Alzheimer’s Disease and inflammation: towards a 2-in-1 treatment strategy?

Treatment strategies for Alzheimer’s Disease (AD), primarily focused on addressing aggregated Amyloid-β and Tau proteins, have seen limited success in clinical trials. Researchers have thus pursued other pathogenic mechanisms implicated in Alzheimer’s Disease, such as neuroinflammation, or inflammation of the central nervous system (CNS), considered to be the “third core pathology” after Amyloid-β plaques and Tau neurofibrillary tangles. Our Healthcare team at Alcimed explores here key aspects of the neuroinflammation hypothesis and how it may impact future treatment options.

From targeting protein aggregates to inflammation in Alzheimer’s Disease

Phase 3 clinical trials centered on addressing protein aggregates have all failed but aducanumab, which was given a second chance in October 2019. For the rest of the drugs and subgroups, these phase 3 clinical trial failures could be due to advanced disease states, improper targeting of the type of aggregates, or perhaps the complexity and multifactorial nature of Alzheimer’s Disease, notably leading to significant heterogeneity among patients enrolled in clinical trials.

Neuroinflammation, along with protein aggregates, has been identified as a central aspect of Alzheimer’s Disease for many years. However, while chronic inflammation or chronic inflammatory diseases such as rheumatoid arthritis are associated with increased cognitive decline, and some genetic variants linked to neuroinflammation increase the risk of developing AD, neuroinflammation is more commonly thought to exacerbate underlying AD triggers rather than cause AD.

How thus does neuroinflammation aggravate the development of Alzheimer’s Disease and how can we translate addressing neuroinflammation into Alzheimer’s Disease treatment strategies?

Two methods to address neuroinflammation in Alzheimer’s Disease

1. Inhibiting causes of inflammation: targeting microglia activation, NLRP3 inflammasome signaling and proinflammatory cytokines

Microglia, or the housekeepers of the CNS, express receptors on their surface that once activated instigate the innate immune system. For example, CD33 and TREM2 receptors act as “on” and “off” switches respectively for neuroinflammation and both have associated gene variants that increase the risk of developing AD.

The innate immune system cascade begins with the upregulation of NLRP3 inflammasome components followed by their activation, leading to the release of inflammatory players including cytokines IL-1β and TNF-α. In AD, Amyloid-β aggregates intervene at multiple points of the signaling cascade, through stimulating microglial receptor expression such as RAGE or initiating NLRP3 inflammasome signaling, eventually completing the vicious cycle with pro-inflammatory cytokine production by microglia that exacerbates Tau or Amyloid-β pathology.

Accordingly, therapies targeting TREM2, CD33, TNF-α or downstream stress-induced proteins, for example, are in clinical trials, with other therapies in pre-clinical stages. Some therapies targeting the NLRP3 inflammasome, for example, are in development not only for AD but also for diabetes, another disease associated with inflammation. These two inflammatory diseases overlapped yet again, when the AD drug candidate Azeliragon, targeting RAGE, was found effective only in the T2D subgroup with elevated HBA1c, leading to an ongoing Phase 2/3 trial for patients with mild AD and high HbA1c. However, doubts grew about blocking inflammation as a strategy to combat AD when Phase 3 clinical trials examining the effect of NSAIDs failed to demonstrate a decrease in cognitive decline.

2. Enhancing neuroinflammation resolution: pro-homeostatic lipids

Typically, inflammation is resolved through a process involving specialized pro-resolving mediators (SPMs). These SPMs, derived from omega-3 and omega-6 fatty acids, bind to multiple receptor classes, initiating the return to homeostasis. However, these receptors can be pro-inflammatory upon activation by other ligands. In brains and cerebrospinal fluid samples from Alzheimer’s Disease patients, SPM levels were decreased while their receptor levels were increased, suggesting that inflammation resolution pathways are unbalanced, favoring inflammation, in Alzheimer’s Disease.

Furthermore, altered inflammation resolution correlated to cognitive decline (MMSE scores) and the presence of aggregated Tau. Thus, treatment with SPMs to restore this balance may be of interest. Animal models for Alzheimer’s Disease or Down Syndrome, which predisposes people to AD, displayed less neuroinflammation and demonstrated better memory performance when treated with SPMs Resolvin E1  and/or lipoxin A4. The ability of SPMs to bind to multiple receptor classes gives reason to believe they could bypass the fate of Pioglitazone, an agonist of one of the types of receptors SPMs target, whose two clinical trials were discontinued in Phase 3 due to lack of efficacy.

Could the success of Alzheimer’s Disease treatment be found with drug repurposing and a 2-in-1 strategy targeting both protein aggregates and neuroinflammation?

Alzheimer’s Disease being a complicated, multifactorial disease, it is likely that an effective way to slow its progression is through a 2-in-1 strategy, targeting not only protein aggregation but inflammation, either through its inhibition or stimulation of its resolution.

For example, researchers have created therapeutics that target both inflammation and protein aggregates at the same time, such as the aforementioned Azeliragon. Alternatively, treatment with anti-inflammatory drugs, for instance IL-1 antagonists on the market for years, could be tested in combination therapy with drugs targeting Amyloid-β and Tau protein aggregates currently in development.

Furthermore, trials involving previously approved and highly monitored drugs and/or derivates are underway, feeding the enticing idea that part of the solution to Alzheimer’s Disease could be hidden in drugs that we already use. One example is the ongoing Phase 3 clinical trial from AZTherapies with ALZT-OP1, containing a blood brain barrier permeable cromolyn, used for asthma and allergies but that also targets Amyloid-β aggregation, and ibuprofen, which reduces inflammation.

The many phase 3 clinical trial failures have elucidated the requirement for new therapeutic strategies to tackle Alzheimer’s Disease. Furthermore, the multifactorial nature of the disease leads to significant heterogeneity among patients. Inflammation plays an undeniable role in Alzheimer’s Disease. Promising pre-clinical and early clinical work on anti-inflammatory treatments, notably in conjunction with therapeutics targeting protein aggregates, give way to a new 2-in-1 strategy that could allow for a vaster treatment of patient profiles.

Abbreviations: AD: Alzheimer’s Disease; CNS: central nervous system; IL-1/IL-1β: interleukin 1/1beta; CD33: cluster of differentiation 33; HbA1c: glycated hemoglobin; MMSE: mini-mental state examination; NLRP3: NOD-like receptor family, pyrin domain containing 3; RAGE: receptor for advanced glycation end products; T2D: type 2 diabetes; TNF-α: tumor necrosis factor-alpha; TREM2: triggering receptor expressed on myeloid cells 2.

About the author

Maya, Consultant in Alcimed’s Healthcare team in France