Medications for Alzheimer's

First-line options

Acetylcholinesterase inhibitors

For mild to moderate Alzheimer's, an acetylcholinesterase (AChE) inhibitor is standard. All three available agents are considered comparable in efficacy.

Donepezil at 5 to 10 mg once daily is the most commonly used. Simple dosing, well-tolerated overall. A 23 mg dose is available for moderate to severe Alzheimer's and produces modest additional benefit at the cost of more GI side effects. Common side effects are nausea, diarrhea, insomnia, muscle cramps, bradycardia, and vivid dreams (dosing in the morning can help).

Rivastigmine is available as an oral capsule (1.5 to 6 mg BID) and a transdermal patch (4.6 mg/24h, 9.5 mg/24h, and 13.3 mg/24h). The patch has fewer GI side effects than the oral form and is often the preferred formulation for patients who can't tolerate oral rivastigmine. Also FDA-approved for Parkinson's disease dementia.

Galantamine at 8 to 24 mg (usually as ER once daily) has an additional nicotinic receptor allosteric modulator effect on top of AChE inhibition. Similar efficacy to donepezil in trials, similar side effect profile.

Onset of benefit is gradual over weeks to months. The effect size is modest: on cognitive testing, benefit corresponds to a 6 to 12 month delay in progression on average. On behavioral symptoms and caregiver burden, effects are also modest but sometimes clinically meaningful. Some patients respond clearly, some show no benefit.

Trials of donepezil or rivastigmine typically run 3 to 6 months before assessing response. If there's no perceived benefit and no meaningful side effects, continuation is a shared decision with family based on other functional domains.

Memantine

Memantine at 5 to 20 mg (titrated up over 4 weeks) is an NMDA receptor antagonist. FDA-approved for moderate to severe Alzheimer's. It doesn't work for mild Alzheimer's (trials in mild disease have been negative), so it's added when disease has progressed to the moderate stage.

Memantine is generally well-tolerated: dizziness, headache, and constipation are the common side effects. It's often used in combination with an AChE inhibitor in moderate to severe disease.

Combination AChE inhibitor plus memantine

For moderate to severe Alzheimer's, combining donepezil with memantine (available as a fixed-dose combination Namzaric) has evidence supporting incremental benefit over either alone. Standard of care in moderate to severe disease.

Second-line and augmentation

Anti-amyloid monoclonal antibodies

The anti-amyloid mAbs represent the first FDA-approved disease-modifying treatments for Alzheimer's. They're available for a narrow patient population: early Alzheimer's disease (MCI due to AD or mild dementia due to AD) with confirmed amyloid pathology (amyloid PET or CSF).

Lecanemab (Leqembi) was FDA-approved 2023. Given as an IV infusion every 2 weeks. Trials showed roughly 27% slowing of cognitive decline over 18 months. The risks that shape use are amyloid-related imaging abnormalities (ARIA): ARIA-E (edema) and ARIA-H (microhemorrhages). Frequency is higher in ApoE4 homozygotes (~15% symptomatic ARIA in this group). Frequent MRI surveillance is required (baseline and before infusions 5, 7, 14).

Donanemab (Kisunla) was FDA-approved 2024. Given as IV infusion every 4 weeks. Similar efficacy to lecanemab, similar ARIA risks. Treatment can be discontinued once amyloid clearance is confirmed on repeat imaging, which is a distinct feature.

Patient selection matters. Baseline MRI to rule out significant microhemorrhage or superficial siderosis. ApoE4 genotyping to inform ARIA risk discussion (some centers now decline treatment for ApoE4 homozygotes because of risk profile). Ongoing MRI surveillance per protocol.

These treatments don't reverse existing damage. They slow progression modestly in early disease. Cost is substantial and access is uneven.

Aducanumab (Aduhelm) was the first approved anti-amyloid mAb but was withdrawn from the market by Biogen in early 2024.

When to consider a different approach

Agitation and behavioral symptoms

Behavioral and psychological symptoms of dementia (BPSD) include agitation, aggression, delusions, hallucinations, sleep disturbance, and depression. Non-pharmacologic management is first-line: address unmet needs (pain, hunger, discomfort, boredom, fear), maintain routine, reduce environmental triggers, ensure adequate sleep and hydration.

When medication is needed for agitation:

Brexpiprazole at 2 to 3 mg was FDA-approved in 2023 specifically for Alzheimer's agitation. This is currently the only FDA-approved antipsychotic for dementia agitation. Trials showed reduced agitation with modest side effect burden. Boxed warning for mortality in dementia still applies.

Other antipsychotics carry the class boxed warning for increased mortality in dementia. Risperidone, olanzapine, aripiprazole, and quetiapine have been used for agitation historically, and the CATIE-AD trial showed olanzapine and risperidone reduced some behaviors but with significant side effects and no clear net benefit. If a non-brexpiprazole antipsychotic is used, doses should be low, duration should be short, and reassessment should be frequent.

Citalopram at 20 to 30 mg has evidence for agitation in dementia (CitAD trial). QT prolongation limits the dose ceiling. In older adults, the FDA-recommended maximum is 20 mg because of QT, though CitAD used 30 mg.

Trazodone at low doses (25 to 100 mg) is often used off-label for sleep and mild agitation. Reasonable evidence, generally well-tolerated in older adults, though orthostasis is a concern.

Cannabinoids (dronabinol, nabilone) have small trial evidence for agitation. Emerging use.

Sodium oxybate and other options are not used for dementia agitation.

Depression comorbid with dementia can worsen agitation. Sertraline is the preferred antidepressant in older adults with dementia because of favorable tolerability and evidence base.

Insomnia in dementia

Trazodone at 25 to 100 mg at bedtime is the practical first-line for sleep in dementia. Ramelteon has some evidence and no controlled substance concerns. Melatonin at low dose is often tried. Suvorexant has some evidence in dementia.

Z-drugs (zolpidem, eszopiclone, zaleplon) and benzodiazepines are avoided in dementia because they worsen cognition, increase fall risk, and increase delirium risk. See Beers Criteria for psychiatric medications and medications for insomnia.

Depression in dementia

Depression is common in dementia and worsens function. Sertraline is the standard first-line antidepressant in dementia because of tolerability and evidence base. Escitalopram is a reasonable alternative with QT dose caps. Mirtazapine at low doses can address depression, poor appetite, and insomnia simultaneously. TCAs and paroxetine are avoided because of anticholinergic burden.

Special considerations

Anticholinergic burden

Anticholinergic medications worsen cognition in dementia and can precipitate delirium. Common offenders include diphenhydramine (Benadryl, Tylenol PM), oxybutynin and other bladder anticholinergics, TCAs, first-generation antipsychotics, and paroxetine. The anticholinergic burden of a patient's full medication list is worth reviewing at each visit.

If a bladder anticholinergic is medically necessary, mirabegron is a non-anticholinergic alternative for overactive bladder.

Statin considerations

Statins don't clearly prevent or treat Alzheimer's, and there's mixed evidence about cognitive side effects. Deprescribing statins in advanced dementia is often appropriate.

Vitamin E

Vitamin E at 2000 IU daily has some evidence for slowing functional decline in Alzheimer's (TEAM-AD trial). It's inexpensive and generally well-tolerated at that dose, though bleeding risk with anticoagulants is a consideration. Reasonable to consider in select patients.

Ginkgo, memantine plus, and other supplements

Ginkgo biloba has been extensively studied without clear cognitive benefit. Coconut oil, coenzyme Q10, and other supplements lack good evidence. Souvenaid (a medical food) has small trials with mixed results.

End-of-life considerations

In advanced dementia, medication burden becomes a quality-of-life issue. Deprescribing statins, aspirin, bisphosphonates, and other primary prevention medications is often appropriate. AChE inhibitors and memantine are often discontinued when they no longer produce meaningful benefit, though the decision to stop is nuanced because abrupt discontinuation can produce clinical worsening. Gradual taper with monitoring is standard.

Antipsychotic use in end-stage dementia requires ongoing justification given the mortality risks and often limited residual benefit.

Dementia with Lewy Bodies

DLB is a distinct diagnosis with specific medication considerations. AChE inhibitors (rivastigmine specifically has evidence in DLB and Parkinson's disease dementia) can produce meaningful cognitive and behavioral benefit. Antipsychotics can produce severe neuroleptic sensitivity in DLB (rigidity, cognitive worsening, autonomic instability). If an antipsychotic is needed, pimavanserin or quetiapine at very low doses are the standard choices; typical antipsychotics are contraindicated.

Frontotemporal dementia

AChE inhibitors don't help FTD and can worsen behaviors. SSRIs (trazodone, sertraline) are used for behavioral symptoms. Antipsychotics carry the same mortality concerns as in Alzheimer's.

What tips the choice

• Newly diagnosed mild to moderate Alzheimer's: donepezil, rivastigmine, or galantamine. Any is reasonable. Donepezil has the simplest dosing.
• Can't tolerate oral AChE inhibitor (nausea, diarrhea): rivastigmine patch.
• Moderate to severe Alzheimer's: add memantine.
• Early Alzheimer's (MCI or mild dementia due to AD) with confirmed amyloid pathology: lecanemab or donanemab if the patient meets selection criteria and can tolerate MRI surveillance and infusion schedule. ApoE4 status informs the conversation.
• Bradycardia or syncope on AChE inhibitor: consider stopping or reducing dose.
• Agitation, non-pharmacologic first-line ineffective: brexpiprazole is the FDA-approved option. Citalopram is reasonable. Other antipsychotics only with informed discussion of mortality risk and short duration.
• Insomnia in dementia: trazodone low-dose, ramelteon, or melatonin. Avoid z-drugs and benzodiazepines.
• Depression in dementia: sertraline first-line. Mirtazapine low-dose if poor appetite and sleep are also issues.
• Dementia with Lewy Bodies: rivastigmine is well-supported. Avoid typical antipsychotics. Pimavanserin or very low-dose quetiapine if needed.
• Advanced dementia: reassess whether medications still serve function. Deprescribing is often appropriate.
• Frontotemporal dementia: SSRIs or trazodone for behaviors. AChE inhibitors don't help and can worsen.

Common questions

Do the Alzheimer's medications actually work? The AChE inhibitors and memantine produce modest symptomatic benefit. On average, they delay cognitive and functional decline by about 6 to 12 months. Some patients respond clearly, some don't. They don't stop the underlying disease. The anti-amyloid antibodies (lecanemab, donanemab) do slow underlying disease progression modestly in early stages, but they're not a cure and they don't reverse existing damage.

What are ARIA and how worried should we be? Amyloid-related imaging abnormalities (ARIA-E is edema, ARIA-H is small bleeds) are the main safety concern with the anti-amyloid antibodies. They're detected on MRI. Most are asymptomatic. A minority (roughly 15% for ApoE4 homozygotes on lecanemab) are symptomatic, and rare cases are severe or fatal. This is why MRI surveillance and careful patient selection are required. Non-carriers of ApoE4 have substantially lower ARIA risk.

When should we start thinking about anti-amyloid treatment? Only in early Alzheimer's disease with confirmed amyloid pathology (amyloid PET or CSF). MCI due to AD or mild dementia due to AD are the trial-supported windows. Moderate or severe dementia has not shown benefit. ApoE4 status, MRI baseline (absence of significant microhemorrhages), and ability to complete infusion and MRI schedule are all part of the eligibility conversation.

What can we do about the agitation? Non-pharmacologic approaches are the first-line: identify and address unmet needs, maintain routine, reduce environmental triggers. When medication is needed, brexpiprazole is the only FDA-approved antipsychotic for Alzheimer's agitation. Citalopram has evidence. Other antipsychotics carry the class mortality warning and should be used at low dose for short durations with reassessment. Trazodone can help mild agitation and sleep.

Should we stop the medications at some point? In advanced dementia, the balance shifts. AChE inhibitors and memantine are often continued while there's perceived benefit and discontinued when they no longer help. Abrupt discontinuation can produce clinical worsening, so tapering is preferred. Other medications (statins, bisphosphonates, aspirin for primary prevention) are often reasonable to deprescribe in advanced disease. Comfort and quality of life become the guiding priorities.

Sources

This guide draws on current prescribing information, treatment guidelines, and public health references. It is reviewed for clinical accuracy and updated as guidance changes.

1. American Academy of Neurology. Practice guideline update: mild cognitive impairment.
2. van Dyck CH et al. Lecanemab in early Alzheimer's disease.
3. Sims JR et al. Donanemab in early symptomatic Alzheimer disease (TRAILBLAZER-ALZ 2).
4. Cummings J et al. Antipsychotic use in dementia and brexpiprazole for agitation.
5. National Institute on Aging. Alzheimer's disease.

Related on PsychiatryRx

• Donepezil
• Rivastigmine
• Galantamine
• Memantine
• Lecanemab
• Donanemab
• Brexpiprazole
• Sertraline
• Trazodone
• Mirtazapine
• Pimavanserin
• Quetiapine
• Beers Criteria for psychiatric medications
• Medications for insomnia
• Comorbidity medication selection