The amyloid hypothesis has been central to Alzheimer’s research for the last decades. It postulates that Alzheimer’s disease derives from the accumulation of the amyloid-beta peptide (A-beta), leading to the deposition of neurofibrillary tangles, made up from the microtubule-associated protein tau.
But Alzheimer’s disease is also characterized by an inflammatory response, primarily driven by the brain’s microglia. Microglia cells are the macrophages of the central nervous system, being the first checkpoint of immune defense in the brain and spinal cord. As this inflammatory response increases with disease progression, it has been mostly regarded as a consequence of the pathophysiological events driving Alzheimer’s progression.
But this view may be shifting. In the last years, emerging data from experimental and clinical studies have hinted to the possibility that neuroinflammation may not be a simple consequence of Alzheimer’s progression, but an actual cause contributing to its pathogenesis.
The identification of links between Alzheimer’s disease and mutations in genes associated with innate immune responses was a key step in this shift. A myriad of immune system molecules has been linked to Alzheimer’s disease, with many of them having been identified in brain tissue from Alzheimer’s patients. The amyloid cascade hypothesis placed these changes as a consequence of A-beta deposition, but it is now becoming apparent that these inflammatory reactions may be associated with the early symptoms preceding Alzheimer’s disease.
But stating that Alzheimer’s is a neuroinflammatory disease is like stepping into quicksand. Although neuroinflammation is, by definition, inflammation of the nervous tissue, this term is usually associated with chronic inflammation rather than with an acute response. Also, there is probably no disorder of the central nervous system (or any other system) in which the immune system is not somehow involved, even if minimally.
Neuroinflammatory diseases, such as multiple sclerosis (MS), are traditionally distinguished from neurodegenerative diseases based on the role of inflammation and on the kind of inflammatory response.
The classic view is that the glial cells’ responses in neurodegenerative diseases is part of the mechanisms of disease progression, whereas immune activation in traditional neuroinflammatory diseases is part of the mechanisms of disease onset. Neuroinflammatory diseases entail tissue invasion of blood-borne cells of the adaptive immune system, namely T and B lymphocytes; on the other hand, inflammation in neurodegenerative diseases such as Alzheimer’s is driven chiefly by innate immune cells residing in the central nervous system, namely microglia.
Microglia cells survey the brain for the presence of pathogens or other menaces and maintain the central nervous system’s stability. In the context of Alzheimer’s disease, microglia cells can sense the presence of protein aggregates and respond to them. It is hypothesized that a contribution to the development of Alzheimer’s disease may come from a loss of microglia’s ability to respond to A-beta aggregation, hence allowing its aggregation and deposition to proceed. This view is supported by genetic studies in patients with Alzheimer’s disease describing mutations in innate immune molecules that can compromise microglia’s responsiveness.
Besides genetic evidence, there are other signs that point to an involvement of the immune system early in the disease’s process. These include, for example, several immunological mediators found in the cerebrospinal fluid of Alzheimer’s patients early on, or epidemiologic evidence indicating that prolonged treatment with nonsteroidal anti-inflammatory drugs reduces the risk of developing Alzheimer’s.
Some experimental studies have even gone so far as to actually propose that an immune challenge may be sufficient to cause Alzheimer’s, at least in certain contexts. Neuroinflammatory responses induced locally as a consequence of traumatic brain injury, for example, or systemic inflammation arising from chronic conditions from outside the central nervous system, such as obesity or type 2 diabetes, may act as a trigger for neurodegenerative conditions. A recent study has even linked oral infections to the development of Alzheimer’s disease.
Furthermore, studies in the aging brain have shown extensive upregulation of genes associated with an innate immune system response. It is possible that in neurodegenerative diseases such as Alzheimer’s, this upregulation process becomes exacerbated, contributing to the disease’s onset.
Although this is still largely hypothetical, the fact is that there is increasing evidence suggesting that Alzheimer’s disease may include a relevant contribution of immunological mechanisms. And this evidence cannot be neglected.
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