TCPR: How do you evaluate memory problems?
Dr. Collier: The first step is to make the correct diagnosis. I screen their cognition with the Montreal Cognitive Assessment (MoCA) or the Saint Louis University Mental Status (SLUMS), which are readily available online, although the MoCA requires training before administration. Depending on my suspicion for cognitive decline, I may repeat this screen annually. If their cognitive symptoms cause impairment in their activities of daily living, or I see a gradual and significant decline in their score, I’ll consider neuropsychological testing. That can stage the illness and detail their cognitive strengths and weaknesses. 

TCPR: How does the type of dementia guide the treatment?
Dr. Collier: Treatment options vary depending on the type of dementia, with the most common types being Alzheimer’s, vascular, Lewy body, frontotemporal, and dementia due to Parkinson’s disease. I think about Alzheimer’s when the history is consistent with a gradual decline in cognition and functioning, which contrasts with the more abrupt onset or stepwise progression we see in vascular dementia. Alzheimer’s is where we have new treatments available—the anti-amyloid monoclonal antibody infusions. Some of our meds can work in other dementias (eg, memantine for Lewy body or Parkinson’s; cholinesterase inhibitors for vascular, Lewy body, and Parkinson’s), but there’s no evidence that the anti-amyloids work outside of Alzheimer’s.

TCPR: When would you use them?
Dr. Collier: They only work in the early or mild stage of the disease (see the table “Cognitive Decline” below). There are two—donanemab (Kisunla) and lecanemab (Leqembi)—and they both reduce amyloid in the brain. A third treatment, aducanumab (Aduhelm), was voluntarily taken off the market due to poor sales; it also wasn’t effective. The tricky part is to balance the risk/benefit. These treatments come with a one in eight chance of brain swelling (Espay AJ et al, eNeuro 2024;11(7):319–323). That can lead to hemorrhages, which can be fatal but are often asymptomatic. Unfortunately, patients at the greatest risk for these adverse effects are individuals carrying the APO-E4 (epsilon-4) gene, who are also those most likely to experience dementia progression.

TCPR: So the risks are high. What are the benefits?
Dr. Collier: Both donanemab and lecanemab slowed the progression of dementia by about seven months. In other words, cognition didn’t improve on them, but it didn’t decline as much as it would have with the progression of the disease. None of our treatments do that. The infusions only worked in the mild stage of Alzheimer’s, and younger patients had the best outcomes. I’d tell patients, “There is a chance that this infusion can remove the amyloid plaques that are responsible in part for development of Alzheimer’s, which may delay the progression of the symptoms and improve your functioning.” 

TCPR: What about tolerability problems?
Dr. Collier: Nausea, flu-like symptoms, and headache are common after the treatments. Also, they are costly and time intensive, with infusions every two weeks for lecanemab or every month for donanemab.

TCPR: What other options are there?
Dr. Collier: I usually start with a cholinesterase inhibitor in mild Alzheimer’s dementia, like donepezil or rivastigmine. Donepezil is once a day, so it’s my go-to, but rivastigmine comes as a patch, which cuts down on GI side effects for some. The benefits are mild, but so are the risks, which include nausea, diarrhea, dizziness, appetite loss, vivid dreams, hypotension, bradycardia, and syncope. If the patient is in the moderate to severe stages, I might use the NMDA antagonist memantine. This one is not approved for mild dementia and not helpful there, but in the later stage we might use it alone or add it to a cholinesterase inhibitor.

TCPR: Some deprescribing algorithms recommend tapering off dementia medications. Why is that?
Dr. Collier: The benefits of these medications are very mild, and they don’t modify the course of illness. On average, it’s 2.4 points on a 70-point scale, the ADAS-Cog (Schneider LS, Continuum (Minneap Minn) 2013;19(2):339–357). If there is no benefit during treatment, or if you notice significant worsening in cognition or behavior, you can try deprescribing. Actually, the behavioral piece is even more important than cognition, as this is what predicts transition to a nursing home.

TCPR: How do you manage behavioral symptoms?
Dr. Collier: I start with nonpharmacological approaches, as the evidence for them in behavioral symptoms is stronger. Physical activity is high on the list, but older adults are not going to exercise because you tell them to. They’ll have more success if they do it with people they care about, so bring the caregivers in. I’ll set goals, often starting with mild aerobics, like walking briskly enough that it’s hard to hold a conversation, for 30 minutes a few times a week. The official recommendation is for 150 minutes a week, but we usually start lower. This kind of activity improves memory, mood, and hippocampal growth.

TCPR: What else?
Dr. Collier: Next, we look for what works to calm the patient. It’s different for each person, but it might be touch, massage, scents like chamomile or lavender, old photos, or music from when they were in their 20s. If they are physically aggressive, we might start with going outside or providing a change of scenery. We want to have a few steps the family can do before they turn to a PRN medication.

TCPR: When do you start medications for agitation?
Dr. Collier: First, we need to consider that a patient might have delirium on top of dementia, especially if there has been a rapid decline. Dementia, in contrast, has a slow and steady progression. If I suspect delirium, I’ll first review the meds for common offenders and look for medical causes. Infections (eg, pneumonia, UTI) and electrolyte and metabolic disturbances are common, and additional workup is based on the patient’s history. After ruling out delirium, I’ll want to know what times of the day they are most agitated and boost up a behavioral intervention in the hour before then. 

TCPR: What medications do you use for behavioral symptoms?
Dr. Collier: Among the dementia medications, donepezil has the best evidence to help with behavioral symptoms (Lockhart IA et al, Dement Geriatr Cogn Dis Extra 2011;1(1):212–227). You will often see more improvement in behavior than cognition on it. You might also consider selective serotonin reuptake inhibitors (SSRIs) in patients with anxiety, but they are not effective for depressive symptoms in dementia. The gains are very modest, but sertraline and citalopram have shown benefits. I’ll usually go with escitalopram to avoid citalopram’s cardiac risks (Seitz DP et al, Cochrane Database Syst Rev 2011;(2):CD008191). I start an SSRI at its lowest dose (escitalopram 5 mg or sertraline 12.5 or 25 mg) and raise it every 1–2 weeks (toward escitalopram 10–15 mg QD or sertraline 50–75 mg QD). After a few months at a therapeutic dose, ask the family if they have noticed any difference. If not, we taper to avoid risks like hyponatremia, falls, and QT prolongation. Another option is mirtazapine (3.75–30 mg HS), which doesn’t have good data for agitation but may help with anxiety, sleep, and appetite (Chen K et al, Front Aging Neurosci 2023;15:1103039). 

TCPR: What about sedatives?
Dr. Collier: Among sedating medications, trazodone (25–50 mg HS PRN) may help agitation, especially in patients who struggle with sleep, but it has a risk of orthostasis and falls. Options that are safer for insomnia include melatonin (0.5–3 mg HS) and ramelteon (8 mg HS), which have some evidence to improve sleep and decrease next-day agitation (Terao I et al, J Alzheimers Dis 2024;98(3):825–835).

TCPR: What should we avoid for behavioral symptoms?
Dr. Collier: A lot of people use benzos, but I avoid them. The data are not good, and they can make agitation worse by causing disinhibition. They raise the risk of falls, accidents, and delirium. I also avoid anticonvulsants—they have poor evidence and lots of risks (Defrancesco M et al, Int J Neuropsychopharmacol 2015;18(10):pyv055).

TCPR: Where does brexpiprazole (Rexulti) fit in all this?
Dr. Collier: Brexpiprazole is the only medication approved for agitation in Alzheimer’s disease (start 0.5 mg QHS, raise by 0.5 mg each week toward target of 2–3 mg QHS). However, the antipsychotics come with many risks, including arrhythmias, falls, tardive dyskinesia, and a higher risk of death in dementia (which was four times higher with brexpiprazole than placebo). Brexpiprazole made a statistically significant difference, but it’s not clear that it was a clinically meaningful difference. We don’t know if it’s more effective than other antipsychotics that treat agitation in dementia: aripiprazole (2–5 mg QHS), olanzapine (2.5–5 mg QHS), quetiapine (50–100 mg QHS), and risperidone (0.5–2 mg QHS) (Lü W et al, BMJ Ment Health 2024;27(1):e301019).

TCPR: Those others are less expensive, too. 
Dr. Collier: Yes, and for that reason I’d start with an older antipsychotic if I had to use one, probably risperidone. But I consider them fourth line, after nothing else has worked and when aggression is severe enough that we’re considering hospitalization.

TCPR: When do you taper antipsychotics in dementia?
Dr. Collier: After improvement, I try to maintain the same dose for at least three months, and then I reduce the dose. I go slow, generally reducing the dose by 25% every one or two weeks to minimize the risk of developing rebound symptoms. Episodes of agitation or aggression are often triggered by a medical illness or environmental change. Even if we don’t know what that trigger was, it may resolve so that the antipsychotic is no longer needed.

TCPR: What about methylphenidate for apathy in dementia?
Dr. Collier: Methylphenidate has some evidence for apathy in dementia, but it also comes with risks, like hypertension, arrhythmias, agitation, and psychosis (Mintzer J et al, JAMA Neurol 2021;78(11):1324–1332). I rarely use it because the evidence is not strong. Apathy is very difficult to treat with a medication.

TCPR: What can patients do to prevent dementia?
Dr. Collier: Some risk factors can be controlled. Anything that affects the heart can affect the brain, so optimizing cardiovascular risk factors can lower a patient’s chance of cognitive impairment. Help patients increase their physical activity and discuss a healthy diet: fruits, vegetables, whole foods, limiting processed foods, and limiting red meat. Brainstorm how to increase their social engagement, which includes addressing hearing impairment. Watching TV is very passive, but speaking with a neighbor about a TV show is active. Also, encourage patients to learn a new skill, like a musical instrument or a hobby (Dominguez LJ et al, Nutrients 2021;13(11):4080). Medically, we want to help patients reduce drugs that can worsen cognition, like benzos and anticholinergics. A patient’s memory concerns can be a motivator for behavioral change. Clinicians can use this opportunity to address smoking and alcohol intake.

TCPR: Thank you for your time, Dr. Collier.