective effects of commonly used systemic therapies for psoriatic disease in the context of AD. These therapies target key mechanistic processes—including chronic systemic inflammation, blood–brain barrier (BBB) disruption mediated by activated microglia and reactive astrocytes, and the formation of amyloid-β plaques and neurofibrillary tangles—which serve as potential bridges between the two conditions.
While preclinical and observational data collectively support a potential neuroprotective role of systemic psoriasis therapies, several large-scale observational studies show that the association between psoriasis and dementia attenuates or disappears after adjusting for comorbidities such as metabolic syndrome and cardiovascular disease. Thus, these findings should be viewed as hypothesis-generating rather than confirmatory.
This suggests that perceived neuroprotective benefits may partly reflect the successful management of systemic inflammatory loads and associated metabolic risks rather than a direct drug-to-brain effect. Nevertheless, the molecular and immunologic correlations identified in our review cannot be neglected, as they offer theoretical benefits for slowing AD progression. To sum up, the neuroprotective benefits of systemic agents likely stem from the direct modulation of shared immunopathological circuits as well as the indirect mitigation of the systemic inflammatory burden that predisposes patients to neurodegeneration.
A deeper understanding of the shared immune dysregulation underlying both conditions may facilitate more precise therapeutic selection for individual patients. Future longitudinal studies and clinical trials are essential to disentangle the true nature of this association and to confirm whether these therapies provide a direct clinical benefit for neurocognitive health beyond their established dermatological efficacy.