|
Novel Therapy in the Treatment of Alzheimer’s Disease
By Lindsey Ghiringhelli, Pharm.D., BCGP, FMPA
Alzheimer’s disease is one of the top 10 causes of death in the United States. In 2020, approximately 5.8 million adults 65 and older had Alzheimer’s disease. This is expected to nearly triple by 2060, to 14 million.
Alzheimer’s is the fifth-leading cause of death in our older adult population. Commonly referred to as “The Long Goodbye,” this disease takes a hefty toll on our patients and their caregivers. While there still remains no cure, new therapies are emerging.
Current Strategies
According to the Centers for Disease Control and Prevention (CDC), there is growing evidence that people who adopt healthy lifestyle habits, such as routine exercise and well-controlled blood pressure, can lower their risk of dementia. These same behaviors are shown to have added benefits, including preventing cancer, diabetes and heart disease in addition to potential risk reduction for cognitive decline.
For mild, moderate, and severe disease, acetylcholinesterase inhibitors (donepezil, galantamine, and rivastigmine) can be used. Medications in this drug class increase the amount of acetylcholine available for synaptic transmission in the cortex and basal forebrain to slow the development of cognitive deficits. Potential side effects include dizziness, nausea, vomiting, diarrhea, anorexia, weight loss, bradycardia, AV block and QT prolongation. These can be problematic in older adults struggling with weight loss or on other QT-prolonging drugs.
Memantine, an NMDA receptor antagonist, can be considered for moderate to severe dementia as monotherapy or adjunct therapy. Memantine blocks glutamate receptors from overstimulation, leading to excitotoxicity and neuronal cell death, which is believed to be a significant contributor to Alzheimer’s disease. Clinical trials show some benefit for functional decline as monotherapy or dual therapy with donepezil, but perhaps no benefit for disruptive behaviors. CNS side effects, which include dizziness, confusion, headache, hallucinations, agitation and delusions, may be related to memantine’s low affinity for the phencyclidine (PCP) site of the NMDA receptor.
Memantine has a long elimination half-life of 60 to 80 hours, so the more costly extended-release products are generally not necessary. Memantine also needs to be renally dosed, which is an important consideration in older adults.
Monoclonal Antibodies for Alzheimer’s Disease
Since the discovery of amyloid beta plaque in the brains of Alzheimer’s disease patients, scientists have been working to develop therapies to target it. What remains unclear is if this is an effective surrogate endpoint. Aducanumab, and now lecanemab, are intravenous monoclonal antibodies for treatment of mild Alzheimer’s disease. Aducanumab is administered intravenously every four weeks. Lecanemab is dosed every 2 weeks. Both were approved through the U.S. Food and Drug Administration’s (FDA) accelerated pathway, but confidence in their clinical effectiveness is lacking to justify their high cost.
Lecanemab showed modest slowing of cognitive decline, which was better than aducanumab, but data proving meaningful outcomes remains to be seen. These medications are not for use in patients without amyloid beta plaque or for more severe disease. There is a considerable amount of diagnostic testing required for these medications to assess the plaque, including a PET or lumbar puncture to confirm presence of amyloid beta pathology prior to initiation and multiple brain MRIs, within one year prior to initiation and regularly throughout therapy. Additional MRIs may be needed if the patient develops amyloid-related imaging abnormalities (ARIA) which are consistent with microhemorrhages and brain swelling. This appears to be a mechanism of fluid shifts following clearance of amyloid from parenchymal plaque and movement into cerebral vessel walls.
Patients should be monitored closely for clinical and MRI changes suggestive of ARIA, including headache, altered mental status, visual changes, dizziness, nausea, gait difficulty and focal neurologic deficits. Anticoagulants and other medications which increase bleed risk should be avoided. Other side effects, including infusion reactions and flu-like symptoms, were a common reason for discontinuation in clinical trials. There are more medications in the pipeline as researchers work to improve upon these initial medications, offering hope to patients and caregivers struggling with Alzheimer’s disease.
References:
-
Alzheimer’s Disease and Related Dementias. Centers for Disease Control; https://www.cdc.gov/aging/aginginfo/alzheimers.htm. 2020 Oct 26; Accessed May 22, 2023.
-
Lexicomp Online, Lexi-Drugs Online. Waltham, MA: UpToDate, Inc.; May 18, 2023. https://online.lexi.com. Accessed May 29, 2023.
- Van Dyck C, Swanson C, Aisen P, et al. Lecanemab in Early Alzheimer’s Disease. N Engl J Med 2023; 388:9-21.
- Shi M, Chu F, Zhu F, Zhu J. Impact of Anti-amyloid-β Monoclonal Antibodies on the Pathology and Clinical Profile of Alzheimer's Disease: A Focus on Aducanumab and Lecanemab. Front Aging Neurosci. 2022 Apr 12;14:870517.
| 
