NSAIDS FOR AD PREVENTION? NAPROXEN ENTERS THE CNS WITHOUT APPARENT EFFECT ON CSF IMMUNE MARKERS

Epidemiological studies from the 1990’s and early 2000’s indicated an inverse association between non-steroidal inflammatory drug (NSAID) use and incidence of Alzheimer's disease (AD).[1] Subsequent clinical trials failed to confirm the benefits of NSAIDs and instead suggested harm.[2-4] The purported benefits of NSAIDs had been attributed to their anti-inflammatory activity, presumed to reduce AD-associated immune activation. However, there has never been any demonstration of NSAIDs’ ability to enter the human brain and affect immune mechanisms. Therefore, we conducted longitudinal investigations of cerebrospinal fluid (CSF) concentrations of the NSAID naproxen as well as several immune markers in INTREPAD, a randomized placebo-controlled trial of naproxen for prevention of AD biomarker progression among healthy elderly at increased risk for AD. Some 160 older adults with a parental or multiple-sibling family history of AD completed the two-year INTREPAD protocol. Of these 124 completed the trial on its prescribed dosage of naproxen 220 mg b.i.d. or placebo. Among these 78 had two or more lumbar punctures, permitting multiplex assay of cerebrospinal fluid (CSF) for 12 immune proteins and apolipoprotein E (apoE). Most of the CSF samples and concurrently collected plasma were also assayed for naproxen concentration using liquid chromatography with repeated mass spectroscopy. Naproxen was detected in plasma and CSF of naproxen-treated individuals only. However, CSF naproxen concentrations were ∼100 times lower than plasma concentrations (protein-bound fractions unknown). When present, CSF naproxen was associated with negligible change in CSF immune markers, but appeared to increase CSF apolipoprotein-E in proportion to drug concentration. Oral naproxen enters the CNS but induces negligible change in CSF immune markers. The disappointing efficacy results of AD prevention trials using naproxen and related drugs may therefore reflect limited blood-brain barrier transfer, or lack of the drugs’ effect on CNS immune processes. However, CSF apoE concentrations increased substantially over a two-year observation interval. This latter phenomenon appeared to be augmented in proportion to CSF concentration of naproxen. Overall, these findings suggest reconsideration of mechanistic assumptions regarding purported benefits of NSAIDs against AD risk. References: [1]int'Veld et al. N Engl J Med.2001;345:1515-21. [2]Aisen, et al. JAMA.2003;289:2819-26. [3]Thal, et al. Neuropsychopharmacology.2005;30:1204-15. [4]AdaptResearchGroup, et al. Neurology.2007;68:1800-8.