LAUSR

Alzheimer’s disease (AD) is chronic progressive dementia in older people. Due to the aging of the global population and a lack of effective medication, AD is becoming a prioritized public health problem. Deposition of amyloid β (Aβ) to form senile plaques in the brain represents the histopathologic hallmark of older adults with AD. Hence the amyloid hypothesis of AD pathogenesis has dominated anti-amyloid drug research and development for more than 30 years. We report the existing clinical evidence from major clinical trials of agents targeting Aβ in older persons at risk of AD. We searched PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov up to May 15, 2018, for all published research reporting on the efficacy and adverse events of amyloid-centric agents tested in AD patients. Changes in cognition were assessed using the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog), with higher scores indicating greater cognitive impairment; Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCSADL), with lower scores indicating worse functioning; Clinical Dementia Rating Sum of Boxes (CDR-SB); and the MiniMental State Examination (MMSE). Studies reported adverse events as an accessible odds ratio (OR), and 95% confidence intervals (95% CIs) were calculated. Quality and risk of bias of studies was critically assessed using domain-based evaluation; studies with a low methodological validity were excluded. All trials included for analysis were placebo controlled, with at least 2 weeks of intervention and observation. In total, 16 randomized controlled trials (5 phase I, 6 phase II, and 5 phase III) testing nine drug candidates in 11 423 subjects were included in the final collaborative analysis. The therapeutic approaches were mainly active and passive immunotherapeutic agents, as well as secretase inhibitors or modulators that sought to reduce the production of Aβ. Prodromal to mild to moderate AD patients were enrolled. All trials reported adequate consequence generation and methods for allocation concealment, and no risk of bias was found. As shown in Table 1, differences in cognitive function echoed by the estimated mean changes in ADAS-cog (−.16; 95% CI = −.56 to .24; P = .44), ADCS-ADL (.32; 95% CI = −.28 to .91; P = .30), and CDR-SB (.01; 95% CI = −.10 to .11; P = .91) scores were not significant between the two groups. MMSE score was slightly higher in patients receiving treatment as compared with placebo (difference in means = .30; 95% CI = .11-.49; P = .002), implying possibly improved cognitive functioning. The treatment group showed a higher risk of adverse events (OR = 1.20; 95% CI = 1.13-1.28; P < .0001), serious adverse events (OR = 1.14; 95% CI = 1.04-1.24; P = .005), and death (OR = 1.38; 95% CI = 1.02-1.88; P = .04). Amyloid-related imaging abnormalities (ARIAs) occurred much more frequently in the treatment group (OR = 2.72; 95% CI = 2.12-3.50), principally attributed to vasogenic edema or effusion (OR = 4.51; 95% CI = 2.19-9.26) rather than hemorrhage (OR = 0.86; 95% CI = .63-1.18). Alarmingly, the risk of ARIAs was extremely high in patients with reduced brain amyloid burden (OR = 20.21; 95% CI = 11.51-35.49; P < .0001), in contrast to those without amyloid plaque clearance (OR = .91; 95% CI = .66-1.24). We further explored the association between decreased level of amyloid burden and ARIAs based on the pooled data. An almost 2-fold increase in the risk of ARIAs was reported in patients with significantly reduced amyloid burden compared with those with no or lower amyloid changes (OR = 1.74; 95% CI = 1.28-2.37). Even more alarmingly, ARIAs often colocalized at sites with the highest level of amyloid reduction. So far, all the amyloid-centric drug candidates tested in major clinical trials have not shown efficacy in cognitive function while increasing the frequency of adverse events. Aloysius Alzheimer initially described the clinical relationship between amyloid deposits in the brain and symptoms of impaired cognitive functions of what is now known as AD more than 100 years ago. In 1984, the major component known as Aβ peptide in brain amyloid plaque was From the Department of Immunology, Guangxi Area of Excellence, Guilin Medical University, Guilin, China.