Alzheimer's Disease Treatment on the Horizon or False Dawn?

William H. Hung, MD, MPH

Disclosures

July 14, 2021

Dementia is a devastating age-related illness that causes significant morbidity, functional decline, and mortality. Alzheimer's disease (AD), characterized by the accumulation of beta-amyloid plaques and neurofibrillary tangles in the brain, is the most common cause of dementia. In this research update, I discuss three recently published articles that have important implications for the treatment and prevention of dementia, including AD.

William H. Hung, MD, MPH

On June 7, 2021, the US Food and Drug Administration (FDA) approved aducanumab, an amyloid monoclonal antibody that targets and reduces beta-amyloid deposits in the brain, for treatment of AD. This decision has triggered substantial controversy, as the drug was approved through the FDA's Accelerated Pathway, and the decision to approve was contrary to the advice of the FDA advisory committee that reviewed the clinical trial data for efficacy. The first article I discuss is a viewpoint whose authors include a member of the advisory committee that reviewed the clinical trial data submitted by the pharmaceutical company. After summarizing their concerns regarding the evidence for aducanumab, the authors conclude that, although there is evidence that the drug clears beta-amyloid protein deposits, data showing clinical efficacy are lacking. The second article presents the results of a phase 2 randomized trial of donanemab, another medication that targets beta-amyloid protein in the pathogenesis of AD. The trial results suggest a modest clinical benefit in cognitive decline and ability to perform activities of daily living. A phase 3 trial will follow these promising results. The third article explores the association between when diabetes mellitus is diagnosed and the subsequent risk of developing dementia, highlighting a potential modifiable factor that may reduce the risk for dementia in late life.

Mixed Evidence for Benefit of Aducanumab in Early Alzheimer's

Medications previously approved for AD have targeted symptoms of the disease, delivering modest improvements in cognition and function, but no treatments can yet modify the disease's clinical progression. Efforts to develop disease-modifying drugs have focused on hallmark pathologic features such as the build-up and reduced clearance of beta-amyloid protein in the brain, which leads to neuronal death and, eventually, cognitive impairment. Aducanumab is a monoclonal antibody against beta-amyloid protein that may modulate the immune system to remove the beta-amyloid plaques. On the basis of early imaging-based clinical trials that demonstrated reduced beta-amyloid plaques with aducanumab treatment, two large phase 3 clinical trials (ENGAGE [NCT02477800] and EMERGE [NCT02484547]) were conducted to examine its effect on clinical outcomes, including cognition and function. The studies were stopped early because interim review of trial data (futility analysis) indicated that the drug was unlikely to produce clinical benefit if the trials were carried to fruition. However, examination of follow-up data collected after the trials were stopped suggested that one of the clinical trials, EMERGE, did demonstrate clinical benefit. A possible explanation for the divergent outcomes between the two trials, suggested by the trials' sponsor, was that more patients in the EMERGE trial received the high-dose regimen of aducanumab, leading to a difference in high-dose aducanumab exposure. However, the lack of clinical effectiveness in the trials as originally designed, coupled with the disparate results in the post-hoc analysis in the high-dose group across the two trials, leaves considerable doubt that the treatment is effective clinically.

The safety and cost of aducanumab must also be considered, given the limited evidence of the drug's clinical effectiveness. Amyloid-related imaging abnormalities (ARIA) have been reported in patients treated with the drug, with a higher incidence among those who received higher doses. Some individuals who experienced ARIA had neurologic symptoms, including confusion and visual disturbance, among other adverse effects. Aducanumab has a wholesale yearly cost of $56,000, as well as costs for administration and imaging to confirm the presence of beta-amyloid plaques and assess response, making this a very costly treatment, particularly for a medication that has limited clinical benefit but high risk for harm. Clinicians considering aducanumab for their patients with early AD should discuss these issues and the potential risks and benefits based on available data.

Efficacy of Donanemab for Early Alzheimer's in Phase 2 Trial

Donanemab, another promising drug that targets beta-amyloid protein, was investigated in a multicenter randomized clinical trial that enrolled 257 patients with early AD. Inclusion criteria were: age 60-85 years; early symptomatic AD where mild cognitive impairment is apparent or mild dementia that meets criteria for AD diagnosis; and a Mini-Mental State Examination score of 20 to 28. Patients underwent florbetapir MRI and PET scans to detect pathogenic tau deposition in the brain at a level consistent with early AD. Those with positive results were then randomly assigned 1:1 to intervention or placebo, with infusions of donanemab every 4 weeks for up to 72 weeks and repeat imaging studies at 24 and 52 weeks, with dose adjustment based on repeat imaging findings. Safety assessments were also conducted by investigators, who were blinded to treatment assignment. The primary outcome was change from baseline in Alzheimer's Disease Rating Scale (iADRS) score at 76 weeks (the iADRS is a validated measure of cognition and functional impairment among those with AD in which a lower score reflects greater cognitive and functional impairment). Secondary outcomes included changes in scores on the Clinical Dementia scale and other clinical measures of cognition. The mean age of the participants was 75 years, more than half (52%) were female, and most (93%) were White. The iADRS score decreased less in the donanemab group compared with the placebo group (–6.86 vs –10.06, P = .04). There were no consistent differences in secondary outcomes between the groups.

Although a more definitive phase 3 trial is needed to confirm these findings and examine other outcomes, this study is a promising step toward improving treatment options for older adults with AD. Nonetheless, the burden of treatment for AD remains substantial, as patients must undergo imaging tests that are not routinely available, both for eligibility and follow-up, as well as repeated infusions and monitoring. Future advances in testing, such as blood tests that could replace imaging tests, and a different route of drug administration, such as injection or oral medication, could alleviate these burdens.

Timing of Onset of Type 2 Diabetes and Dementia in Late Life

Potentially modifiable factors associated with risk for dementia have been explored in observational studies. The latest such study has identified age at onset of type 2 diabetes as a risk factor for dementia. This prospective observational study (Whitehall II) involved a population-based cohort from the UK that was established in 1985 and followed by clinical examination in multiple years and linkage to electronic records up to 2019, with a median follow-up time of 31.7 years. The cohort includes 10,308 participants who were aged 35-55 years in 1985-1988; more than two thirds (67.3%) were men. In the follow-up period, 639 participants developed dementia, ascertained through linkage to national databases with diagnosis codes, and 16.9% of all participants developed type 2 diabetes and were categorized by the age of onset of diabetes. Rates of dementia at age 70 years were examined in each group. Dementia rates were 8.9 per 1000 person-years among those without diabetes, 10.0 per 1000 person-years among those with diabetes onset up to 5 years earlier, 13.0 per 1000 person-years among those with diabetes onset of 6-10 years earlier, and 18.3 per 1000 person-years among those with onset 10 years earlier. After adjustment for sociodemographic factors, health behaviors, and other health-related measures, participants with diabetes onset more than 10 years earlier were 2.12 times more likely to develop dementia at age 70, as compared to those without diabetes (hazard ratio, 2.12; 95% CI, 1.50-3.00). For each 5-year interval of age of onset of type 2 diabetes, participants were 1.24 times more likely to develop dementia by age 70 (hazard ratio, 1.24; 95% CI, 1.06-1.46).

These data indicate a strong association between age of onset of diabetes and subsequent risk for dementia. Because diabetes is associated with modifiable factors such as weight and health behaviors such as exercise and diet, delaying and averting the onset of type 2 diabetes may represent an opportunity to reduce the risk for dementia.

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