With an estimated global prevalence of 46.8 million affected individuals in 2015, Alzheimer’s disease (AD) remains the leading cause of dementia worldwide (1). The majority of new AD cases are sporadic and late-onset in nature, and without a major therapeutic breakthrough, it is estimated that the prevalence will quadruple by the middle of this century (2), ultimately reaching a global prevalence of approximately 131.5 million (1). The major neuropathological hallmarks of AD include extracellular senile plaques composed of aggregates of beta-amyloid (Aβ) protein (3), and intraneuronal neurofibrillary tangles made up of aggregated tau protein (4, 5). Although the German psychiatrist and neuropathologist Alois Alzheimer described the neuropathological hallmarks of AD over a century ago (6), the role of inflammation in the pathogenesis of the disease was not fully appreciated until several decades later.

Recent work has demonstrated that the termination of the acute inflammatory response is dependent on an active process termed “resolution” (7–9). In this review, we will review the scientific evidence linking the impairment or failure of resolution to AD, the specific neuropathological consequences of resolution failure in this neurodegenerative disorder, and the potential for the restoration of resolution to serve as a therapeutic target in AD.

Neuroinflammation has been implicated in playing a key role in the pathogenesis of AD, with studies suggesting various mechanisms including astrocyte (10–13) and microglial activation (14–18), increases in pro-inflammatory molecules such as cytokines and chemokines [reviewed in Ref. (19)]. Moreover, there is evidence to suggest that the activation of endothelial cells of the neurovascular unit, oligodendrocytes, and even neurons may be involved [reviewed in Ref. (20)]. In AD patients, the role of neuroinflammation is clinically supported by PET studies demonstrating microglial activation (21–23), increased serum (24–26), and brain (27, 28) pro-inflammatory cytokine levels as well as the downregulation of anti-inflammatory molecules in postmortem brain tissue (29). Moreover, although the CNS was once considered an immunologically privileged site, it is now recognized that peripheral inflammation can exacerbate the inflammatory environment of the brain and contribute to chronic neuroinflammation and neurodegeneration (30, 31).

The initiation of the acute inflammatory phase, usually in response to trauma, infection, tissue injury, neoplasia, or other major homeostatic stressors, has been well characterized by the increased release of pro-inflammatory mediators such as prostaglandins and leukotrienes, leading to polymorphonuclear (PMN) leukocyte recruitment and monocyte-macrophage proliferation. It was initially believed that the acute response to inflammation passively dissipated over time; however, it has been more recently appreciated that acute inflammation is actually kept in homeostatic balance by resolution (32, 33), which ultimately results in the clearance of recruited granulocytes and a restoration of pre-activation immune profiles [reviewed in Ref. (7, 9)]. Failure of resolution has been associated with the development of chronic inflammation (34), which has been implicated in the pathogenesis of many diseases including asthma, periodontitis, rheumatoid arthritis, ulcerative colitis, multiple sclerosis, and AD [reviewed in Ref. (9)].

The resolution of inflammation is initiated by a change in eicosanoid signaling that shifts from a pro-inflammatory to a pro-resolution, anti-inflammatory state, which is characterized by the biosynthesis of specific mediators. Sophisticated advances in lipidomics and metabolomics, spearheaded by seminal investigations by Serhan and his colleagues, have resulted in the identification and functional classification of these specialized pro-resolving mediators (SPMs) that drive resolution (7–9, 35–38). During the initiation phase of the acute inflammatory response, mediators derived from arachidonic acid become up-regulated and contribute to changes in vascular permeability and PMN leukocyte recruitment (39). However, the generation of these pro-inflammatory autacoids is eventually terminated by subsequent dynamic changes in prostaglandins E2 and D2 (39). This can be seen as a switch where increased levels of SPMs, including pro-resolving lipoxins [e.g., Lipoxin A4 (LXA4)], diminish inflammatory molecules such as prostaglandins, leukotrienes, and cytokines (Figure 1A). Pivotal to this switch is a class of lipid mediators, or SPMs, which are biosynthesized from the omega-3 fatty acids (ω-3 FAs), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and regulate acute inflammation by promoting active resolution (Figure 1B). These SPMs include the resolvin D series compounds, protectins/neuroprotectins, and maresins, which are derived from DHA, as well as the resolvin E series compounds derived from EPA (Figure 1B) [reviewed in Ref. (34, 38, 40)]. The pro-resolving effects of the lipoxins and the ω-3 FA-derived SPMs collectively exert key features of resolution: suppression of PMNs, decrease vascular permeability, promotion of non-phlogistic monocyte recruitment, and increase macrophage-mediated clearance of apoptotic PMNs. However, during chronic inflammatory states, including neurodegeneration, this balance is disrupted and the predominance of arachidonic acid-derived pro-inflammatory lipid mediators contributes to the impaired resolution of inflammation and the persistence of a generalized pro-inflammatory state.

Although age is the greatest risk factor for developing late-onset AD, only recently have investigators started to appreciate the impact of aging on resolution in humans. Gangemi et al., measured urine LXA4 and pro-inflammatory leukotriene levels in 30 healthy humans who were divided into three average age groups: 43.5, 77.9, and 102.5 years (59). Compared to the youngest group, both older age groups had significant lower urinary excretion of LXA4; moreover, there was a significant decrease in the LXA4/leukotriene ratio in these older age groups. These findings suggest that, in response to a pro-inflammatory stimulus, the capacity for arachidonic acid-derived pharmacology to switch from the production of pro-inflammatory leukotrienes toward increased lipoxin formation decreases with age.

In terms of AD specifically, by examining levels of SPMs and receptor expression in human CSF and brain tissue, Wang et al. performed one of the initial human investigations demonstrating that the neurodegenerative disorder is associated with impaired resolution (60). Levels of LXA4 and RvD1 were measured in CSF collected from humans with AD, mild cognitive impairment (MCI), or subjective cognitive impairment (SCI). Interestingly, levels of LXA4 in CSF and hippocampal tissue were significantly lower in the AD group versus the MCI and SCI groups; whereas, no group-related differences in hippocampal or CSF RvD1 levels were observed. Of note, there was a positive correlation between CSF LXA4 and RvD1 levels and cognitive performance as measured by the mini-mental state examination (60). In this same investigation, when compared with control subjects, immunohistochemical analyses of hippocampal tissue from AD patients revealed higher levels of the SPM receptors, ALX/FPR2 and ChemR23, the latter a receptor for RvE1. They also observed increased levels of 15-LOX-2, a key enzyme involved in the production of LXA4, as well as decreased levels of IL-10, an anti-inflammatory cytokine associated with the resolution of inflammation (61, 62).

A more recent study by Zhu et al. has provided additional evidence that resolution is impaired in humans with AD (58). These investigators measured SPM levels in the entorhinal cortex of AD patients and age-matched controls at 18–21 h post mortem. Compared to age-matched controls, levels of maresin 1, protectin 1, and resolvin D5 were decreased, while levels of prostaglandin D₂ were decreased in the entorhinal cortex of patients with AD. Again, these changes are consistent with an impairment of resolution in AD and the predominance of a chronic inflammatory state.

As SPMs are biosynthesized from ω-3 FAs (8, 9, 34, 37, 38, 40, 63), the question of whether polyunsaturated fatty acids (PUFAs) impact the resolution of inflammation in AD has logically arisen. ω-3 FA-derived EPA and DHA have been demonstrated to modulate arachidonic acid metabolism in such a manner as to reduce the production of pro-inflammatory mediators. For example, DHA has been shown in astroglial cell cultures to decrease levels of pro-inflammatory thromboxane B2, 6-keto-Prostaglandin F1 alpha, and 12-hydroxyeicosatetraenoic acid (64), whereas EPA has been demonstrated to decrease the pro-inflammatory arachidonic acid derivatives, prostaglandin E2 and leukotriene B4 (65, 66). Patients with AD have lower plasma (67) and brain levels of DHA (68), suggesting that PUFA supplementation may provide beneficial effects on the neuropathology and cognitive function. Furthermore, in AD patients with moderate plaque and tangle pathology, Lukiw et al. demonstrated that levels of NPD-1, a DHA-derived protectin compound with pronounced neuroprotective and anti-inflammatory effects, were significantly decreased in the CA1 region of the hippocampus (68). Aging itself also appears to negatively affect FA metabolism (69, 70); hence, a better understanding of the impact of ω-3 FAs on mechanisms associated with the resolution of inflammation is important to fully elucidate the potential therapeutic role of these compounds in AD.

In vitro studies have demonstrated that DHA and EPA enhance Aβ₄₂ phagocytosis in CHME3 human microglial cell culture (71). Moreover, this occurred in a biphasic pattern characterized by an increase at 2 h followed by a quiescent period and then another phase of activated phagocytosis at 24 h. The late phase activation of Aβ₄₂ phagocytosis was postulated to involve the time-dependent accumulation of SPMs such as resolvins and maresins. Levels of SPMs were not measured in cell culture to confirm this; nevertheless, the time frame is consistent with possible activation of non-phlogistic phagocytosis.

In animal studies incorporating the use of transgenic AD rodent models, ω-3 FAs have been shown to have beneficial effects on Aβ pathology, tau pathology, and neuroinflammation [reviewed in Ref. (72)]. In terms of AD-related pathology, ω-3 FAs have been observed to specifically induce the following potentially therapeutic effects: reductions in Aβ accumulation (73) and Aβ plaque density (74), changes in Aβ ratios favoring the less fibrillogenic forms of the peptide (75), protection against tau hyperphosphorylation (76), reduced inflammation (77), and improved cognitive performance (73, 74, 76). Furthermore, a systematic review and meta-analysis focusing on the impact of ω-3 FAs on cognition and AD pathology in AD animal models revealed that long-term supplementation, which was defined as a minimum of 10% of total life span, was associated with decreased Aβ levels, improved cognition, and decreased neuronal loss (78).

Despite this preclinical evidence, in humans with AD, clinical trials incorporating ω-3 FA supplementation have demonstrated more modest benefits. One of the largest trials to date is the OmegAD study, a randomized double-blind placebo-controlled study, which randomized 204 patients with mild-to-moderate AD to 1.7 g DHA and 0.6 g EPA or placebo treatment for 6 months followed by 6 months of open treatment in both groups (79). These investigators observed that ω-3 FA treatment did not alter the rate of cognitive decline; however, in a small subset of patients with the baseline mini-mental state examination scores of >27, ω-3 FA supplementation significantly decreased cognitive decline. In a subset of patients from the OmegAD study, who were treated with ω-3 FAs for 6 months, increased plasma levels of DHA and EPA were accompanied by a concurrent decrease in plasma arachidonic acid levels (80). In this same investigation, peripheral blood mononuclear cells from the AD patients were incubated in cell culture medium containing Aβ₄₀, which had been previously demonstrated to decrease production of the anti-inflammatory cytokine IL-10 (60). Interestingly, in patients treated with ω-3 FAs, levels of LXA4 and RvD1 remained stable, whereas decreases in these SPMs were observed in placebo-treated patients. Hence, in the ω-3 FA-treated group, a preservation of secreted SPM levels was evident, albeit by some unclear mechanism. In patients with MCI, ω-3 FA supplementation has been also shown to ameliorate the AD-associated impairment of Aβ phagocytosis by macrophages, increase macrophage levels of RvD1, as well as decrease cytokine transcription observed in AD patients with peripheral blood mononuclear cell evidence of pre-existing neuroinflammation [reviewed in Ref. (81)].

Nevertheless, the overall impact of ω-3 FA supplementation on the clinical course of AD in humans remains unclear. A recent systematic review of the literature of placebo-controlled clinical trials examining the impact of ω-3 FA supplementation in patients with mild-to-moderate AD concluded that there is little benefit in terms of cognitive function, daily functioning, or mental health after 6 months of treatment, whereas after 12 months of treatment, one study observed a modest improvement observed in activities of daily living (82). A more recent, larger systematic review of placebo-controlled ω-3 FA clinical trials in AD concluded that supplementation may be of benefit primarily early in the course of the disease; however, the cognitive benefits appear to be quite modest (83). Interestingly, Salem et al. reviewed two recent clinical trials examining the impact of DHA supplementation on cognitive function (84), the Memory Improvement after DHA Study (85), and the Alzheimer’s Disease Cooperative Study (ADCS) (86), which examined the impact of DHA supplementation on memory and respectively demonstrated mnemonic benefit in healthy elderly subjects and no such benefit in AD patients. However, based on the observation that in the ADCS study, lower cognitive decline was observed over an 18-month period in apolipoprotein E4 (APOE4) allele negative patients, Salem et al. have postulated that APOE4 may mechanistically impact the neuropathogenesis of AD by decreasing DHA transport into the brain (84). Therefore, in clinical trials focusing on the cognitive benefits of ω-3 FA supplementation in patients with or at risk for AD, APOE4 genotype may be an important factor regulating therapeutic benefit and should be taken into consideration in the subgroup analyses.

Resolution is an active process that terminates the acute phase of inflammation and restores tissue homeostasis. Multiple preclinical and clinical investigations support the hypothesis that resolution of neuroinflammation is disrupted in AD and that this perturbation may lead to the exacerbation of AD-associated pathology and even cognitive decline (Figure 2). Additional studies focusing on the impact of impaired resolution on tau-related neurofibrillary pathology and function are warranted, as there is a relative dearth of tau studies versus those focusing on Aβ pathology. Furthermore, some studies have demonstrated that SPM treatment may reduce tau phosphorylation in mouse models of AD-like pathology (49).

Despite evidence that failed resolution may play a neuropathogenic role in AD, many mechanistic questions still remain unanswered. Whether the defect of resolution in AD is a consequence of a true or relative decrease in SPM levels and/or their receptor-mediated downstream effects needs to be further addressed. Other resolution-related mechanisms that may be related to AD and warrant further investigation in humans include decreased SPM production due to neuronal loss and reactive gliosis, alterations in the levels and efficiency of various enzymes responsible catalyzing SPM production, changes in arachidonic acid metabolism favoring the production of pro-inflammatory products such as leukotrienes, prostaglandins, thromboxanes, and HETE, acquired defects in SPM receptor-mediated signaling as well as decreases in adequate brain levels of the ω-3 FAs.

Although they theoretically could have beneficial effects on resolution, human studies remain inconclusive as to whether supplementation with ω-3 FAs can actually alter the clinical course of AD. Hitherto, the cognitive benefits observed with ω-3 FAs have been modest and primarily observed very early in the course of the disease. The mechanisms underlying the lack of impactful clinical benefit observed with ω-3 FAs supplementation in AD are probably multifactorial and may involve, in part, inadequate conversion of the parent ω-3 FA compounds to SPMs, alterations in SPM receptor function, and limited transport of ω-3 FA to the brain as a consequence of APOE4 genotype. Therefore, as the SPMs themselves become more readily available for clinical investigations, human clinical trials should be considered to examine whether these compounds have a therapeutic effect in AD via the restoration of normal resolution physiology, and whether their direct administration obviates some of the limitations observed, thus far, with ω-3 FA supplementation.

RW, EP, and NT conceived, wrote, and revised the manuscript.

The authors declare that this review was designed and written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.