Donanemab Significantly Slows Progression of Alzheimer’s Disease, Study Finds

The drug donanemab significantly slowed the clinical progression of Alzheimer’s disease among patients with mild cognitive impairment or mild dementia, according to a study published yesterday in JAMA.

Donanemab is an antibody designed to target and remove beta-amyloid proteins that have clumped together to form plaques in the brain. It is manufactured by Eli Lilly and Company, which stated in a news release that it has submitted the drug for U.S. Food and Drug Administration (FDA) approval and expects regulatory action by the end of this year. Eli Lilly funded the study.

John Sims, M.D., of Eli Lilly and colleagues conducted a phase 3 randomized clinical trial including participants aged 60 to 85 years with early symptomatic Alzheimer’s disease who had amyloid and tau pathology (abnormal tau proteins and amyloid plaque are considered markers of Alzheimer’s). Participants were randomized to receive either donanemab (700 mg for the first three doses and 1,400 mg thereafter) or placebo, administered intravenously every four weeks for up to 72 weeks.

The study participants received MRIs at 4, 12, 24, 52, and 76 weeks to monitor amyloid plaque abnormalities, with additional MRIs scheduled at investigators’ discretion. (Amyloid-related imaging abnormalities—which can result in headache, confusion, as well as more severe symptoms—are associated with investigational interventions targeting amyloid proteins.)

Participants’ cognition and daily functioning were assessed using the integrated Alzheimer’s Disease Rating Scale (iADRS). They were also assessed using the Clinical Dementia Rating Scale, the Alzheimer’s Disease Assessment Scale, and the Alzheimer’s Disease Cooperative Study-Instrumental Activities of Daily Living scale.

Among 1,736 participants, 68.1% had low/medium tau pathology and 31.8% had high tau pathology (higher tau deposits in the brain are associated with greater memory and/or attention problems). When comparing iADRS measures between baseline and 76 weeks, Alzheimer’s disease progressed 22.3% more slowly in all participants receiving donanemab compared with the placebo group. In those with low/medium tau levels, the disease progressed 35.1% more slowly in participants receiving donanemab compared with the placebo group. Similarly, donanemab significantly slowed disease progression according to the three other scales the authors used in the study. At 76 weeks, disease progression with donanemab in the participants with low/medium tau was delayed by 4.36 months on the iADRS and 7.53 months on the Clinical Dementia Rating Scale.

The incidence of death was 1.9% in the donanemab group and 1.1% in the placebo group. Three participants with serious amyloid-related imaging abnormalities in the donanemab group died. Either amyloid-related imaging abnormalities or microhemorrhages occurred in 36.8% of participants receiving donanemab and 14.9% of those receiving the placebo.

“If approved by the FDA for the treatment of mild cognitive impairment and mild dementia due to Alzheimer’s disease, this will be the third disease-modifying medication available for the treatment of this devastating illness,” Rajesh Tampi, M.D., M.S., past president of the American Association for Geriatric Psychiatry, told Psychiatric News. “However, widespread use of this medication may remain elusive, due to the need for facilities that can conduct infusions and the monitoring of [amyloid-related imaging abnormalities] using MRI scans.”

Tampi also pointed out that equitable access to donanemab may be an issue. A high cost would make this drug unavailable for many patients with Alzheimer’s unless the Centers for Medicare and Medicaid Services and other payers covered the cost.

Other experts echoed Tampi’s points. The study found the greatest benefit in people with mild symptoms of Alzheimer’s, but minoritized groups are typically diagnosed at later stages, Jennifer Manly, Ph.D., of Columbia University Irving Medical Center and Kacie Deters, Ph.D., of the University of California, Los Angeles wrote in an accompanying commentary.

“Clinicians and the public will need to weigh the potential benefit of treatment (delay of progression of about 4 months on average) with the financial and quality-of-life costs of infusions, MRI monitoring, and risk of amyloid-related imaging abnormalities and brain volume loss,” Manly and Deters wrote.

For related information, see the Psychiatric News article “Aduhelm for Alzheimer’s: Questions Remain About Cost, Clinical Effectiveness.”

(Image: iStock/Jolygon)

---

Help Shape the Future of Psychiatric News

APA is seeking applicants for the position of medical editor-in-chief of Psychiatric News. This is a compensated, influential position that offers a prime opportunity to impact psychiatric knowledge and skills. Applications are due tomorrow: Wednesday, July 19.

LEARN MORE

FDA Approves Second Monoclonal Antibody Medication for Alzheimer’s

The Food and Drug Administration (FDA) on Friday approved lecanemab for the treatment of Alzheimer’s disease. Lecanemab (brand name Leqembi) is the second monoclonal antibody approved for Alzheimer’s that targets a biological component of the disease. The approval of the other monoclonal antibody called aducanumab (Aduhelm) in 2021 was met with some controversy. Both medications attach to amyloid proteins in the brain and prevent the formation of amyloid plaques, which are associated with Alzheimer’s.

Lecanemab was approved under the FDA’s accelerated approval pathway, which expedites the approval of medications for life-threatening illnesses by allowing companies to use surrogate endpoints (in this case amyloid buildup) rather than wait potentially years before clinical benefits become evident. According to the drug label, lecanemab should be initiated in individuals with mild cognitive impairment or mild dementia.

“Alzheimer’s disease immeasurably incapacitates the lives of those who suffer from it and has devastating effects on their loved ones,” said Billy Dunn, M.D., director of the FDA Office of Neuroscience in a news release by the FDA. “This treatment option is the latest therapy to target and affect the underlying disease process of Alzheimer’s, instead of only treating the symptoms of the disease.”

Lecanemab’s efficacy was demonstrated in a phase 3 clinical trial of 1,795 participants whose results were recently published in the New England Journal of Medicine. Adults aged 50 to 90 with mild cognitive impairment or mild dementia and amyloid buildup (confirmed via a PET scan or cerebrospinal fluid testing) were randomly assigned to receive lecanemab (10 mg/kg) or placebo infusions every two weeks for 18 months.

After 18 months, the adults who received lecanemab showed significant reductions in amyloid buildup relative to those who received placebo, as well as slightly slower declines in cognitive performance. For example, average Clinical Dementia Rating–Sum of Boxes (CDR-SB) scores rose by 1.21 points in the lecanemab group compared with 1.66 points in the placebo group.

The participants who received lecanemab experienced a higher rate of adverse events compared with those who received placebo. Infusion-related side effects such as nausea or vomiting occurred in 26.4% of lecanemab participants compared with 7.4% of placebo participants. Additionally, amyloid-related imaging abnormalities (known as ARIAs)—which may indicate swelling or bleeding in the brain—occurred in 21.5% of lecanemab participants compared with 9.5% of placebo participants.

Kostas Lyketsos, M.D., the Elizabeth Plank Althouse Professor for Alzheimer’s Research at Johns Hopkins Medicine, said that the approval of lecanemab is a positive development, but far from a breakthrough given the modest cognitive benefits, side effects associated with the medication, and high cost ($26,500 for a year). However, he noted that the approval may lead Eisai and Biogen (developers of lecanemab) to design trials exploring whether the medication might prevent or slow cognitive impairment in adults with amyloid buildup but no other symptoms.

Additional coverage of the drug’s approval will appear in Psychiatric News.

---

What Happens When the Public Health Emergency Ends?

Since March 2020, psychiatrists have been practicing under flexibilities granted by state and federal governments. These flexibilities were intended to ensure access to care during the Public Health Emergency (PHE). APA members are invited to participate in a webinar on Wednesday, January 11, at 1 p.m. ET that will describe the changes that will take place once the PHE ends and how psychiatrists can continue to practice in a way that meets their patients’ needs.

REGISTER

Circadian Dysfunction Precedes Cognitive Changes in Patients With Preclinical Alzheimer’s Disease

People with Alzheimer’s disease (AD) tend to experience significantly fragmented sleep patterns that suggest underlying problems with their circadian clocks. A study published today in JAMA Neurology suggests that these changes in sleep patterns begin long before people show cognitive symptoms of AD.

“Our findings suggest that circadian dysfunction could contribute to the earliest stages of AD pathogenesis, and that understanding this association could open the door to new diagnostic and therapeutic strategies,” wrote lead author Erik Musiek, M.D., Ph.D., of Washington University School of Medicine and colleagues.

Musiek and colleagues assessed 189 cognitively normal older adults who were participating in longitudinal studies of memory and aging at the Washington University Knight Alzheimer’s Disease Research Center. The participants were all given wrist activity monitors, which measured a range of sleep parameters for 7 to 14 days. The participants also underwent amyloid beta imaging and had cerebrospinal fluid (CSF) analyzed to determine if they had preclinical AD (Previous studies have shown that amyloid plaque pathology in the brain precedes symptomatic cognitive impairment by 15 to 20 years). Of the 189 participants in the study, 139 were amyloid negative.

The authors found that several measures of sleep disturbances were associated with positive amyloid status, even after factoring in sleep problems associated with older age.

“Among the several circadian endpoints examined, we found that the nonparametric IV [intradaily variability] index was most consistently sensitive to both aging and AD pathology,” Musiek and colleagues wrote. “Intradaily variability was designed to detect fragmentation of rest-activity rhythm, suggestive of more periods of daytime rest (or sleep) and increased nighttime activity (or wake).” The authors also noted that interdaily stability, which measures how consistent circadian rhythms are on a day-to-day basis, increased with older age, but only in amyloid-positive participants.

To read more about this topic, see the Psychiatric News article “Study to Examine Amyloid PET Scans as Diagnostic Tool for Alzheimer’s.”

(Image: iStock/monkeybusinessimages)

---

Have You Voted in APA’s 2018 Election Yet?

Time is running out for you to vote in the APA 2018 Election. Learn about the voting process and meet the candidates for President-elect, Treasurer, Trustee-at-Large, and more. Click here to vote now.

Follow Psychiatric News on Twitter!

Breakthrough in Cultured Neural Cells With Alzheimer's Could Speed Drug Testing

Neural cells with the genes for Alzheimer’s disease (AD) were successfully grown in culture, developing the amyloid-β plaques and neurofibrillary tangles believed to be characteristic of the disease.

Researchers at the Genetics and Aging Research Unit at the Massachusetts General Institute for Neurodegenerative Disease and several other institutions have successfully grown “Alzheimer’s in a petri dish,” as the breakthrough was called in a New York Times article. The work was published in a report in the journal Nature. “We have successfully recapitulated amyloid-β and tau pathology in a single 3D human neural cell culture system,” the researchers stated.

Alzheimer’s experts say the breakthrough could dramatically speed the testing of drugs for treating AD. “This is a ground breaking study that will enable researchers to investigate the process of progression of Alzheimer’s disease and, more importantly, test large numbers of possible treatments in a relatively short order,” past APA President Dilip Jeste, M.D., (pictured above) told Psychiatric News. “Clinical trials take a long time to complete, and animal models such as those using mice or rats have uncertain applicability to the human disease. I believe these investigators’ work will open the door to study many other brain diseases too.” Jeste is a distinguished professor of psychiatry and neurosciences and the director of the Sam and Rose Stein Institute for Research on Aging at the University of California, San Diego.

“One note of caution is that we do not know to what extent plaques and tangles in a petri dish replicate the complex living brain of a person with Alzheimer’s disease,” Jeste added. “Nonetheless, this work opens a new and exciting line of research into neurodegenerative and other brain diseases.”

For more on AD research, see the Psychiatric News article, “High BDNF Levels May Offer Protection Against Alzheimer’s.” Also see the book Clinical Manual of Alzheimer Disease and Other Dementias from American Psychiatric Publishing.

APOE-e4 Carriers May Be Able to Reduce Alzheimer's Risk

Individuals who have one or more copies of APOE-e4, the well-documented Alzheimer risk gene variant, may be able to lessen their risk for getting Alzheimer's, a study headed by Karen Rodrigue, Ph.D., an assistant professor of behavior and brain sciences at the University of Texas at Dallas, and published in JAMA Neurology suggests. And the way they may be able to do so is by controlling high blood pressure.

The study included 118 cognitively normal adults aged 47 to 89, who were screened for APOE-e4, high blood pressure, and amyloid plaque deposits in the brain—a hallmark of Alzheimer's. The researchers found that subjects who had one or more copies of APOE-e4 and high blood pressure had more amyloid deposits than did those who had one or more copies of APOE-e4 and no high blood pressure. However, individuals who had APOE-e4 and were taking medication for high blood pressure showed significantly fewer amyloid deposits than did subjects with APOE-e4 and unmedicated high blood pressure.

Rodrigue and her colleagues will be following these subjects to see how the groups compared in terms of development of Alzheimer's, she told Psychiatric News. However, "Keep in mind that our study was focused on a normal aging population, so it may be several years out before any of them show clinically significant decline," she said.

See a report on research on the APOE-e4 variant in Psychiatric News. More information about Alzheimer's can be found in American Psychiatric Publishing's Clinical Manual of Alzheimer Disease and Other Dementias.

(Image: Lightspring/Shutterstock.com)

Reducing Cerebrovascular Disease May Prevent Cognitive Decline

Which factor is a greater contributor to cognitive decline in seniors? Vascular brain injury or amyloid plaques? Vascular brain injury, a study headed by Natalie Marchant, Ph.D., of the University of California, Berkeley, and published in JAMA Neurology suggests. Marchant and colleagues used brain imaging on a sample of 61 older individuals, average age 78, who were cognitively normal, had mild cognitive impairment, or were mildly demented. They wanted to explore the relationship between vascular injury or amyloid plaque deposition and cognitive decline. They found that vascular injury was more influential in accounting for cognitive decline than amyloid plaques were.

"Although mild cognitive impairment is clearly a significant risk factor for Alzheimer's disease, the present data suggest that the impact of vascular brain injury should be  considered when defining the etiology of mild cognitive impairment," the researchers concluded. And more crucially, "Reductions in cerebrovascular disease may be important in preventing mild cognitive impairment," they asserted.

But previous research has shown that vascular injury and amyloid-plaque buildup aren't the only factors linked with cognitive decline. Data show that smoking may contribute to cognitive decline as well. To read research on that link, see Psychiatric News here. And as researchers learn more about the elements of cognitive decline, they have also discovered an association with hearing loss. Read about that research in Psychiatric News here.

(Image: Fabio Berti/Shutterstock.com)

Exercise Can Boost Memory and Restore Nerve Synapses

Old rats are generally not so good at recognizing places, and this deficiency in turn appears to be due to a loss in nerve synapses in the hippocampus. But 12 weeks of voluntary running was found to restore both recognition-memory and hippocampus nerve synapses in them. So reported Michael Valenzuela, Ph.D., of the University of Sydney in Australia, and his coworkers July 16 in Biological Psychiatry.

Exercise appears to benefit the brains of humans as well, another study has shown. It was conducted on cognitively normal subjects aged 45 to 88. In that study, individuals who exercised at or above levels recommended by the American Heart Association had lower levels of amyloid plaques—the hallmark of Alzheimer's disease—in their brains than did individuals who exercised less. The exercise benefit also extended to individuals who carried the APOE-e4 variant, which is a well-documented risk factor for Alzheimer's.

To learn more about the relationship between exercise and Alzheimer's plaques, see Psychiatric News.

(Image: Zhabska Tetyana/Shutterstock.com)