Alzheimer's Disease Anti-inflammatory Prevention Research Articles

Precision Medicine for Preventing Alzheimer's Disease: Analysis of the ADAPT Study.

The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) was the first-ever large-scale anti-inflammatory prevention trial targeting Alzheimer's disease. The overall goal of this study was to evaluate predictive blood biomarker profiles that identified individuals most likely to be responders on NSAID treatment or placebo at 12 and 24 months. Baseline (n = 193) and 12-month (n = 562) plasma samples were assayed. The predictive biomarker profile was generated using SVM analyses with response on treatment (yes/no) as the outcome variable. Baseline (AUC = 0.99) and 12-month (AUC = 0.99) predictive biomarker profiles were highly accurate in predicting response on Celecoxib arm at 12 and 24 months. The baseline (AUC = 0.95) and 12-month (AUC = 0.9) predictive biomarker profile predicting response on Naproxen were also highly accurate at 12 and 24 months. The baseline (AUC = 0.93) and 12-month (AUC = 0.99) predictive biomarker profile was also highly accurate in predicting response on placebo. As with our prior work, the profiles varied by treatment arm. The current results provide additional support for a precision medicine model for treating and preventing Alzheimer's disease.

The transitioning from trials to extended follow-up studies.

Investigators may elect to extend follow-up of participants enrolled in a randomized clinical trial after the trial comes to its planned end. The additional follow-up may be initiated to learn about longer term effects of treatments, including adverse events, costs related to treatment, or for reasons unrelated to treatment such as to observe the natural course of the disease using the established cohort from the trial. We examine transitioning from trials to extended follow-up studies when the goal of additional follow-up is to observe longer term treatment effects. We conducted a literature search in selected journals from 2000 to 2012 to identify trials that extended follow-up for the purpose of studying longer term treatment effects and extracted information on the operational and logistical issues in the transition. We also draw experience from three trials coordinated by the Johns Hopkins Coordinating Centers that made transitions to extended follow-up: the Alzheimer's Disease Anti-inflammatory Prevention Trial, Multicenter Uveitis Steroid Treatment trial, and Childhood Asthma Management Program. Transitions are not uncommon in multicenter clinical trials, even in trials that continued to the planned end of the trial. Transitioning usually necessitates new participant consents. If study infrastructure is not maintained during the transition, participants will be lost and re-establishing the staff and facilities will be costly. Merging data from the trial and follow-up study can be complicated by changes in data collection measures and schedules. Our discussion and recommendations are limited to issues that we have experienced in transitions from trials to follow-up studies. We discuss issues such as maintaining funding, institutional review board and consent requirements, contacting participants, and combining data from the trial and follow-up phases. We conclude with a list of recommendations to facilitate transitions from a trial to an extended follow-up study.

Follow-up evaluation of cognitive function in the randomized Alzheimer's Disease Anti-inflammatory Prevention Trial and its Follow-up Study

ObjectiveThe Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) and Follow-up Study (ADAPT-FS) examined effects of naproxen and celecoxib on cognition in the elderly. We report here results describing trajectories of cognitive evaluation test scores. MethodsA total of 2356 participants completed baseline and at least one follow-up cognitive evaluation between 2001 and 2004. Study treatments were discontinued in 2004, but participants were followed until 2007. A total of 1537 participants were reevaluated in 2010 to 2011. Outcomes include seven cognitive evaluations administered yearly in person in ADAPT and three of these evaluations that were administered by telephone near the end of ADAPT and again in ADAPT-FS. ResultsThere were no important differences over time by treatment group on any ADAPT cognitive measure, a global composite, or the three cognitive measures reassessed in ADAPT-FS by telephone. ConclusionsTreatment for 1 to 3 years with naproxen or celecoxib did not protect against cognitive decline in older adults with a family history of AD.

THREE CARDINAL LESSONS FROM ADAPT – 10 YEARS ON

The Alzheimer's Disease Anti-inflammatory Prevention Trial was a placebo-controlled three-arm pharmaco-prevention trial of the non-steroidal anti-inflammatory drugs naproxen sodium and celecoxib for prevention of incident Alzheimer's disease (AD) dementia in older (aged 70 and over) adults. Although subjects were at increased risk of symptoms because of a firstdegree family history, they were meant to be cognitively healthy at enrollment. ADAPT encountered several problems that resulted in the termination of its treatments after only two years on average. Interim results were complex but potentially interesting. In the end, however, the results were null. We describe the complications that prevented ADAPT from achieving conclusive results, and suggest that these could have been avoided if the trial design and execution had been better guided by preliminary data. We believe such data should be available before beginning further ambitious phase III trials of this sort, and we suggest a broad method by which such data can be accumulated with reasonable economy.

Simulating effects of biomarker enrichment on Alzheimer's disease prevention trials: Conceptual framework and example

BackgroundWe present a conceptual framework for simulations to determine the utility of biomarker enrichment to increase statistical power to detect a treatment effect in future Alzheimer's disease prevention trials. We include a limited set of simulation results to illustrate aspects of this framework. MethodsWe simulated data based on the Alzheimer's Disease Anti-Inflammatory Prevention Trial, and a range of sample sizes, biomarker positive predictive values, and treatment effects. We also investigated the consequences of assuming homogeneity of parameter estimates as a function of dementia outcome. ResultsUse of biomarkers to increase the sample fraction that would develop Alzheimer's disease in the absence of intervention from 0.5 to 0.8 would increase power from 0.35 to 0.69 with n = 200. Ignoring sample heterogeneity resulted in overestimation of power. ConclusionBiomarker enrichment can increase statistical power, but estimates of the expected increase are sensitive to a variety of assumptions outlined in the framework.

Screening by Telephone in the Alzheimer's Disease Anti-inflammatory Prevention Trial

Compared with in-person assessment methods, telephone screening for dementia and other cognitive syndromes may improve efficiency of large population studies or prevention trials. We used data from the Alzheimer's Disease Anti-Inflammatory Prevention Trial to compare performance of a four-test Telephone Assessment Battery (TAB) that included the Telephone Interview for Cognitive Status (TICS) to that of a traditional in-person Cognitive Assessment Battery. Among 1,548 elderly participants with valid telephone and in-person screening results obtained within 90 days of each other, 225 persons were referred for a full cognitive diagnostic evaluation that was completed within six months of screening. Drawing on results from this panel of 225 individuals, we used the Capture-Recapture method to estimate population numbers of cognitively impaired participants. The latter estimates enabled us to compare the performance characteristics of the two screening batteries at specified cut-offs for detection of dementia and milder forms of impairment. Although our results provide relatively imprecise estimates of the performance characteristics of the two batteries, a comparison of their relative performance suggests that, at selected cut-off points, the TAB produces results broadly comparable to in-person screening and may be slightly more sensitive in detecting mild impairment. TAB performance characteristics also appeared slightly better than those of the TICS alone. Given its benefits in time and cost when screening for cognitive disorders, telephone screening should be considered for large samples.

Results of a follow-up study to the randomized Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT)

ObjectivesThe Alzheimer's Disease Anti-inflammatory Prevention Trial Follow-up Study (ADAPT-FS) was designed to evaluate the efficacy of naproxen and celecoxib for the primary prevention of Alzheimer's disease (AD) several years after cessation of treatment in ADAPT. MethodsADAPT was a randomized, double-masked, multicenter clinical trial of naproxen or celecoxib vs placebo (1:1:1.5 assignment ratio) at six U.S.-based clinics. The trial enrolled 2528 people between 2001 and 2004. Treatments were discontinued in December 2004 and participants were monitored regularly until 2007. In 2010 and 2011, ADAPT-FS screened 1537 participants by telephone and, if indicated, examined them in person using standardized clinical assessments. The primary outcome was time to diagnosis of AD. Death index searches were performed for participants not located. ResultsEighty-nine additional AD events were identified (24 celecoxib, 25 naproxen, and 40 placebo) yielding a total of 161 events (48 [6.6% of randomized participants] celecoxib, 43 [6.0%] naproxen, and 70 [6.5%] placebo) across ADAPT and ADAPT-FS. Adjusted hazard ratios (HRs) comparing each treatment with placebo showed no overall reduction in risk of AD: HR celecoxib vs placebo, 1.03 (95% confidence interval [CI], 0.72–1.50; P = .86); HR naproxen vs placebo, 0.92 (95% CI, 0.62–1.35; P = .66). There were 349 deaths (110 [15.2%] celecoxib, 96 [13.4%] naproxen, and 143 [13.2%] placebo). Risk of death was similar for the naproxen- and placebo-assigned groups (HR, 0.99; 95% CI, 0.76–1.28; P = .93) and slightly higher for celecoxib compared with the placebo-assigned group (HR, 1.15; 95% CI, 0.90–1.48; P = .27). ConclusionsThese results acquired during a follow-up of approximately 7 years (which included a median of less than 1.5 years of treatment) do not support the hypothesis that celecoxib or naproxen prevent AD in adults with a family history of dementia.

Celecoxib or Naproxen Treatment Does Not Benefit Depressive Symptoms in Persons Age 70 and Older: Findings From a Randomized Controlled Trial

Several lines of evidence suggest that inflammatory mechanisms may be involved in the severity and progression of depression. One pathway implicated is the production of prostaglandins via the enzyme cyclooxygenase (COX). Although late-life depression in particular has been associated with inflammation, we know of no published studies using COX inhibitors, such as nonsteroidal anti-inflammatory drugs (NSAIDs), in the treatment of depressive syndromes in this population. To evaluate the effect of the NSAIDs celecoxib and naproxen on depressive symptoms in older adults. The Alzheimer's Disease Anti-inflammatory Prevention Trial was a randomized, placebo-controlled, double-masked clinical trial conducted at six U.S. memory clinics. Cognitively normal volunteers age 70 and older with a family history of Alzheimer-like dementia were randomly assigned to receive celecoxib 200 mg twice daily, naproxen sodium 220 mg twice daily, or placebo. The 30-item version of the Geriatric Depression Scale (GDS) was administered to all participants at enrollment and at yearly follow-up visits. Participants with a GDS score greater than 5 at baseline were classified as depressed. Of 2,528 participants enrolled, 2,312 returned for at least one follow-up visit. Approximately one-fifth had significant depressive symptoms at baseline. Mean GDS score, and the percentage with significant depressive symptoms, remained similar over time across all three treatment groups. Furthermore, there was no treatment effect on GDS scores over time in the subgroup of participants with significant depressive symptoms at baseline. In longitudinal analysis using generalized estimating equations (GEE) regression, higher baseline GDS scores, a prior psychiatric history, older age, time in the study, and lower cognition interacting with time, but not treatment assignment, were associated with significantly higher GDS scores over time. Treatment with celecoxib or naproxen did not improve depressive symptoms over time compared with placebo. While inflammation has been implicated in late-life depression, these results do not support the hypothesis that inhibition of the COX pathway with these NSAIDs at these doses alleviates depressive symptoms in older adults.

Trajectories of Preparation for Future Care Among First-Degree Relatives of Alzheimer's Disease Patients: An Ancillary Study of ADAPT

This study examines the longitudinal patterns of Preparation for Future Care (PFC), defined as Awareness, Avoidance, Gathering Information, Decision Making, and Concrete Plans, in first-degree relatives of people with Alzheimer's disease (AD). Eight time points across 6.5 years from a subsample of adults aged 70 years and older who were participating in the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) were analyzed using latent growth modeling. Baseline attitudes toward planning for future care and demographic variables functioned as predictors in the conditional analyses. Awareness, Gathering Information, Decision Making, and Concrete Planning increased across time, but Avoidance did not. Covariates were more often associated with the initial levels of planning behavior than with change across time. Women engaged in more initial Decision Making than men. Education was associated with more initial Gathering Information, Decision Making, and less Avoidance. Favorable attitudes toward planning were more predictive of baseline Awareness, Gathering Information, Avoidance, and less so for Decision Making or Concrete Planning. Older adults with an elevated risk for AD increase in positive PFC behaviors gradually across time. Demographic characteristics and attitudes predict initial levels of planning, making it possible to identify individuals who might need help progressing to more advanced levels of planning. Future studies are needed to understand rates of change in planning behaviors.

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

Epidemiologic evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) delay onset of Alzheimer's dementia (AD), but randomized trials show no benefit from NSAIDs in patients with symptomatic AD. The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) randomized 2,528 elderly persons to naproxen or celecoxib versus placebo for 2 years (standard deviation = 11 months) before treatments were terminated. During the treatment interval, 32 cases of AD revealed increased rates in both NSAID-assigned groups. We continued the double-masked ADAPT protocol for 2 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 Aβ(1-42.) Including 40 new events observed during follow-up of 2,071 randomized individuals (92% of participants at treatment cessation), there were 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 who were given naproxen. CSF biomarker assays suggested that the latter result reflected reduced Alzheimer-type neurodegeneration. These data suggest a revision of the original ADAPT hypothesis that NSAIDs reduce AD risk, as follows: 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. Thus, treatment effects differ at various stages of disease. This hypothesis is consistent with data from both trials and epidemiological studies.

Effects of non‐steroidal anti‐inflammatory drug treatments on cognitive decline vary by phase of pre‐clinical Alzheimer disease: findings from the randomized controlled Alzheimer's Disease Anti‐inflammatory Prevention Trial

We examined the effects of non-steroidal anti-inflammatory drugs on cognitive decline as a function of phase of pre-clinical Alzheimer disease. Given recent findings that cognitive decline accelerates as clinical diagnosis is approached, we used rate of decline as a proxy for phase of pre-clinical Alzheimer disease. We fit growth mixture models of Modified Mini-Mental State (3MS) Examination trajectories with data from 2388 participants in the Alzheimer's Disease Anti-inflammatory Prevention Trial and included class-specific effects of naproxen and celecoxib. We identified three classes: "no decline", "slow decline", and "fast decline", and examined the effects of celecoxib and naproxen on linear slope and rate of change by class. Inclusion of quadratic terms improved fit of the model (-2 log likelihood difference: 369.23; p < 0.001) but resulted in reversal of effects over time. Over 4 years, participants in the slow-decline class on placebo typically lost 6.6 3MS points, whereas those on naproxen lost 3.1 points (p-value for difference: 0.19). Participants in the fast-decline class on placebo typically lost 11.2 points, but those on celecoxib first declined and then gained points (p-value for difference from placebo: 0.04), whereas those on naproxen showed a typical decline of 24.9 points (p-value for difference from placebo: <0.0001). Our results appeared statistically robust but provided some unexpected contrasts in effects of different treatments at different times. Naproxen may attenuate cognitive decline in slow decliners while accelerating decline in fast decliners. Celecoxib appeared to have similar effects at first but then attenuated change in fast decliners.

Elevated Ratio of Urinary Metabolites of Thromboxane and Prostacyclin Is Associated with Adverse Cardiovascular Events in ADAPT

Results from prevention trials, including the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT), have fueled discussion about the cardiovascular (CV) risks associated with non-steroidal anti-inflammatory drugs (NSAIDs). We tested the hypotheses that (i) adverse CV events reported among ADAPT participants (aged 70 years and older) are associated with increased ratio of urine 11-dehydrothromboxane B2 (Tx-M) to 2′3-donor–6-keto-PGF1 (PGI-M) attributable to NSAID treatments; (ii) coincident use of aspirin (ASA) would attenuate NSAID-induced changes in Tx-M/PGI-M ratio; and (iii) use of NSAIDs and/or ASA would not alter urine or plasma concentrations of F2-isoprostanes (IsoPs), in vivo biomarkers of free radical damage. We quantified urine Tx-M and PGI-M, and urine and plasma F2-IsoPs from 315 ADAPT participants using stable isotope dilution assays with gas chromatography/mass spectrometry, and analyzed these data by randomized drug assignment and self-report compliance as well as ASA use. Adverse CV events were significantly associated with higher urine Tx-M/PGI-M ratio, which seemed to derive mainly from lowered PGI-M. Participants taking ASA alone had reduced urine Tx-M/PGI-M compared to no ASA or NSAID; however, participants taking NSAIDs plus ASA did not have reduced urine Tx-M/PGI-M ratio compared to NSAIDs alone. Neither NSAID nor ASA use altered plasma or urine F2-IsoPs. These data suggest a possible mechanism for the increased risk of CV events reported in ADAPT participants assigned to NSAIDs, and suggest that the changes in the Tx-M/PGI-M ratio was not substantively mitigated by coincident use of ASA in individuals 70 years or older.

Cardiovascular Safety of Celecoxib on Top of Dual Antiplatelet Therapy

Cardiovascular Safety of Celecoxib on Top of Dual Antiplatelet Therapy

Serum Abeta levels as predictors of conversion to mild cognitive impairment/Alzheimer disease in an ADAPT subcohort.

Recent evidence suggests an association of beta-amyloid (Abeta) with vascular risk factors and the medications to treat them, which could potentially obfuscate the usefulness of Abeta for prediction of mild cognitive impairment (MCI) or Alzheimer disease (AD). In a subcohort from the Alzheimer's Disease Anti-inflammatory Prevention Trial (enriched for family history of AD), we investigated whether systolic blood pressure, total cholesterol, triglycerides, serum creatinine, apolipoprotein E, and use of statins and antihypertensives influenced the predictive value of serum Abeta for MCI/AD during a 2-year period. We collected blood samples to quantify serum Abeta from cognitively normal participants (n = 203) at baseline and ascertained the outcome of MCI/AD (n = 24) for a period of approximately 2 years. In an unadjusted model, the lowest quartile of Abeta(1-42) (hazard ratio [HR] = 2.93, 95% CI [1.02-8.32], P = 0.04) and of the Abeta(1-42)/Abeta(1-40) ratio (HR = 3.53, 95% CI [1.24-10.07], P = 0.02), compared with the highest quartile, predicted conversion to MCI/AD, but no impact of Abeta(1-40) was observed. No relationship between nonsteroidal antiinflammatory drug interventions and Abeta on MCI/AD risk was evident. Once data were adjusted for potential confounders (age, sex, and education), vascular risk factors, and the medications listed above, the lowest quartiles of Abeta(1-42) (HR = 4.47, 95% CI [1.39-14.39], P = 0.01), and of the Abeta(1-42/)Abeta(1-40) ratio (HR 4.87, 95% CI [1.50-15.87], P = 0.01) became strong predictors of conversion to MCI/AD. In this subcohort of individuals at risk for AD, the association of Abeta with vascular risk factors and medications to treat these conditions did not interfere with Abeta's predictive value for MCI/AD.

Alzheimer's Disease Anti-Inflammatory Prevention Trial: Design, methods, and baseline results

Background The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) was designed to address whether non-steroidal anti-inflammatory drugs (NSAIDs) can prevent or delay the onset of Alzheimer's disease (AD). Methods ADAPT was a randomized, double-placebo-controlled, multicenter chemoprevention trial conducted at six U.S. dementia research clinics. At entry, participants were required to test “normal” on a battery of cognitive tests and to be age 70+ with a family history of Alzheimer-like dementia. Persons were randomly assigned to 200 mg b.i.d. celecoxib (Celebrex, Pfizer), 220 mg b.i.d. naproxen sodium (Aleve, Bayer), or placebo. The primary outcome measure was AD. Secondary outcome measures were cognitive decline and measures related to safety of the treatments when used long term. ADAPT was designed to detect a 30% reduction in AD incidence with 80% power. The estimated sample size requirement was 2,625. Results Enrollment began in March 2001 and ended in December 2004 when treatments were suspended because of concerns regarding cardiovascular safety of the treatments. Followup ranged from 1 to 46 months. The achieved enrollment was 2,528. Recruitment was achieved primarily via mailings to people aged 70+ living in the catchment areas of the six field sites.

High serum Abeta and vascular risk factors in first-degree relatives of Alzheimer's disease patients.

The main objective of this study was to determine whether elevated blood beta-amyloid (Abeta) levels among the first-degree relatives of patients with Alzheimer's Disease (AD) are associated with vascular risk factors of AD. Serum Abeta was measured in samples from 197 cognitively normal first-degree relatives of patients with AD-like dementia. Study participants were recruited as part of an ancillary study of the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT subpopulation). The ADAPT subpopulation was found to be similar in age, sex, and ethnicity to another cognitively normal cohort (n = 98). Using cross-sectional analyses, we examined the association of Abeta with blood pressure, lipid levels, apolipoprotein E genotypes, and the use of prescribed medication to treat vascular risk factors in the ADAPT subpopulation. Abeta(1-40) was positively associated with age, use of antihypertensives, and serum creatinine, and we observed a marginal negative interaction on Abeta(1-40) associated with systolic blood pressure and use of antihypertensives. Serum Abeta(1-42) was associated with statin use and a positive correlation of Abeta (1-42) with HDL was observed among statin nonusers. These findings suggest that high Abeta in the periphery among the family history-enriched cohorts may be due to enrichment of vascular risk factors and may reflect presymptomatic AD pathology. It remains to be determined whether the association of Abeta with medications used for treating vascular risk factors indicates prevention of AD. Longitudinal evaluation of blood Abeta in this cohort will provide a better understanding of the significance of this association in AD etiology.

Reduced Risk of Incident AD with Elective Statin Use in a Clinical Trial Cohort

Statins have been reported to reduce the risk and be of benefit in the treatment of Alzheimer's disease (AD). Individuals enrolling in the randomized controlled trial testing two anti-inflammatory agents for primary prevention of AD (Alzheimer's Disease Anti-inflammatory Prevention Trial; ADAPT) were allowed the elective use of statins. Our objective was to assess whether statin use is associated with reduced risk of incident AD among ADAPT participants. In primary ADAPT study , participants were assessed annually for cholesterol levels and cognitive status. If impairment in cognition was noted, a dementia evaluation was performed. Onset of mild cognitive impairment (MCI) or AD was taken as the date of this evaluation. Time-to-onset was analyzed in six-month intervals following enrollment. Without knowledge of primary treatment assignment in ADAPT, participants were grouped by their self-reported use of lipid-lowering agents (LLA). In the current ancillary ADAPT study we found that elective statin use was associated with significantly reduced risk of incident AD after adjustment for age, gender, education and Apolipoprotein E (ApoE) genotype. The findings were similar when comparing all LLA use (statin and non-statin LLA) to non-LLA use. Cholesterol levels were lower among statin users compared with non-LLA users, but the MMSE scores were equivalent. The data suggest that statin therapy may be of benefit in reducing the risk of AD.

Large Studies Provide Clues to Alzheimer's Risk, Prevention

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessLarge Studies Provide Clues to Alzheimer's Risk, PreventionJoan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:4 Jul 2008https://doi.org/10.1176/pn.43.13.0018aIn 1994 some 1,000 older Catholic priests, nuns, and brothers signed up for a mission that had nothing to do with saving souls but plenty to do with saving minds.The mission, headed by David Bennett, M.D., director of the Rush University Alzheimer's Disease Center, was called the Rush Religious Orders Study. Subjects were evaluated medically, neurologically, cognitively, and psychologically, both at the start of the study and annually thereafter. Differences between those who develop Alzheimer's and those who do not are being analyzed to identify factors that might predict subsequent susceptibility to Alzheimer's.During the past few years, the study has identified several putative Alzheimer's risk factors. One is rapidly progressing Parkinson's disease (Psychiatric News, June 20, 2003). Another is an enduring tendency to experience negative emotions (Psychiatric News, July 20, 2007). yet a third is depression.And now still more results from the study, published in the April Archives of General Psychiatry, go a step further by suggesting that depression is truly a risk factor for Alzheimer's and not the result of the disease itself.In this phase of the study, 917 subjects without Alzheimer's were evaluated annually for 13 years to determine both whether they were depressed and whether they might be developing Alzheimer's. Of the 917 subjects, 190 developed the illness during this time span. Consistent with earlier findings in this cohort, having more depressive symptoms at the start of the study was linked with an increased risk of developing Alzheimer's. However, Bennett and his coworkers did not find that the subjects who developed Alzheimer's experienced an increase in depressive symptoms during the four years or so leading up to the onset of their Alzheimer's. So depressive symptoms indeed seem to be a risk factor for Alzheimer's rather than an early sign of its pathological process, Bennett and his colleagues concluded.Yet if, as these data imply, depressive symptoms are a risk factor for Alzheimer's, how might they be contributing to the risk? Since major depression has been linked with brain atrophy, such atrophy in turn might make the brain more susceptible to Alzheimer's, Bennett and his team speculated. Understanding the means by which depression preps the brain for Alzheimer's might lead to some way of preventing Alzheimer's, they suggested.Meanwhile, two other groups of scientists have been looking into whether nonsteroidal anti-inflammatory drugs (NSAIDs) might do so.In the first study, Steven Vlad, M.D., of Boston University and coworkers evaluated prescription NSAID use by some 49,000 veterans who had developed Alzheimer's and by some 197,000 veterans who had not. The NSAID classes assessed included arylpropionic acids such as ibuprofen or naproxen, enolic acids such as piroxicam, COX-2 inhibitors such as celecoxib, nonacetylated salicylates such as salsalate, and high-dose aspirin.The researchers found that the odds of developing Alzheimer's decreased with longer NSAID use. Compared with persons not using NSAIDs, the odds of getting Alzheimer's decreased from 0.98 among those with use for one year or less to 0.76 for those using NSAIDs for more than five years. However, the researchers found that the protective effect did not seem to be identical for each NSAID. Some, such as ibuprofen, showed clear protective effects; others, such as the COX-2 inhibitors, did not, and in yet others the effect on Alzheimer's risk was unclear. The results appeared in the May 6 Neurology.In the second study, Barbara Martin, Ph.D., of Johns Hopkins University and her colleagues allocated some 2,100 subjects aged 70 years or older and with a family history of Alzheimer's to one of three treatment arms—200 mg of celecoxib twice daily, 220 mg of naproxen twice daily, or a placebo. The researchers followed the subjects for three years to see whether those getting either celecoxib or naproxen were better protected against Alzheimer's than those getting a placebo.The answer was no, the researchers found. In fact, there was weak evidence that the cognitive function of the naproxen group was inferior to that of the placebo group. Thus, neither celecoxib nor naproxen appears to shield people against Alzheimer's, Martin and her group concluded in their study report, which was posted May 12 on the Archives of Neurology Web site.All three studies were financed by the National Institutes of Health.An abstract of “Change in Depressive Symptoms During the Prodromal Phase of Alzheimer Disease” is posted at<http://archpsyc.ama-assn.org/cgi/content/abstract/65/4/439>. An abstract of “Protective Effects of NSAIDs on the Development of Alzheimer Disease” is posted at<www.neurology.org/cgi/content/abstract/70/19/1672>. An abstract of “Cognitive Function Over Time in the Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT)” is posted at<http://archneur.ama-assn.org/cgi/content/abstract/2008.65.7.nct70006v1>.▪ ISSUES NewArchived

O2-01-02: Onset of Alzheimer's dementia occurs commonly without prior cognitive impairment: Results from the Alzheimer's disease anti-inflammatory prevention trial (ADAPT)

O2-01-02: Onset of Alzheimer's dementia occurs commonly without prior cognitive impairment: Results from the Alzheimer's disease anti-inflammatory prevention trial (ADAPT)

Cardiovascular and Cerebrovascular Events in the Randomized, Controlled Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT)

Objectives:The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) was designed to evaluate the conventional NSAID naproxen sodium and the selective COX-2 inhibitor celecoxib for primary prevention of Alzheimer's dementia (AD). On 17 December 2004, after the Adenoma Prevention with Celecoxib (APC) trial reported increased cardiovascular risks with celecoxib, the ADAPT Steering Committee suspended treatment and enrollment. This paper reports on cardiovascular and cerebrovascular events in ADAPT.Design:ADAPT is a randomized, placebo-controlled, parallel chemoprevention trial with 1–46 mo of follow-up.Setting:The trial was conducted at six field sites in the United States: Baltimore, Maryland; Boston, Massachusetts; Rochester, New York; Seattle, Washington; Sun City, Arizona; and Tampa, Florida.Participants:The 2,528 participants were aged 70 y and older with a family history of AD.Interventions:Study treatments were celecoxib (200 mg b.i.d.), naproxen sodium (220 mg b.i.d.), and placebo.Outcome measures:Outcome measures were deaths, along with nonfatal myocardial infarction (MI), stroke, congestive heart failure (CHF), transient ischemic attack (TIA), and antihypertensive treatment recorded from structured interviews at scheduled intervals. Cox proportional hazards regression was used to analyze these events individually and in several composites.Results:Counts (with 3-y incidence) of participants who experienced cardiovascular or cerebrovascular death, MI, stroke, CHF, or TIA in the celecoxib-, naproxen-, and placebo-treated groups were 28/717 (5.54%), 40/713 (8.25%), and 37/1070 (5.68%), respectively. This yielded a hazard ratio (95% confidence interval [CI]) for celecoxib of 1.10 (0.67–1.79) and for naproxen of 1.63 (1.04–2.55). Antihypertensive treatment was initiated in 160/440 (47.43%), 147/427 (45.00%), and 164/644 (34.08%). This yielded hazard ratios (CIs) of 1.56 for celecoxib (1.26–1.94) and 1.40 for naproxen (1.12–1.75).Conclusions:For celecoxib, ADAPT data do not show the same level of risk as those of the APC trial. The data for naproxen, although not definitive, are suggestive of increased cardiovascular and cerebrovascular risk.