Neuroinflammation represents a common theme amongst genetic and environmental risk factors for Alzheimer and Parkinson diseases

Astrocytes and microglia are the resident immunomodulatory cell types in the brain (Fig. 1). Microglia are tissue-specific macrophages that, when activated, act as the first line of defense against pathogens and cellular damage. Microglia also function to stimulate myelin repair and remove neurotoxic protein aggregates [29]. As such, microglia become activated upon sensing DAMPs from Aβ plaques (Fig. 2). In the brain, microglial-specific receptors, including triggering receptor expressed on myeloid cells 2 (TREM2) and Sialic Acid-Binding Ig-Like Lectin 3 (SIGLEC3/CD33), modulate phagocytosis of Aβ by microglia [30, 31]. The activated microglia surrounding these plaques initiate proinflammatory cascades involving tumor necrosis factor (TNF) and interleukin 1β (IL-1β), that can trigger the NLR family pyrin domain containing 3 (NLRP3) inflammasome and lead to cell death and tissue damage [32]. In fact, studies of AD patients revealed increased numbers of activated microglia accompanied by elevated levels of TNF and IL-1β, and other pro-inflammatory cytokines [33]. Paradoxically, clearance of Aβ by microglia may exacerbate Aβ pathology: as chronically activated microglia release pro-inflammatory mediators and become even more pro-inflammatory, their capacity for clearing Aβ diminishes [32, 34] (Fig. 2). These observations are consistent with the knowledge that increased susceptibility to infection and disease result from age-related immune dysfunction (immunosenescence), and that age is the greatest risk factor for AD.

In the ageing brain, immunosenescence impedes the ability of microglia to resolve insult by reducing process length and arborized area of microglia [35]. This may diminish the phagocytic activities of microglia which, in turn, leads to a mounting density of Aβ plaques (Fig. 2). Thus, immunosenescence and Aβ plaque-associated microglia are among the main drivers of neuroinflammation in the progression of AD pathology. Aβ plaque deposition precedes the presence of NFTs in the AD brain. Microglial activation and the release of pro-inflammatory cytokines are sufficient to induce tau phosphorylation and lead to neurotoxicity through the production of reactive oxygen species (ROS) [36, 37] (Fig. 2). Elevated levels of ROS are inextricably linked to altered neuronal signaling, inflammatory response, and neuronal death. This is a vicious cycle, in which ROS and oxidative stress are both triggers and consequences of inflammatory response [38]. This inflammatory feedback loop can result in increasing cytokine production, which can signal to and recruit other immune cells, including T cells.

Upon stimulation, the production of microglial second messengers can also facilitate crosstalk with astrocytes (Fig. 1). “Protective” A2 astrocytes are characterized by the expression of neurotrophic factors and function to mediate tissue repair, defend against oxidative stress, and maintain neuronal homeostasis [39]. However, release of pro-inflammatory cytokines from activated microglia can lead to the activation of A1 astrocytes, characterized by an NFκβ-dependent program. This reinforces microglial activation, exacerbates neuroinflammation, and further contributes to an expanding cycle that includes oxidative stress, ROS production, neurotoxicity, and apoptosis [39] (Figs. 1, 2). Post-mortem studies of brain tissue from AD patients have revealed elevated levels of destructive A1 astrocytes, as well as upregulation of astrocytic γ-aminobutyric acid (GABA) [39, 40]. Animal models of AD have demonstrated that this excessive release of GABA from reactive astrocytes is associated with impairment of memory and synaptic plasticity [40]. Therefore, as the role of glia, immunosenescence, oxidative stress, and ROS are increasingly acknowledged in both initiating and contributing to AD pathology through inflammatory pathways, the mechanistic contributions of inflammation-pertinent genetic risk factors can be better evaluated.

There is mounting evidence suggesting that genetically driven, immune-related processes are causative of AD pathology, but also elicit downstream effects of cell damage. One of the major functions of APOE, the strongest genetic predictor of AD risk, is to regulate lipid levels in plasma and tissues by serving as a ligand in low-density lipoprotein receptor-mediated endocytosis. In the CNS, APOE is predominantly expressed by astrocytes, but also by neurons and activated microglia, and is responsible for lipoprotein clearance and cholesterol transport to neurons. APOE is expressly involved in Aβ clearance; indeed, lipidated APOE binds soluble Aβ and facilitates Aβ uptake through cell-surface receptors [41]. However, the APOE4 isoform impairs Aβ clearance, relative to APOE3 and APOE2, which promotes a pro-inflammatory state (Fig. 2).

While murine ApoE lacks natural isotypes akin to human APOE2 and APOE4, transgenic (Tg) models expressing humanized APOE4 exhibit a significant increase in serum and brain levels of TNF and interleukin 6 (IL-6) [42], as well as elevated microglia nitric oxide (NO) release [43], compared to APOE3-Tg mice. These results have been recapitulated in human populations, showing that TNF, IL-6, and IL-1β levels in plasma are associated with AD patients possessing the ε4 allele [44], and that immune-activated, human monocyte-derived macrophages from APOE4 patients demonstrate a significant increase in NO production [43]. APOE3 plays an essential anti-inflammatory role in the CNS, while APOE4 amplifies the proinflammatory response induced by Aβ, thus resulting in a robust inflammatory phenotype that causes neuronal dysfunction. The mechanisms behind the immunomodulatory functions of APOE are not well-understood; however, it is theorized that higher retention of cholesterol in lipid rafts enhances TLR signaling in macrophages (i.e., microglia) [45]. APOE4 is reported to be less effective than APOE3 at inducing macrophage ATP binding cassette A1 (ABCA1) expression; thus, reducing cholesterol efflux and promoting cholesterol accumulation within the cell membrane of macrophages [46]. This may be due to the abnormal structure of the APOE4 isoform, caused by a single amino acid substitution (C112R) that results in a C–N domain interaction and decreases phospholipid binding capacity [47].

The amyloid precursor protein (APP) is cleaved by secretases and processed into the small Aβ peptides that embody pathognomonic protein aggregation in AD (Fig. 2). There are approximately 49 known mutations implicated in AD at the APP locus (https://​www.​alzforum.​org/​mutations/​app). These mutations have recognized roles in Aβ overproduction and misfolding [48‐50], which promotes plaque formation and onset of a robust, pro-inflammatory response, as described above. The pathological effects of APP overproduction are consistent with the high prevalence of AD and associated dementias in people with Trisomy 21, as APP is encoded on chromosome 21 [51]. Mutations in the presenilin genes (> 300 in PSEN1; > 55 in PSEN2) are also commonly implicated in familial AD (https://​www.​alzforum.​org/​mutations/​psen-1; https://​www.​alzforum.​org/​mutations/​psen-2). PSEN1 and PSEN2 encode subunits of γ-secretase, the enzyme involved in APP cleavage, and mutations in these genes most often result in an altered ratio between the aggregation-prone 42-residue Aβ peptide and the 40-residue variant (Fig. 2). The accumulating proportion of this aggregate-prone protein is sufficient to induce an inflammatory response that can be compounded by the effects of immunosenescence, oxidative stress, and ROS production. This ratio, together with APOE genotype, is used as an effective biomarker of AD progression [52].

The gene encoding TREM2 is also consistently implicated in AD, and variants at this locus act as a modifier in AD risk [53]. TREM2 is a transmembrane, immunoglobulin receptor that modulates microglial activity and survival (Fig. 2). TREM2 is required for sensing DAMPs and plays key roles in the ability of microglia to phagocytose, clear neural debris, and produce anti-inflammatory cytokines [54]. In addition, TREM2 is a receptor for Aβ; thus, variants at this locus can contribute to AD risk through dysregulated microglial activation, Aβ clearance, and apoptosis [55]. In fact, TREM2 haplodeficient mice exhibit larger, more diffuse, and less compact plaques—morphology that is shared by AD patients with TREM2 loss-of-function variants [56].

Further to these examples, GWASs have uncovered a strong overlap between AD risk loci and a swath of immunomodulatory genes. While not as well-studied as APOE, many of these genes, including CD33, ATP Binding Cassette Subfamily A Member 7 (ABCA7), Clusterin (CLU), Complement receptor 1 (CR1), and CD2-Associated Protein (CD2AP), play immunomodulatory roles in AD. ABCA7, such as ABCA1, encodes a transmembrane lipid transporter primarily expressed in the brain by microglia. ABCA7 is required for the transport of proteins bound to APOE, as well as microglial clearance of Aβ [57]. The proteins encoded by CD33 and CLU have been shown to mediate Aβ clearance by microglia [30, 31]. CR1, and other risk loci that are essential components of the complement cascade, similarly play roles recruiting microglia to clear Aβ, as well as modulating inflammation [58]. CD2AP regulates interactions between T-lymphocytes and antigen-presenting cells, and may modulate neuroinflammation in the context of chronic infection [59]. Additional AD risk loci, specifically the Human leukocyte antigen (HLA) locus and Inositol Polyphosphate Multikinase (IPMK), have been found to harbor variants that are pleiotropically associated with other immune-related diseases, such as Crohn disease and psoriasis [60]. Taken together, these findings suggest that AD risk can be mediated both by genetically driven inducers of inflammation, as well as by genetic variation resulting in dysfunction of immune-response pathways.

The multifactorial nature of AD is highlighted by sex bias in disease incidence, variable age of onset, and variable expressivity of clinical presentation. Hence, in addition to the substantial contribution of genetic factors toward AD risk, disease onset and progression are further modulated by environmental factors. Many early cellular and molecular studies have emphasized the “amyloid cascade hypothesis,” suggesting that Aβ deposition marks the pathogenesis of AD [61]. In support of this, certain elements in the human exposome, termed “Alzheimerogens,” are thought to promote the production of Aβ plaques; thus, inciting a neuroinflammatory response that results in neurodegeneration [62]. For example, pesticides and herbicides have been recognized by epidemiological studies and meta analyses as environmental risk factors for AD/dementia [63, 64]. Rodents exposed to various pesticides showed signs of Aβ aggregation, tau hyperphosphorylation, neuroinflammation, neurodegeneration, and cognitive deficit [65, 66] (Fig. 2).

While Aβ accumulation remains both a potential trigger and consequence of neuroinflammation, AD is becoming increasingly recognized as a neurological disease in which immunosenescence and inflammation are major drivers and sensitizing factors of disease onset/progression [67]. Consistent with our underlying thesis, common environmental risk factors of AD and associated dementias can trigger an inflammatory response in the CNS that can tip the balance toward initiating disease and exacerbating the progression of AD neuropathology.

Traumatic brain injury (TBI) is a common neuroinflammatory insult experienced by over 69 million people worldwide—including military personnel, amateur and professional athletes, adults and children subject to falls, and individuals who have experienced motor vehicle collisions or other traumas/penetrating insults [68]. Compared to controls, individuals who have experienced moderate or severe TBI have a twofold or four-and-a-half-fold risk of developing AD, respectively [69]. Case–control and cohort studies have found that a history of head injury is associated with elevated risk of AD and dementia (OR = 1.58–2.29) [70, 71]. Critically, TBI can induce chronic neuroinflammation, as evidenced through the activation of microglia and the detection of pro-inflammatory biomarkers up to 12 months following a TBI [72‐74] (Fig. 2). Furthermore, both human and rodent models demonstrate that there is a marked increase in the production of APOE and APP following a brain injury [75, 76], revealing a clear GxE interaction that may modulate AD risk (Fig. 2). In fact, individuals with the ε4 allele experienced worse recovery outcomes following TBI, compared to injured individuals lacking the ε4 allele [77]. Other studies suggest that aberrant APP processing can occur following a TBI, as evidenced by a greater density of Aβ plaques and NFTs in the postmortem brains of TBI patients, compared to non-injured controls [78]. In support of this, the deposition of Aβ plaques, and other neural changes, can be detected as early as 2 h following a TBI [79]. Interestingly, repetitive TBI can lead to chronic traumatic encephalopathy (CTE), a neurodegenerative condition that is also characterized by NFT and memory loss [80].

Chronic stress, including post-traumatic stress disorder (PTSD), is another common risk factor for AD. Furthermore, inflammatory response associated with a TBI may actually contribute to PTSD symptoms [81], suggesting a comorbidity, where inflammation is the common denominator [82]. Pro-inflammatory biomarkers are also seen in individuals who have experienced early life trauma and depression [83]. Notably, indicators of chronic stress, such as depression and hypertension, are considered risk factors for AD [84]. Furthermore, overexpression of corticotropin releasing factor, which modulates the stress response, revealed increased phosphorylation of β-secretase and tau in female mice [85]. These female mice exhibited increased Aβ plaque disposition and cognitive impairment relative to males, which mirrors female vulnerability to AD in human populations. The inflammatory response associated with chronic stress is not restricted to the brain, but also exists at the periphery, rendering AD at least partially systemic [67, 86].

The “endotoxin hypothesis of neurodegeneration,” also invokes an inflammatory foundation of AD, postulating that chronic infection by gram-negative bacteria, or the inability to effectively clear endotoxin, can elicit neurodegeneration [87]. Sustained peripheral immune reactivity to endotoxin can bolster immune cell memory, trafficking, and communication that may contribute to this neuronal vulnerability through an exaggerated inflammatory response. Lipopolysaccharide (LPS) endotoxin is found on the outer membrane of gram-negative bacteria, and the main receptor for LPS, TLR4, is preferentially expressed on microglia [88]. TLR4 activation can elicit NF-kB activation of a broad pro-inflammatory transcriptional response, including pro-inflammatory cytokines. Rats given LPS injections exhibit a pro-inflammatory response, upregulation of APP and β-secretase, downregulation of Aβ clearance, and cognitive impairment, suggesting a role of chronic inflammation in promoting AD pathology [89] (Fig. 2). Studies of AD patients have shown colocalization of endotoxin with Aβ plaques [90], in addition to blood and brain endotoxin levels that are two-to-threefold higher compared to controls [91]. Again, there is evidence of a GxE interaction, where individuals with the APOE4 allele are more sensitive to environmental insults, in this case LPS endotoxin, in a manner that may further exacerbate their risk for AD [92]. A breadth of research is emerging that supports the role of gut–brain-axis in AD. Early predictive pathology of AD is posited to take place in the gut as a result of microbiota dysbiosis that increases intestinal permeability, activates immune cells, and impairs the blood–brain barrier (BBB) [93]. This is thought to alter cell signaling in the brain, as well as permitting the influx of peripheral immune cells and inflammatory cytokines into the brain [93]. One longitudinal study found that individuals with inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis (UC), have a greater risk of dementia [94]; however, a retrospective cohort study found that only UC was significantly associated with dementia [95]. There is also evidence that AD patients exhibit altered profiles of gut microbiota [96]. Chronic viral infections, including influenza and respiratory tract infections [97], have also been suggested to play a role in the risk of AD onset and progression. Human herpesvirus (HHV) infection is posited to elevate risk and accelerate disease as a consequence of increased Aβ deposition, as seen in a 5XFAD mouse model and 3D human neural cell culture infected with herpes simplex virus type-1 (HSV-1), HHV-6A, and HHV-6B [98]. Furthermore, the chronic pro-inflammatory milieu set by human immunodeficiency virus (HIV) is consistent with the increased risk of neurological symptoms in these patients, such as HIV-associated neurocognitive disorders and HIV-associated dementia [99]. Thus, the “inflammatory-infectious hypothesis” of AD is gaining increasing support over the “amyloid cascade hypothesis” and is beginning to inform the search for therapeutic strategies for AD.

Since the first description of AD over 100 years ago, efforts to identify strategies that would slow, or halt, disease progress have generated limited success. The most common treatment strategies include cholinesterase inhibitors and N-methyl d-aspartate (NMDA) antagonists that serve to modulate the cognitive and behavioral symptoms of AD. The search for improved, accessible AD treatment strategies and early disease detection remain driven by the unrelenting nature of AD progression and the associated health and economic burden (USD$355 Billion in 2021) [3]. Thus, earlier detection carries with it the hope for preventing or significantly delaying the onset and progression of debilitating clinical features. The prodromal phase of AD is characterized by mild cognitive impairment, depressive symptoms, and pathophysiological changes to biomarkers in cerebrospinal fluid (i.e., P-tau217, Aβ oligomers) that may precede neuron loss and dementia by as many as 25 years [20, 100]. As such, neural injury and brain changes are likely to occur decades before onset of overt cognitive impairment, at which point, treatment strategies targeting the mechanisms underlying disease risk may prove ineffective in halting disease progression. Therefore, identifying the window of optimal clinical intervention is paramount.

One emerging strategy, directed at early disease stages, seeks to target Aβ aggregation with the prediction that reduced Aβ would retard disease progression and ameliorate symptoms. In 2021, the USFDA accelerated approval of the first disease-modifying immunotherapy for AD, Aducanumab—a human monoclonal antibody that selectively targets Aβ aggregates and reduces soluble and insoluble Aβ in a dose-dependent manner [101]. Approval of Aducanumab is not without controversy, as results from phase III trials (ENGAGE: NCT 02477800; EMERGE: NCT 02484547) lack unequivocal evidence of the drug’s safety and efficacy [102, 103], which, despite these results, is proposed to cost individual patients USD$56,000 annually [103].

Studies of nonsteroidal anti-inflammatory drug (NSAID) use in Tg rodent models of AD (14 studies; reviewed in McGeer and McGeer [104]) have largely found that NSAID use reduces neuroinflammation and microglial activation through inhibition of cyclooxygenase (COX) isoforms and reduces Aβ₄₂ accumulation through γ-secretase modulation [104]. Epidemiological studies and meta-analyses have shown that long term use of NSAIDs may be protective against cognitive decline and AD risk; however, these results are not consistently corroborated in the literature, and most clinical trials predicated on encouraging epidemiological and model system data have failed to support a beneficial role for NSAID use in the treatment or slowing of AD [104, 105]. These trials have been relatively small and have included patients already presenting with mild to moderate cognitive decline. Reviews by McGeer and McGeer [104] and Villarejo-Galende et al. [105] have highlighted these inconsistencies. Many reasons could underlie the different results, including study size, population, differences in study design, or missing the window of optimal therapeutic intervention [106]. It is also likely that immune pathology in AD is more complex than COX-2-mediated pathophysiology and NSAIDS are simply not the right agents to target dementia-causing inflammation in the brain.

Interestingly, the NSAID derivative, and γ-secretase modulator, CHF5074 has shown promise in cell and rodent models of AD; CHF5074 treatment suppressed expression of pro-inflammatory markers (TNF, IL-1β, and iNOS), increased expression of anti-inflammatory markers (MRC1/CD206 and TREM2), and demonstrated favorable reductions in plaque and NFT formation, neurodegeneration, neuroinflammation, and cognitive deficit [107‐111]. CHF5074 (also known as Itanapraced or CSP-1103) has gone through phase II trials (NCT01303744; NCT01602393; NCT01723670) [112], and preliminary studies of human subjects have shown that CHF5074 treatment is associated with a reduction in neuroinflammation [113]. However, one study found that cognitive improvement was restricted to APOE4 AD patients [114].

While there has been a shift in focus toward the development of pharmaceuticals that target neuroinflammation in AD [112], emerging data also suggest that non-traditional, anti-inflammatory treatments may display ameliorative properties. For example, curcumin, a polyphenol found in turmeric, exhibits anti-inflammatory, antioxidant, and anti-protein aggregation effects. In murine and cell models, curcumin has been shown to suppress microgliosis, inhibit the production of pro-inflammatory cytokines (IL-1β, IL-6 and TNF), reduce oxidative damage, and reduce Aβ deposition [115, 116]. In small human trials, curcumin has been shown to decrease Aβ₄₂:Aβ₄₀ ratio and protect against AD and cognitive decline, with no discernible side-effects (34–96 participants; 1 epidemiological study of 1010 participants) [117‐120]. Trials employing formulations that increase the bioavailability of curcumin (i.e., Longvida®, Theracurmin®) have seen even greater improvements in mood and cognition, as well as decreases in Aβ levels in sera, as well as Aβ plaque and NFT accumulation in brain regions modulating mood and memory [119, 121‐123]. These studies agree with data from cell and rodent models, in which curcumin treatment was consistently associated with a decrease in Aβ levels, inflammation, microglial activation, and cognitive impairment (7 in vitro studies, 7 in vivo studies; reviewed in Mandal et al. [124]). Collectively, these studies underscore the therapeutic potential of curcumin.

The next steps in exploring the value of immunomodulation or anti-inflammatory compounds in preventing or slowing AD onset are not immediately clear. However, the established roles of genetic and environmental factors in modulating inflammatory response and AD risk suggest they may remain a target of therapeutic value. Therefore, substantial follow-up studies may be necessary to re-evaluate the prophylactic and therapeutic efficacy of these strategies in trial participants before the onset of cognitive decline or neurodegeneration. As such, future clinical trials for AD would greatly benefit from the knowledge of the timeframe in which clinical intervention may be most effective.

Dopaminergic neurons of the SN are preferentially vulnerable in PD; thus, it is worth noting that these neurons are also preferentially vulnerable to the effects of an inflammatory response. Several factors appear to conspire to elevate neuronal vulnerability. Compared to the rest of the CNS, studies of adult mice have shown that the SN has the highest density of resting microglia (which account for 12% of cells in this region) [139] (Fig. 3). As outlined above, stimulation of microglia can release pro- or anti-inflammatory cytokines that subsequently activate other mediators of inflammation, growth, and repair. Like in AD, cellular communication between microglia and astrocytes serves to maintain homeostatic balance in the CNS, and pro-inflammatory cytokine production by activated microglia activates A1 astrocyte signaling cascades (Fig. 1) associated with synaptic destruction and neurotoxicity in PD [39].

Normally, the SN contains a low ratio of astrocytes to microglia, potentially contributing to SN DA neuron vulnerability to ROS, protein aggregation, and other initiators of the inflammatory response [29]. SN vulnerability in PD is further exacerbated by high concentrations of neuromelanin—the pigmented by-product of catecholamine catabolism for which this region of the brain was named. Under normal conditions, neuromelanin plays a neuroprotective role, as the main storage molecule in SN DA neurons for iron and other metals [140]. Detection of extracellular neuromelanin in the degenerating DA neurons of PD patients activates microglia, which triggers pro-inflammatory pathways (i.e., NF-κB and Mitogen-Activated Protein Kinase; MAPK), and results in neuromelanin engulfment [141] (Fig. 3). Evidence suggests that when extracellular neuromelanin is phagocytosed by microglia, iron is released from neuromelanin and produces ROS through Fenton reactions with H₂O₂ generated by the deamination and autoxidation of DA [140, 142]. This is thought to further accelerate oxidative stress and neurotoxicity in the PD brain. Studies of PD patient serum and post-mortem human and mouse brain tissues have revealed increased levels of activated microglia and pro-inflammatory cytokines [143, 144], destructive A1 astrocytes [39, 145] (Fig. 3), and infiltration of CD8+ and CD4+ T lymphocytes [146]. Neuroimaging studies have further confirmed the involvement of an inflammatory response in the brain and its contribution to DA neuron loss in PD patients [147]. Therefore, it should be no surprise that genetic risk factors in PD may impact the likelihood and extent of inflammatory response, and that environmental factors that promote/suppress inflammatory response may modulate PD risk/progression (Fig. 3).

PD risk loci exert their effect through variable mechanisms of action; however, the consequential activation and persistence of an inflammatory response represents the emergence of a common theme. Many PD mutations are now believed to elicit this response through pathways involving oxidative stress [148], and numerous pan-ethnic PD risk loci (i.e., DJ-1, GBA and HLA) have functional roles in the immune system [149]. Several genes implicated in PD play direct roles in immune/inflammatory response, and common genetic risk variants have been shown to convey risk of both PD and autoimmune diseases [150]. Furthermore, GWASs and meta-analyses suggest a strong involvement of the innate and adaptive immune systems in genetic susceptibility to PD [151, 152]. However, in contrast with AD, many PD risk loci currently lack such a direct attribution.

As part of its role as a major driver of PD pathology, mutant SNCA elicits a proinflammatory response. Mutations resulting in SNCA overexpression and aggregation can trigger microgliosis, since SNCA aggregates act as DAMPs that activate pro-inflammatory microglia, and promote the production of pro-inflammatory cytokines, such as IL-1β [153] (Fig. 3). While there is some evidence of T-cell reactivity to nitrated SNCA epitopes (this post-translational modification is not recognized as a self-protein) in early PD [154], studies assaying anti-SNCA B-cell antibody levels in PD patients present discordant data [155]. Aggregation of SNCA is also thought to induce an inflammatory response as a result of ROS production (Fig. 3), through interactions with the microglial P2X7 receptor [156]. As in AD, ROS production and oxidative stress in PD are both inducers and consequences of an inflammatory response, and further contribute to neurotoxicity.

ROS, and subsequent inflammation, can also be a consequence of mitochondrial damage. PD risk loci PINK1 and PRKN are involved in the clearance of dysfunctional mitochondria, but mutations in these genes can impair this function and result in the production of ROS and mitochondrial-DAMPs that can activate an immune response [157] (Fig. 3). This response, characterized by increased levels of IL-6, is thought to be activated in a CGAS (cyclic GMP–AMP synthase)/STING (stimulator of interferon genes)-dependent manner [157]. PRKN and PINK1 also share roles in the modulation of inflammatory cytokines [149], and transcriptomic studies have found that Pink1^−/− mice show altered gene expression profiles of genes involved in innate immunity [158].

The role of an inflammatory response in PD onset can also be influenced by the LRRK2 risk locus, since high levels of LRRK2 expression is seen in human peripheral blood mononuclear cells [159] and murine microglia [160]. In addition to roles that overlap inflammatory response, such as mitochondrial function, vesicle trafficking and endocytosis, retromer complex modulation, and autophagy, it is thought that LRRK2 may modulate cytokine production in both a TLR-dependent and TLR-independent manner [161]. As such, mutations at this locus could increase susceptibility to infection and inflammation (Fig. 3). A transcriptomic study of PD patients with LRRK2 mutations found disruptions in pathways involved in immune response signaling, MAPK signaling, apoptosis, and mitochondrial oxidation [162]. LRRK2 is thought to be pro-inflammatory; in fact, mouse models that are genetically predisposed toward developing PD, but lack Lrrk2, show impaired microglial activation and LB formation [163]. Lrrk2 deficiency has also been shown to be protective against certain environmental insults, such as chemical toxins and viral inducers of inflammation [164, 165] (Fig. 3). Collectively, these studies establish a common theme that genetic predisposition toward inappropriate modulation of an inflammatory response may elevate long-term disease risk.

Several features of PD highlight the potential for combined genetic and environmental roles in disease, including variable age of onset and variable expressivity of disease phenotypes. Exposure to chemical neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) results in selective destruction of DA neurons in the SN and permanent PD pathology, albeit lacking LB inclusions. MPTP, a by-product in the synthesis of the opioid desmethylprodine (1-methyl-4-phenyl-4-propionoxy-piperidine; MPPP), was first identified as an irreversible inducer of rapid-onset PD pathology in humans who had intravenously injected the chemical as a contaminant of illicit narcotics [166]. Glial cells metabolize MPTP to 1-methyl-4-phenylpyridinium (MPP+), which is taken up by DA neurons. This results in in oxidative stress, mitochondrial damage, and neuron death by inhibiting complex I (NADH-dehydrogenase) of the electron transport chain [167] (Fig. 3). In these cases, patients showed evidence of microglial activation that persisted years after drug clearance, in addition to neuromelanin seen both extracellularly and within microglia (Fig. 3). Consequently, MPTP is used to experimentally induce symptoms of PD in animal models. These models have further illuminated how inflammation may contribute to PD, by identifying that CD4+ T lymphocytes contribute to neurodegeneration through the FasL pathway [146].

Akin to the mechanism of action of MPP+, rotenone induced neuron death is associated with inhibition of NADH-dehydrogenase, and contributes to PD pathology through oxidative stress, ROS production, and inflammatory response (Fig. 3). Rotenone is a pesticide, insecticide and piscicide, exposure to which is also associated with increased risk of developing PD (OR = 2.5) [168]. Exposure to other pesticides, such as Paraquat, also cause oxidative stress and the onset of a pro-inflammatory milieu, and is similarly associated with increased risk of PD (OR = 2.5) [168].

In addition to chemical exposures, there is substantial evidence that the strong inflammatory response associated with TBI is also a risk factor for PD. Years of athletic participation in contact sports are associated with an elevated risk of developing parkinsonism and Lewy Body Disease (OR = 1.30 per year) [169]. As previously discussed, studies highlighting elevated levels of inflammatory biomarkers, specifically IL-6 and TNF, demonstrate that a prolonged inflammatory response follows TBI [72, 83] (Fig. 3). This response is thought to cultivate a pro-inflammatory milieu that renders mbDA neurons vulnerable to neurodegeneration. Indeed, among veterans and military personnel, TBI is associated with a 56% increase in PD risk [170]. Interestingly, mouse models with TBI have been shown to induce HIF-1α-dependent overexpression of the pro-inflammatory PD risk locus Lrrk2 [171] (Fig. 3). Similar observations have supported an association between inflammatory biomarkers and PTSD in PD [83, 172]. Patients with PTSD are at an elevated risk for PD, alluding to an insidious role of chronic stress in PD risk [173]. Consistent with these data, several studies of humans and rodents have shown that stress increases an individual’s lifetime risk of PD [174‐176]—observations that are consistent with the known correlation between cortisol levels and increased PD risk [177].

Inflammation associated with viral and bacterial infections is also an increasingly appreciated risk-factor for PD. Infectious burden, measured by antibody titers to cytomegalovirus, Epstein Barr virus, HSV-1, Borrelia burgdorferi, Chlamydophila pneumoniae, and Helicobacter pylori has been shown to be elevated in PD patients and associated with increased levels of serum SNCA, IL-1β, and IL-6 [178]. In a mouse model infected with H5N1 influenza, microglia activation was noted 90 day post-infection, in addition to SNCA aggregation, phosphorylation at Ser129 (pS129 α‐Syn), and degeneration of DA neurons [179] (Fig. 3). Human macrophages stimulated by LPS and IL-1β upregulate SNCA in a concentration-dependent fashion [180] (Fig. 3). Murine models given LPS injections display increased levels of pro-inflammatory cytokines and microglia activation, loss of DA neurons, and induction of PD phenotypes [181, 182] (Fig. 3). Interestingly, there is evidence to suggest that intranasal LPS can activate microglia and inflammatory cytokines and trigger SNCA overexpression, aggregation, and pS129 α‐Syn in the olfactory bulb—a response that spread to the SN and striatum of mice within 6 weeks, resulting in PD pathology [183]. The “endotoxin hypothesis of neurodegeneration” postulates a dual-hit hypothesis for PD, where elevated endotoxin plus α-synuclein aggregation results in neurodegeneration [87].

Increasing evidence supports the idea that PD pathology can begin in the enteric nervous system (ENS) and spread to the brainstem via the vagus nerve. It is thought that intestinal stimuli modulate signaling pathways in the brain as an effect of vagal afferent signaling (reviewed in Houser and Tansey [184]). This model of pathogenesis posits that intestinal inflammation triggers an initial immune response resulting in gut dysbiosis, increased intestinal permeability, and increased expression and aggregation of α-synuclein. In support of this model, PD patients display LB pathology in intestinal enteric nerves and increased intestinal permeability [185]. Chronic intestinal inflammation and permeability may promote systemic inflammation, which can increase BBB permeability, permit the influx of peripheral immune cells into the brain [184], and result in neuroinflammation/degeneration (Fig. 3). There is also a growing body of evidence demonstrating that risk of PD in patients with chronic gut inflammation, such as in Crohn’s disease and UC, may be 20–90% higher than those without inflammatory bowel disease [186]. These hypotheses are further supported by the incidence of gastrointestinal complications in as many as 80% of PD patients [184].

While more rigorous studies of these mechanisms are required, they are collectively posited to elicit a chronic neuroinflammatory response that significantly contributes to the pathogenesis of progressive neurodegeneration in PD [187]. Ageing is thought to exacerbate these effects since oxidative damage, and the subsequent inflammatory response, is expected to naturally increase over time in these already vulnerable regions of the brain [2]. Proinflammatory processes are inherent in the pathological development of PD and the effects of genetic and environmental risk factors; thus, inflammation itself may serve as a risk factor for the onset and progression of PD.

Presently, there is no cure for PD. In addition to physical and occupational therapy, individuals with PD are most often prescribed a form of levodopa. Levodopa is as DA precursor that is used to supplement DA in PD patients, since it can cross the BBB. While levodopa is considered the gold-standard in PD treatment, its efficacy diminishes over time, and prolonged use with increasing effective dose can result in significant side-effects, including levodopa-induced dyskinesia. Current treatment strategies are only employed upon the clinical presentation of PD, by which point, 40–60% of mbDA neurons have already been lost [128]. Furthermore, the economic impact of clinically defined PD is great, costing Americans nearly USD$52 billion in 2018 alone [188]. As such, the prodromal phase of PD may be the most medically and cost-effective window of therapeutic or prophylactic intervention.

Localized pro-inflammatory response, increased oxidative stress, and selective DA neuronal damage, are all drivers of PD progression. This observation has sparked interest in the potential ameliorative capacity of anti-inflammatory therapies, pharmaceuticals, nutraceuticals, and behaviours. While rigorous follow-up studies are necessary to evaluate the efficacy and mechanism of action of these approaches in preventing or slowing the progression of PD, they contribute to a common narrative that reinforces the potential role of inflammation in PD risk. Consequently, there is an increasing body of literature evaluating the therapeutic value of impeding inflammatory response in mitigating and treating PD. As with AD, epidemiological, model system, and clinical intervention paradigms have been employed with variable results.

Several emerging therapeutic strategies in trials for PD set out to target the endogenous proinflammatory response [189]. Glucagon-like peptide 1 receptor (GLP1R) agonists have recently emerged as valuable neuroprotective agents with potential therapeutic value to PD. Recent work has revealed that NLY01, a potent GLP1R agonist, acts to block A1 astrocyte activation by microglia [190]. In doing so, it reduced DA neuron loss and behavioral deficits in an SNCA–PFF (preformed fibril) PD mouse model, as well as prolonging life and reducing behavioral deficits in the hA53T SNCA PD mouse model [190]. In fact, multiple GLP1R agonists are currently being evaluated in clinical trials (Exenatide—Phase 3 NCT04232969; Liraglutide—Phase 2 NCT02953665, Lixisenatide—Phase 2 NCT03439943; NLY01—Phase 2 NCT04154072) [189].

While some epidemiological studies and meta-analyses have found an association between regular NSAID use (particularly ibuprofen) and reduction in PD risk [191‐193], most studies report non-significant therapeutic effects alongside considerable risk of heart attack, stroke, gastrointestinal bleeding, and kidney problems [194]. One recent study of LRRK2 PD mutant and PD-risk variant carriers demonstrated that regular NSAID use was associated with reduced PD risk [195]. However, additional clinical trials are warranted in evaluating the potential of alternative immunomodulatory therapeutic approaches in PD. Here again, identifying the optimal timespan to therapeutically target neuroinflammation in these disorders may be paramount for the success of future clinical studies.

Curcumin also represents an intriguing prospect for PD risk reduction. Curcumin displays neuroprotective effects in animal and cell models of PD [124, 196‐198] and has been shown to improve motor symptoms in a mouse model of PD overexpressing Snca [199]. Curcumin is most commonly used for culinary and medicinal purposes in Southeast Asia, India and China, where, interestingly, PD risk is significantly lower than in North America, Europe, Australia, and South America [200]. While this evidence is circumstantial, it suggests value in both epidemiological studies and clinical trials to evaluate the therapeutic potential of curcumin for PD risk reduction.

However, both epidemiological and animal studies have implicated caffeine intake as a risk reducer for PD (reviewed in Ren and Chen [201]): in an MPTP mouse model, intraperitoneal administration of caffeine attenuated microglia reactivity, as well as demonstrating a decrease in loss of DA neurons. Its neuroprotective properties are thought to act through the adenosine 2A receptor, since genetic deletion and pharmacological blockade of this receptor is protective against DA neuron degeneration and rescues synaptic and cognitive deficits in animal models of PD [201]. Furthermore, supporting the increasingly acknowledged role of the gut–brain axis, caffeine is reported to modulate gut microbiota in preclinical PD models [201].

Both genetic and environmental factors clearly modulate neuroinflammation and PD risk; thus, suggesting that targeting the inflammatory response is of prophylactic and therapeutic value. Consequently, additional studies are necessary to identify the critical time window in which this inflammatory response may contribute to disease risk, such that the development and evaluation of interventional strategies may be more robustly undertaken.