Alzheimer’s Treatments
Disease Modification versus Symptom Treatment
To be considered disease modifying for Alzheimer’s, a treatment must alter the amount or progression of one or more of the Alzheimer’s pathologies – amyloid beta accumulation, neurofibrillary tau tangles, and neurodegeneration.
Other treatments prescribed to Alzheimer’s patients may ameliorate disease symptoms like agitation and memory for some period of time but cannot ultimately stop disease worsening. Since these symptoms are not unique to Alzheimer’s disease, patients with cognitive and dementia symptoms caused by other diseases or conditions may also be prescribed these drugs.
The only disease modifying drugs approved in the United States and multiple other countries are anti-amyloid monoclonal immunotherapies. All drugs in this class work the same way: they tag aggregated beta amyloid proteins in the brain for high-priority removal by brain-resident immune cells called microglia. In two-year phase 3 clinical trials, the approved drugs in this class (donanemab aka Kisunla® and lecanemab aka Leqembi®) achieved high levels of beta amyloid removal and approximately 25-30% slowing of cognitive decline in people who had beta amyloid accumulation in their brains but only minimal cognitive symptoms. Trial data suggested that the benefits were highest for participants who were younger; had less tau pathology; and/or who had lower levels of cognitive symptoms at the start of the trial. Real-world evidence has been consistent with the efficacy and safety findings of the Phase 3 trials.
Who can benefit
To benefit from these drugs, a patient must have beta amyloid accumulation in their brain. Ongoing trials are assessing whether these drugs can benefit people who are at high risk of Alzheimer’s but who do not yet have symptoms; as of now, these drugs are only approved for use in people who have some degree of cognitive symptoms.
ARIA risk
All current versions of these drugs have a risk of side effects of brain bleeds and swelling (ARIA). Mild versions of these side effects are relatively common but are typically subclinical, meaning there are no symptoms and they are transient. In rare instances, however, they are catastrophic, so monitoring for them using regularly scheduled brain MRIs is a key part of the treatment protocol. Since APOE4 gene variant carriers are at higher risk, some clinical systems restrict access to people who carry zero or one copy of APOE4. Other potential exclusionary issues include too many preexisting white matter hyperintensities, use of blood thinners, and/or a history of cerebrovascular disease or stroke. Although ARIA is currently poorly understood, companies are working to develop new versions of these drugs with lower risk of ARIA.
Cost and burden of treatment
Anti-amyloid antibody immunotherapy manufacturing and all the associated medical oversight, dose administration, and monitoring for efficacy and safety involved in treatment are cumbersome and expensive for patients, medical systems, and payors. Each patient will need to compare their personal valuation of the potential benefit with the totality of the associated risks of treatment and financial and other costs with their care team.
From Eisai and Biogen. Treatment protocol is every-other-week dosing for 18 months or longer until beta amyloid levels are subthreshold, then ongoing maintenance dosing. Dosing can be by infusion (one or two times per month depending on treatment phase) or subcutaneous injection (weekly, can be self-administered via a preloaded syringe).
From Eli Lilly. Treatment protocol is infusion monthly dosing until beta amyloid levels are subthreshold. Treatment can be repeated if amyloid reaccumulates, but early data indicate that over 80% of patients who became amyloid negative within a year of starting Kisunla were still amyloid negative three years after their last dose.
Withdrawn disease-modifying drugs over the last 10 years
Aduhelm® (aducanumab) from Biogen. Controversially approved by the FDA after mixed Phase 3 results. Withdrawn from market in 2024 after low patient uptake and successful launch of Leqembi®.
Drugs Prescribed to Alleviate Symptoms Associated with Alzheimer’s Disease
The drugs discussed in this section are FDA approved specifically for use in Alzheimer’s disease. While these drugs will not stop or slow disease progression, they may offer help with the management of cognitive and behavioral symptoms of the disease. They may not work for every patient; they may only work for a limited amount of time; and they may cause gastrointestinal or other side effects that make them hard to tolerate.
Unfortunately, very few symptom-targeting drugs have been specifically tested in and consequently officially approved for use in the Alzheimer’s population. Because symptoms like agitation and insomnia can be very challenging, patients, caregivers and clinicians may then choose to try drugs tested and approved for these symptoms in other patient populations. This section does not address these drugs. “Off-label” prescribing is common in medical practice, but since older adults react to and metabolize drugs differently than do younger adults, it’s particularly important for Alzheimer’s patients to take only drugs prescribed to them by an experienced clinician. Regular review of all drugs and supplements a patient is taking is important to ensure that they are all of continuing value, that their benefits outweigh any side effects, and that they do not interfere with one another.
Drugs Supporting Cognitive Function
As Alzheimer’s pathology accumulates and spreads in the brain, communication among neurons in affected areas becomes dysfunctional, undermining the brain’s ability to support learning, memory, and cognition. Cholinesterase inhibitors are a class of drugs designed to preserve the activity of a chemical (acetylcholine) that neurons use to communicate. Because these drugs support the function of living neurons but cannot extend the life of a neuron, as more neurons are lost due to Alzheimer’s pathology, the drugs become less helpful. However, some drugs in this class have been approved for all stages of Alzheimer’s. Cholinesterase inhibitors have been available for a long time, so they are sold in both branded and generic forms as a pill or liquid. Commonly prescribed cholinesterase inhibitors include galantamine (Razadyne®), donepezil (Aricept®) and rivastigmine (Exelon®) is one version; it can be delivered through a skin patch). Gastrointestinal and muscular side effects can be challenging for some patients.
Neurons in the brain become hyperactive as Alzheimer’s progresses, disrupting their proper function, impairing cognition, and contributing to eventual loss of neurons and circuitry. NMDA (N-methyl-D-aspartate) receptor antagonist drugs reduce this hyperactivity by blocking the action of the chemical messenger glutamate. Patients with moderate to severe Alzheimer’s disease are commonly prescribed the generic memantine or a branded version, Namenda®, as a pill or liquid. Dizziness, confusion, and agitation side effects can be challenging for some patients.
Drugs to Address Agitation and Psychosis
Although Alzheimer’s disease is commonly associated with memory decline, for many patients and caregivers agitation is the most challenging symptom for daily living. Patients may be physically vigorous and highly stressed, confused by the experience of fading cognition, and even hallucinatory and/or psychotic. Effectively managing agitation is important for patient and caregiver safety and quality of life.
Brexpiprazole (Rexulti®) is an antipsychotic pill approved specifically for agitation associated with Alzheimer’s dementia. It modulates neurotransmitter activity by acting at several different receptors, but the specifics of its mechanism of action are poorly understood. The FDA label warns that antipsychotic medicines like brexpiprazole increase risk of death for older adults with dementia-related psychosis symptoms like delusions and hallucinations.
Auvelity® combines two drugs, dextromethorphan and bupropion, into an extended-release tablet to treat agitation associated with Alzheimer’s dementia. Dextromethorphan targets receptors in the brain, and bupropion maintains dextromethorphan availability. Auvelity is not an antipsychotic and does not confer the increased risk of death associated with that drug class.
Drugs to Address Sleep Issues
Cognitive behavioral therapy and good sleep hygiene can be highly effective at treating insomnia in the general population but may not be viable for Alzheimer’s patients. Data show that improved sleep improves cognitive function and health outcomes in older adults with and without Alzheimer’s pathology.
Belsomra® (suvorexant) from Merck is FDA-approved specifically to help patients with mild-to-moderate Alzheimer’s disease sleep longer and wake up less often. An ongoing clinical trial is investigating whether long-term use will slow brain amyloid accumulation (NCT04629547) but its existing approval relied on sleep improvements rather than disease modification. Taken as a pill, it works by blocking the action of orexin, a neurotransmitter that promotes wakefulness.
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