Alzheimer's disease, like most neurodegenerative conditions, has a strong inflammatory component. The importance of inflammation is one possible way to explain why Alzheimer's risk appears to have a significant lifestyle component: Alzheimer's disease is associated with excess visceral fat tissue and all of the choices made along the way of gaining and retaining that fat tissue. Fat tissue is a notable source of chronic inflammation, acting to accelerate all of the common process and conditions of aging. There are numerous other paths to inflammation, of course.

If chronic inflammation is important in Alzheimer's disease, how useful is a chronic anti-inflammatory treatment? Various groups have considered this over the years, but the one noted here appears more optimistic than most - and the data is fairly compelling. As an aside, nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen have been shown to modestly slow aging and extend life in a few laboratory species, though the exact mechanisms are up for debate. I normally point this out to dampen enthusiasm for any novel pharmaceutical shown to have similarly sized effects in short-lived species - one shouldn't expect anything more interesting than NSAIDs to result, and the data to date suggests that NSAIDs don't in fact do a great deal for human life span. Can simple, proven methods of suppressing inflammation help people who are declining into Alzheimer's disease, however? That is a separate question, and it will be interesting to see how this line of research progresses.

In 1990, we wrote a short report indicating a substantial sparing of Alzheimer's disease (AD) in patients with rheumatoid arthritis. We suggested that anti-inflammatory therapy might be the explanation. We chose rheumatoid arthritis for the study since it typically commences at an earlier age than AD, and is universally treated with anti-inflammatory agents. Our report of AD sparing in patients consuming anti-inflammatory agents was soon confirmed in 17 epidemiological studies of patients consuming nonsteroidal anti-inflammatory drugs (NSAIDs) compared with controls. There was one consistent caveat in these epidemiological studies. The NSAIDs needed to have been started at least 6 months, and preferably as long as 5 years, before the clinical diagnosis of AD. A new field of research had been opened up with these epidemiological studies. It required that some important questions be answered. Why was it necessary to commence taking NSAIDs so long before the clinical onset of AD? What was the appropriate NSAID dose? And was it necessary to take NSAIDs on a continuing basis? New techniques were required to provide answers to these questions. We emphasize here the two most important of these: positron emission tomography revealing that deposits of amyloid-β protein (Aβ) build up in the brain of AD cases; and cerebrospinal fluid (CSF) Aβ levels revealing their consequent reduction. These two techniques are complementary. Since the brain Aβ deposits accumulate over time, the effect is integral. Since CSF turns over every few hours, the effect is differential. Disease development, as revealed by biomarker studies, follows this sequence of events. It commences with Aβ deposits developing in the brain of AD cases. These deposits can be detected by positron emission tomography (PET). The depositions result in a concomitant decrease of Aβ in the CSF. Years later, less definitive biomarkers become positive. These later biomarkers reveal loss of brain tissue. When they become positive, cognitive deficits have already appeared. Together, these studies indicate that AD onset commences more than a decade before clinical signs develop. The ability to identify the onset of AD a decade or more before clinical signs appear creates a window of opportunity to intervene in the process. Moreover, it explains the epidemiological data in which NSAIDs must be commenced years before clinical detection. The missing link is a simple, non-invasive method for identifying those at risk at an age well below the typical age of AD onset. Analysis of saliva for Aβ42 may provide the missing link. We first developed a simple method for determining Aβ42 levels in tissues as well as saliva. The results showed that Aβ42 is produced in all tissues of the body, and not just in brain as many have believed. Aβ42 secretion in saliva is a reflection of its production by submandibular glands. The non-AD cases resolved into two distinct categories: those with low levels in the 19-25 pg/ml range, and those with high levels in the AD range of 41-60 pg/ml. Significantly, there were no overlapping cases. Analysis of Aβ42 levels in saliva demonstrates three remarkable facts. Firstly, controls, who are not at risk for AD, secrete levels close to 20 pg/ml, regardless of sex or age. Secondly, this production is constant, being invariant with time of day, and from day to day. Thirdly, those at risk for AD secrete levels comparable to AD cases. Widespread application of this test to detect high levels, followed by NSAID consumption, could substantially reduce the prevalence of AD.

Link: https://doi.org/10.3233/JAD-170706