Extended results of the Alzheimer's disease anti‐inflammatory prevention trial

Abstract

Background Epidemiologic evidence suggests that non-steroidal anti-inflammatory drugs (NSAIDs) delay onset of Alzheimer’s dementia (AD), but randomized trials show no benefit from NSAIDs in symptomatic AD. ADAPT randomized 2,528 elderly persons to naproxen or celecoxib vs. placebo for two years (s.d. 11 months) before treatments were terminated. During the treatment interval, 32 cases of AD revealed increased rates in both NSAID-assigned groups. Methods We continued the double-masked ADAPT protocol for two additional years to investigate incidence of AD (primary outcome). We then collected cerebrospinal fluid (CSF) from 117 volunteer participants to assess their ratio of CSF tau to Aβ1–42. Results Including 40 new events observed during follow-up of 2,071 randomized individuals (92% of participants at treatment cessation), there were now 72 AD cases. Overall NSAID-related harm was no longer evident, but secondary analyses showed that increased risk remained notable in the first 2.5 years of observations, especially in 54 persons enrolled with Cognitive Impairment – No Dementia (CIND). These same analyses showed later reduction in AD incidence among asymptomatic enrollees given naproxen. CSF biomarker assays suggested that the latter result reflected reduced Alzheimer-type neurodegeneration. Conclusions These data suggest a revision of the original ADAPT hypothesis that NSAIDs reduce AD risk, thus: NSAIDs have an adverse effect in later stages of AD pathogenesis, while asymptomatic individuals treated with conventional NSAIDs like naproxen experience reduced AD incidence, but only after 2 – 3 years. Thus, treatment effects differ at various stages of disease. This hypothesis is consistent with data from both trials and epidemiological studies.

What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research

“…The results of a recent Alzheimer's Disease Antiinflammatory Prevention Trial (ADAPT) which randomized 2,528 elderly persons to naproxen or celecoxib versus placebo for 2 years + 2-year extension period, suggest a revision of the original ADAPT hypothesis that NSAIDs reduce AD risk (Breitner et al 2011). In line with these results, NSAIDs have an adverse effect in later stages of AD pathogenesis, whereas asymptomatic individuals treated with conventional NSAIDs such as naproxen experience reduced AD incidence, but only after 2 to 3 years.…”

Dementia

“…[47] • Non-steroidal anti-inflammatory drugs (NSAIDs). Conventional NSAIDs such as ibuprofen and voltaren [48] as well as naproxen used for as little as 2 -3 years [49] may protect against AD.…”

Combination of Aβ clearance and neurotrophic factors as a potential treatment for Alzheimer’s disease

“…Besides, since inflammation may participate in the neurodegenerative process of AD, the use of non-steroidal anti-inflammatory medications such as naproxen may reduce AD incidence in vulnerable subjects [88] . Oxidative stress is also reported to play a role in the process of AD, as strongly proposed by Smith and Perry [89,90] , and antioxidants may be associated with a lower risk of AD [91] .…”

“…Barthel et al, using positron emission tomography (PET) images of florbetaben (an 18 F-labeled Aβ-targeted PET tracer), demonstrated that nine of ten mildmoderate probable AD participants (DSM-IV and NINCDS-ADRDA criteria) were Aβ-positive, compared to only one of ten healthy controls [49] . Furthermore, in a global phase 2, open-label, non-randomized, multi-center study recruiting a total of 81 men and women with probable mild-to-moderate AD and 69 cognitively unimpaired healthy volunteers aged 55 years and older, florbetaben scans indicated a sensitivity of 80% (95% CI 71-89) and a specificity of 91% (84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98) for discriminating participants with AD from healthy controls [50] .…”

“…The role of GSK-3 in the development of AD-like cognitive decline was supported by Liu et al [86] who found that inhibition of phosphoinositol-3 kinase and protein kinase C results in overactivation of GSK-3, leading to tau hyperphosphorylation and eventually impaired spatial memory. Lithium, a GSK-3 inhibitor, has been shown to reduce the amount of altered tau protein in animal studies and improve cognitive and biological outcomes in participants with amnestic mild cognitive impairment in a phase 2 clinical study [87] .Besides, since inflammation may participate in the neurodegenerative process of AD, the use of non-steroidal anti-inflammatory medications such as naproxen may reduce AD incidence in vulnerable subjects [88] . Oxidative stress is also reported to play a role in the process of AD, as strongly proposed by Smith and Perry [89,90] , and antioxidants may be associated with a lower risk of AD [91] .…”