23 April 2018
In their recent publication, McGeer and colleagues  recommend a simple diagnostic test at age 55 to identify people who, as they elsewhere describe, are “fated to develop Alzheimer’s” , further suggesting that they could benefit from a daily dose of a generic anti-inflammatory drug for prevention. However, their paper presents no real data (positive and negative predictive values) on how the test would perform if used clinically. We argue that the evidence provided for their diagnostic test in their recent  and previous  articles is insufficient to support their recommendations on widespread diagnosis and prevention.
The idea that anti-inflammatory treatment may slow or prevent Alzheimer’s disease has been around for a long time, and despite promising observational study data, no randomized clinical trial data has borne out the promise . NSAIDs, especially with long term use, have significant side effects, including increased cardiovascular risk  (which itself a risk factor for Alzheimer’s disease ), liver and kidney damage, and gastrointestinal bleeding . It is important to conclude accurately based on the results, as inappropriate conclusions can often lead to confusion and misrepresentation of science. As NSAIDs are available over-the-counter and no diagnostic tests are readily available to the public, this warrants due caution in reporting findings.
It appears as though the objective of this publication is to recommend widespread use of the diagnostic saliva test developed, and patented , by their company. Yet, they provide no information on the validity, sensitivity, or specificity of the test in their publications or patent filings describing the test [1,3,8]. In a previous publication, the authors describe their saliva test as “diagnostic,” saying:
“the high salivary Aβ42 levels confirm that the risk in these cases is definite rather than possible. Overall, the data demonstrate that AD can be diagnosed as well as predicted on the basis of salivary Aβ42 levels. Values in the range of 20 pg/ml indicate no risk, while values over 40 pg/ml indicate AD or pre-AD” 
This assertion was made on the basis of a study sampling saliva concentrations of Aβ42 from 10 cases and 27 controls . Most of the controls members were markedly younger than the cases, and there was no follow-up to see whether they ended up developing AD . As such, it is highly presumptive to claim that there is “no risk” in those showing low salivary levels of Aβ42, and “definite risk” in those with high levels. Especially since the cases presented in McGeer’s 2018 study found 6 controls with high levels of Aβ42, but that did not present with AD . Again, the authors provide no mention of follow-up for confirmation of whether or not the subjects developed AD. Moreover, the authors claim that normal controls “at risk for AD secrete [saliva Aβ42] levels comparable to AD cases” , but they fail to provide any explanation as to how they concluded these patients were at high risk. Of further importance is that 13 of the 25 non-AD controls were below 55 years old (the typical age of onset) and without following these controls to determine whether they develop Alzheimer’s, the assertion that they “are not at risk for AD”  is highly speculative. Both of these studies [1,3] have considerable limitations: the directionality thwarts any certainty as to whether biomarkers definitively precede clinical presentation; the small sample size limits quality of evidence; and, no other information was provided on the patients, how they were recruited, or how AD cases were diagnosed.
A crucial question in Alzheimer’s research is whether the focus should be on preventing pathological changes in the brain, or preventing cognitive impairment . Clinical significance, argues Solomon et al., should be the priority, considering the uncertainties in the literature on the association between biomarkers and clinical presentation . The relationship is poorly understood, but Solomon et al. argue that, based on clinicopathological studies, not all those exhibiting pathological brain changes will develop overt cognitive impairment .
With the potential risks of long-term daily NSAID use, and the psychological suffering associated with such a diagnosis, any diagnostic test for widespread use must have clearly defined predictive values. Similarly, treatments would need to have careful weighting of evidence of associated benefits and harms. Until this information can be provided by higher quality prospective studies, these recommendations—for widespread application of this test and subsequent preventive therapy with over-the-counter drugs—are exceedingly premature, and potentially dangerous.
Lance G. Shaver, MPH(c)1*, Susan Molchan, MD, MA2, Ahmed Khawer, MPH(c)1
1Division of Community Health and Humanities, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
2Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
*Correspondence to: Lance G. Shaver, MPH, Candidate and Graduate Research Assistant in the Division of Community Health and Humanities, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL A1B 3V6, Canada. Tel: +1 250 589 9035; E-mail: email@example.com
 McGeer PL, Guo JP, Lee M, Kennedy K, Mcgeer EG (2018) Alzheimer’s disease can be spared by nonsteroidal anti-inflammatory drugs. J Alzheimers Dis 62, 1219–1222.
 IOS Press (2018) Neuroscientists say daily ibuprofen can prevent Alzheimer’s disease. ScienceDaily, http://www.sciencedaily.com/releases/2018/03/180326140239.htm, Posted 26 March 2018, Accessed 30 March 2018.
 Lee M, Guo J-P, Kennedy K, McGeer EG, McGeer PL (2017) A method for diagnosing Alzheimer’s disease based on salivary amyloid-β protein 42 levels. J Alzheimers Dis 55, 1175-1182.
 Wang J, Tan L, Wang H, Tan C, Meng X, Wang C, Tang S, Yu J (2015) Anti-inflammatory drugs and risk of Alzheimer’s disease: an updated systematic review and meta-analysis. J Alzheimers Dis 44, 385–396.
 Varga Z, Sabzwari S, Vargova V (2017) Cardiovascular risk of nonsteroidal anti-inflammatory drugs: an under-recognized public health issue. Cureus 9, e1144.
 Solomon A, Mangialasche F, Richard E, Andrieu S, Bennett DA, Breteler M, Fratiglioni L, Hooshmand B, Khachaturian AS, Schneider LS, Skoog I, Kivipelto M (2014) Advances in the prevention of Alzheimer’s disease and dementia. J Intern Med 275, 229–250.
 Moore N, Pollack C, Butkerait P (2015) Adverse drug reactions and drug-drug interactions with over-the-counter NSAIDs. Ther Clin Risk Manag 11, 1061–1075.
 Aurin Biotech Inc, McGeer PL, Moonhee L, Guo J-P, Kennedy K, McGeer EG (2018) Salivary Abeta42 levels as prognostic indicators for Alzheimer’s disease. Patent No. WO2018018138.