An estimated 7.2 million Americans age 65 and older are living with Alzheimer’s disease (AD), which is the most common cause of dementia.¹ With the baby boomer population aging, this number is expected to grow to approximately 13 million by 2050, because the risk of AD increases with advancing age; however, AD is not a natural part of aging.¹ Notwithstanding the exponential rise in the number of individuals living with AD in the United States, these estimates are even higher when considering Americans of all ages with dementia, not just those 65 or older, and other causes of dementia, not just AD. These data strongly suggest that healthcare providers must understand the underlying pathophysiology of AD and the ongoing medical needs of individuals living with all types of dementia.²

Unfortunately, there is no proven way to prevent Alzheimer’s disease and related dementias (ADRD), and there is currently no cure for the disease.¹ Thus, medications are critical for the management of ADRD to enhance quality of life and function throughout the disease course. Several medications are available to help manage symptoms, and two are specifically designed to alter the underlying biology of AD and slow disease progression (Table 1). This article provides an overview of the past, present, and future medications for ADRD, with an emphasis on managing AD.

Table 1. FDA-Approved Medications for Alzheimer’s Disease¹

*Approved for the treatment of insomnia, but safe and effective in individuals living with AD.

The Past

Medications for Cognitive Dysfunctions

For decades, the standard of medication management for AD has been treatment with cholinesterase inhibitors (ChEIs), like donepezil, and N-methyl-D-aspartate (NMDA) receptor antagonists, like memantine. These medications may temporarily mitigate or stabilize some symptoms of dementia, particularly those in the cognition and function domains, but they do not slow, stop, or reverse the underlying brain changes that cause AD, nor do they alter disease progression.^1,3,4 Instead, they help compensate for the brain changes of AD by affecting certain chemicals, known as neurotransmitters, such as acetylcholine and glutamate, that brain cells use to communicate with each other.^1,3 Because AD is relentlessly progressive, leading to damage and eventual death of neurotransmitter-producing neurons, ChEIs and NMDA receptor antagonists lose their ability to help the brain compensate for the changes, which eventually renders the medications ineffective. The effectiveness of ChEIs, for instance, appears to wane after one year of treatment, although some benefits may persist for up to five years.^4,5 The compensatory mechanism of ChEIs may be further compromised with the concomitant use of anticholinergic medications, which directly oppose the action of ChEIs and reduce their effectiveness.^6,7 In addition to their limited duration of effectiveness, these dementia-specific medications have side effects, such as gastrointestinal issues (e.g., appetite loss, nausea, vomiting, diarrhea) and neurological symptoms (e.g., headache, dizziness, fatigue, insomnia) with ChEIs, that must be considered, especially in the context of the complexity of AD care.^3,4

Medications for Non-Cognitive Symptoms

Dementia affects more than just cognition and function. The quality of life of an individual living with ADRD and their family members may be impacted by a variety of behavioral and psychological symptoms of dementia (BPSD), such as agitation, delusions, hallucinations, and sleep disturbances.^2,3 While the chief cause of BPSD is the progressive deterioration of brain cells, some medications (e.g., anticholinergics, sedatives, stimulants), certain interactions among medications, and medication nonadherence can cause or trigger symptoms or make them worse.^2,3 Although trigger modifications and non-medication treatments are the preferred first-line management strategies for BPSD, there are times when medication management is warranted.^1-3,8,9

Many medications have been used “off-label” to treat BPSD with variable effectiveness and safety profiles.^2,3

For example, antipsychotics are often used to manage BPSD. While frequently effective, antipsychotics are associated with serious risks including, but not limited to, clinically meaningful drug interactions,¹⁰ clinically significant adverse effects such as extrapyramidal symptoms, metabolic abnormalities, and QT interval prolongations,¹¹ and substantially amplified hazards of stroke and death.^11,12 Based on an abundance of risks, experts and guidelines recommend limiting the use of antipsychotics to situations where non-medication treatments have failed and/or where symptoms are severe, are dangerous, and/or cause significant distress to the individual with dementia.^3,8,9,13 Additionally, it is recommended that non-medication treatments be used continually, that the need for sustained use of antipsychotics is reviewed regularly, that efforts be made to reduce antipsychotic dosages periodically, and that attempts be made to deprescribe and, ultimately, discontinue antipsychotic use when possible or necessary.^2,8,13

The Present 

New Medications for Non-Cognitive Symptoms

Within the last five years, the FDA has approved one medication to treat agitation associated with AD and one medication to treat insomnia that has shown effectiveness in individuals living with mild-to-moderate AD (Table 1).³ Brexpiprazole is the only antipsychotic that is FDA-approved for the treatment of agitation associated with dementia due to AD.^3,9 Like other antipsychotics, brexpiprazole is thought to lessen agitation through its effects on dopamine and serotonin receptors in the brain.^1,14 Despite its recent FDA approval, brexpiprazole has a similar side effect profile to other atypical antipsychotics, and it carries the same “black box” safety warning for increased mortality risk in older adults with dementia-related psychosis as other medications in the class.¹⁴

Suvorexant is an orexin receptor antagonist that inhibits the activity of orexin, a type of neurotransmitter involved in the sleep-wake cycle.^1,3 Approved for the treatment of insomnia in the general population, suvorexant has been shown in studies to effectively manage problems with falling asleep and staying asleep that can occur in individuals with mild-to-moderate dementia due to AD.^1,3,15 Possible side effects of this medication include, but are not limited to, impairing alertness and motor coordination, worsening of depression or suicidal thinking, developing complex sleep behaviors (e.g., sleep-walking, sleep-driving), experiencing sleep paralysis, and compromising respiratory function.^1,3,15 Notwithstanding FDA approval of brexpiprazole and suvorexant, these medications, like those from the past, only help manage symptoms of dementia.

Disease-Altering Medications

Despite the guideline-directed medication management strategies described above, AD progresses over time. Most recently, the FDA has approved the monoclonal antibodies donanemab and lecanemab that work in AD by targeting and removing beta-amyloid, a protein that accumulates into plaques, from the brain.^3,16,17 These novel, anti-amyloid medications have been shown to slow the progression of the disease and to reduce the decline of cognition and function in a meaningful way for some individuals in the early stages of AD, ultimately, giving them more time to participate in daily life and live independently.^3,16-18 While anti-amyloid medications have the potential to revolutionize the management of AD, healthcare professionals and individuals living with the disease must consider the benefits and risks of these medications before deciding to initiate treatment (Table 2).

Table 2. Considerations for Anti-amyloid Medications^1,16-20 

^{Abbreviations: AD = Alzheimer’s disease; ApoE ε4 = apolipoprotein E ε4; ARIA = amyloid-related imaging abnormalities; CSF = cerebrospinal fluid; IV = intravenous; MCI = mild cognitive impairment; MRI = magnetic resonance imaging; PET = positron emission tomography.}

^*Lecanemab is administered every two weeks over approximately one hour, and donanemab is administered every four weeks over approximately 30 minutes.^{1,16,17,19,20} After 18 months of treatment with lecanemab, some patients may be transitioned to a maintenance dosage administered via subcutaneous injection once a week.^17,20

Donanemab and lecanemab are FDA-approved for use in individuals diagnosed with AD, and their safety and effectiveness have only been established in those with early-stage disease, specifically mild cognitive impairment (MCI) or mild dementia due to AD (i.e., stages 3 and 4).^1,18-20 To be eligible for treatment with one of these anti-amyloid medications, an AD diagnosis must be confirmed with tests showing elevated levels of beta-amyloid in the brain.^1,16-18 Establishing this diagnosis with confirmation testing can be a lengthy process, often involving multiple steps and various healthcare professionals.¹⁸

The most concerning side effect of anti-amyloid medications is amyloid-related imaging abnormalities (ARIA), characterized as ARIA with edema (ARIA-E) and ARIA with hemosiderin deposition (ARIA-H).^19,20 Although ARIA is usually asymptomatic, causing a temporary swelling in areas of the brain that usually resolves over time, serious and life-threatening events (e.g., intracerebral hemorrhages, neurologic deficits, seizures) can occur.^1,19,20 The FDA encourages healthcare professionals to test individuals for apolipoprotein E ε4 (ApoE ε4) status before initiating treatment with this class of medications because homozygote carriers of the ApoE ε4 gene have a higher risk of developing ARIA compared to heterozygotes and non-carriers.^1,19,20 Additionally, to ensure ARIA is identified should it occur during treatment, experts recommend that healthcare professionals obtain a baseline brain MRI scan and repeated scans before select subsequent infusions.¹

The Future

Dementia-Related Research

There is exciting progress being made in dementia-related research that is creating promising new medications for people living with the disease. For example, although the safety and effectiveness of anti-amyloid medications beyond the length of their pivotal studies is not yet fully recognized, this is expected to change, as registries and systems, such as the Alzheimer’s Network for Treatment and Diagnostics (ALZ-NET), have been established to track the health outcomes of patients treated with these medications.¹ Researchers will use the data these registries and systems produce to answer remaining questions about the safety and effectiveness of anti-amyloid medications, including the impact of their use over longer follow-up periods.¹ Healthcare professionals should encourage patients to participate in real-world data collection (e.g., registries) to help further the understanding of AD and the impact of anti-amyloid treatments on the disease.^19,20 In fact, ALZ-NET is approved by the Centers for Medicare & Medicaid Services (CMS) as a Coverage with Evidence Development (CED) study and can be used as a pathway to Medicare coverage for anti-amyloid medications that have received traditional FDA approval, like donanemab and lecanemab.³

Beyond anti-amyloid medications, an assortment of other medications targeting the underlying biological changes of ADRD are being developed and studied.¹ They address many of the known brain changes associated with ADRD, including altered cellular metabolism, inflammation, and tau accumulation.^1,21 Ultimately, the path to safe and effective medication management for dementia is through studies. Other than funding, recruiting and retaining study participants is now the greatest obstacle to developing the next generation of medications.³ The Alzheimer’s Association provides a free, easy-to-use studies matching service for individuals living with ADRD, caregivers, and healthy volunteers. Healthcare providers should help individuals navigate this service and explain study eligibility criteria, benefits, and risks to bolster participation in dementia-related research.

Dementia-Related Biomarkers

Lastly, the identification and validation of biomarkers for AD have changed the landscape of dementia-related research.¹ For example, biomarkers have facilitated the discovery that AD begins 20 years or more before the onset of symptoms, enabling earlier detection of the brain changes of AD and giving those affected the opportunity to address modifiable risk factors that may slow or delay cognitive decline.¹ Biomarkers have also made it possible to identify individuals who may qualify for studies of new or experimental medications targeting these biomarkers to prevent or delay the onset of symptoms, as occurred with donanemab and lecanemab.¹ In addition, advancements in biomarker research offer the potential to expand our understanding of which medications or combination of medications may be most effective at which points in the ADRD continuum.¹ While much remains to be understood about biomarkers and how they can best be used for diagnosis and treatment, biomarkers will be of paramount importance in helping the nation prepare for the inevitable dementia surge.