Time Stamps

• 02:27 Deep Dive 1:  How do we deliver the news of a diagnosis of dementia?
• 09:41 Deep Dive 2: Prescribing medications for cognitive decline
• 29:30 Deep Dive 3: Patient-centered management for a patient with cognitive decline
• 35:46 Deep Dive 4: Planning for an uncertain future

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Show Notes

DEEP DIVE 1: How to Deliver the News of Dementia

• Begin by assessing the current level of understanding and openness to hearing the diagnosis
  • “What do you understand about your brain health?”
  • “How much do you want to know about what to expect?”
• Deliver a clear headline: 
  • “Based on our evaluation, I am concerned you have dementia.” 
• Be direct, but tailor the approach to the patient’s readiness to discuss the diagnosis.
  • Sometimes “memory loss” is a gentler entry point for defensive patients, allowing the conversation to continue.
• Emphasize that dementia is a spectrum, with highly variable progression.
  • Use functional examples and simple graphics to explain decline over time.
  • Explain importance of identifying support systems early
• Provide reassurance to families:
  • Age is the biggest risk factor.
  • Only ~1% of Alzheimer’s cases have autosomal dominant inheritance.

DEEP DIVE 2: Prescribing Medications for Cognitive Decline

Cholinesterase Inhibitors

• • Donepezil 
  • Rivastigmine
  • Galantamine
• Indications
  • MILD to SEVERE DEMENTIA: Donepezil is FDA-approved 
  • MILD to MODERATE DEMENTIA: Galantamine and rivastigmine are FDA-approved for
    • Though rivastigmine patch approved for severe as well
• Not be shown to be effective for mild cognitive impairment (MCI)
  • Side effects tend to be cholinergic, actively monitor and screen for symptoms while on medication
    • Most common: diarrhea (15–20%)
    • Others: nausea, vivid dreams, muscle aches, joint aches
    • Rare: bradycardia
• Impact:
  • Expected Benefit is a modest improvement lasting 6–12 months
    • Does not slow progression
    • Effects wear off after ~1 year
• PRO TIP: 
  • Donepezil can be effective at the starting dose (can still titrate up)
  • Galantamine and Rivastigmine are not effective at starting doses
    • Galantamine and Rivastigmine MUST be titrated up

Memantine (NMDA receptor antagonist)

• Indications:
  • Approved for MODERATE to SEVERE Alzheimer’s disease
  • Dose adjust for renal impairment
• Impact:
  • Generally well tolerated
  • Improvement in Severe Impairment Battery testing over 6 months 
• PRO TIP:
  • Can be used as combination therapy with cholinesterase Inhibitors with modest additional benefit

When to Consider Stopping These Meds (Cholinesterase Inhibitors and Memantine)

• If no observable benefit after a year
• If there was an initial benefit, but the patient has been on the medication for 6-12 months without ongoing benefit
  • Practice patterns vary!
    • Some people are proactive about whether medications are still providing benefit as they have been only been shown to be beneficial for dementia for a limited period of time
    • CAVEAT: There may be some symptom stabilization and if you stop it, may risk worsening neuropsychiatric and cognitive symptoms!
• If side effects outweigh benefits or medication becomes too hard to take.
• Some feel there may be some symptom stabilization on the medication and risk of worsening neuropsychiatric and cognitive symptoms if stopped. 
  • They may choose to continue the medications.

Anti‑Amyloid Monoclonal Antibodies

• Examples: Lecanemab, Donanemab
• Indications:
  • Mild cognitive impairment or mild dementia due to Alzheimer’s with proven amyloid
  • Not for moderate or severe dementia
• Benefits:
  • Slows decline by ~30% over 18 months. 
    • NOTE: this benefit was seen on testing and the clinical benefit is more controversial 
  • Does not improve symptoms
  • Most trial participants were also on cholinesterase inhibitors or memantine because of off-label use of these medications.
• Side Effects:
  • Infusion reactions:  Flu-like and GI symptoms 
    • Generally mild and self limited
  • ARIA- Amyloid Related Imaging Abnormalities: Can be dangerous, requires monitoring
    • ARIA‑E (edema) — ~12.5% incidence
    • ARIA‑H (microhemorrhages) — ~10% incidence 
    • Mild symptoms: headache, dizziness, blurry vision
    • Rare severe symptoms: seizures, stroke‑like episodes, delirium
• How to Monitor:
  • Generally administered by subspecialists. 
  • Test for susceptibility gene – Apo E – that puts patients at higher risk for ARIA.
  • Frequent MRIs (at least 4 within first 6 months) to screen for ARIA
    • If mild ARIA – Monthly MRIs to ensure it’s not worsening on images. 
    • If moderate ARIA – Temporarily stop, can consider restart if stable. 
    • If severe ARIA – Discontinue 
  • May discontinue antibody medications entirely if amyloid clears on PET at 12 months or if patient develops neutralizing antibodies

DEEP DIVE 3: Deprescribing in Patients with Cognitive Decline 

• Simplify medication lists—aim for the regimen that your patient can actually follow.
  • Goal =INCREASE adherence + DECREASE side effects and pill burden 
    • not make a “perfect” regimen!
  • A useful resource is: https://deprescribing.org/
• Prioritize stopping, adjusting, or substituting medications that have:
  • More difficult dosing regimens
    • Substituting twice‑daily “gold standard” meds for once‑daily “silver/bronze” alternatives can improve compliance
  • High side‑effect burden 
    • particularly consider those with high fall risk
      • Beta blockers
      • Diuretics
  • Low long‑term benefit
• Deprescribing builds patient trust—start with what’s making them feel bad.
• Support medication adherence:
  •  by printing medication lists 
  • sending updated medication lists via a patient portal
  • utilizing home health and OT support
• It is important to remember that dementia is progressive — the medication plan must evolve with the disease.

DEEP DIVE 4: Planning for an Uncertain Future

1. Ongoing functional assessment — revisit the “functional one‑liner” each visit to track changes and determine what patient needs help with now and will need help with in the near future
2. Advance care planning as a longitudinal process — not a one‑time form. 
   • Ask questions about code status, health care proxy, and also what acceptable quality of life means/”what matters most”
3. Build the safety network early:
   • Social work
   • Case management
   • Community resources (church, neighbors, support groups)
   • Family
   • Home‑based care
4. Identify patient & family “lines in the sand”:
   • When will living alone no longer feel safe?
   • When would driving stop voluntarily?
   • When is facility care acceptable?

Transcript

Dr. Nick Villano: Welcome back to Gray Matters, where we unpack how medical management is rarely black or white.

Dr. Indu Partha: And go on lots of deep dives along the way. 

Dr. Nick Villano: Hey, everyone! I’m Dr. Nick Villano, and today I’m joined by…

Dr. Indu Partha: Hi everyone. I’m Dr. Indu Partha, a general internist and PCP at the University of Arizona College of Medicine in Tucson and Banner University Medicine.

Dr. Nick Villano: Awesome. Welcome back, Indu. And for everyone listening, this is actually episode two of our two-part episode on dementia. Okay, so I don’t know about the rest of you, but personally, I’ve been anxiously waiting and wondering what’s about to happen with our patient because we were just about to break the news of dementia to her. Were we Indu?

Dr. Indu Partha: Yes, we sure are. And we definitely left everyone hanging last episode, Nick. You, our listeners, and most of all Ms. Wise, our patient who had recently been diagnosed with Alzheimer’s disease. And you know what? I have watched plenty of soap operas in my time, and I appreciate the art of the cliffhanger.

Dr. Nick Villano: Definitely a lost art these days. Well, in the spirit of TV, let’s do a recap then.

Dr. Indu Partha: All right, you got it. So last time on Gray Matters, we met my patient, Ms. Wise, who had come in for her routine blood pressure management, but we found her to be really confused with our prior instructions. We realized we had to pivot and look into her cognition, and we found that her Mini-Cog was abnormal. So we quickly ran our list. Was her hearing okay? We reviewed her medications, her sleep habits, and her mood. And then we moved on to the MoCA, which was abnormal, but her labs found nothing reversible. And we also learned that it’s now standard to get MRIs for patients with cognitive deficits. And unfortunately, Nick, hers showed medial temporal lobe atrophy, which suggested a diagnosis of Alzheimer’s disease.

Dr. Nick Villano: Wow, that was definitely a lot of great learning, but it’s also still a really tough diagnosis to have to break to Ms. Wise and her daughter. And I’m sure their first question’s going to be, what can you do for them? I mean, this is a really familiar and difficult place for me personally, and Indu, I’m kind of looking to you to throw us all a lifeline here.

Dr. Indu Partha: You bet. So let’s get back to it and move to this episode’s

Deep Dive 1: How do we deliver the news of a diagnosis of dementia?

Mary Beth Kuebrich, NP: So if they’re in the earlier stages, I want to be really clear after I’ve done the workup at delivering a clear headline that based on my evaluations and the changes we’ve seen, I worry you have dementia, and I’m really clear about that.

Dr. Indu Partha: Listeners, that’s Nurse Practitioner Mary Beth Kuebrich.

Dr. Nick Villano: Okay. So I think it’s great that she’s advocating for us being so direct, but this also kind of feels like a minefield. I mean, are they going to accept the diagnosis of dementia?

Dr. Indu Partha: Yeah. Honestly, even after being a PCP for years, I get nervous about how to broach this topic. We just had a patient in resident clinic who literally yelled at the resident and told her talking about his cognitive issues, was totally focusing on the wrong thing, and just kept asking, “What are we going to do about his pain?” And I felt so bad because I could just see his wife in the background, totally distressed and embarrassed.

Dr. Nick Villano: Oh man, that’s really tough. And you don’t get that kind of pushback often when you’re breaking other hard diagnoses. So I guess the question here is how are you clear with patients, but also taking into account how ready they may be to hear the diagnosis?

Dr. Indu Partha: I think the goal here that we need to concentrate on is to keep the conversation going so that we’re able to deliver the news in a way that they’re willing to hear. I mean, we need to remember that the goal is to ensure that we keep a line of conversation open with our patient. Saying memory loss instead of the word dementia may sometimes seem dishonest or a cop out, but if it will keep a defensive patient returning for follow-up, I mean, words can matter, Nick, and we definitely don’t want our patient to avoid coming back to see us.

Mary Beth Kuebrich, NP: I usually start by just asking what they understand about their current diagnosis. So I might say, “Help me understand what you understand about your brain health or your memory, and that way I’m not repeating things they already know, we can move forward.” And then I also ask what and how much they’d like to know about what to expect over time, recognizing that some people want all of the information, some people do not want to know what to expect, and that may differ for the person with dementia and the caregiver. The person with dementia may not want to know, but their caregiver wants to know.

Dr. Indu Partha: So I guess what I’m taking away is we often will have to tailor how we deliver the news, and sometimes even our word choices, but our core message has to be clear. You have a progressive brain disease, and your life and abilities are going to be impacted over time.

Mary Beth Kuebrich, NP: I also really like to explain to patients with dementia and their caregiver that dementia is a spectrum and that each person is going to progress differently over time. I think some people really lock onto the fast and think it should be exactly that progression, but we know that some people progress more quickly and some more slowly, depending on a variety of factors and whether or not they have a new medical exacerbation that might speed up their trajectory.

Dr. Indu Partha: We began our discussion with Ms. Wise by just asking her, “Are you having any problems remembering to take your medicine and how are you handling your day-to-day life at home?” She told us she was actually having trouble with her medications, sometimes just taking them out of her pill box and holding onto them, unsure if she had already taken them. And she expressed a lot of frustration and annoyance at herself and just told us, “I just can’t seem to do it all by myself anymore. What is going on?”

Dr. Nick Villano: I mean, that sounds really hard for her, but it also sounds like a potential opening for your conversation, right? I mean, you can say maybe one reason you’re having so much trouble at home is because of this diagnosis that we think you have, Alzheimer’s disease.

Dr. Indu Partha: Yeah, we thought so too. After getting her permission, we called Ms. Wise’s daughter and let her know that her mom had been diagnosed with dementia based on our cognitive testing and the MRI results. And her daughter understood and really just wanted to get her mom as much help as soon as possible.

Mary Beth Kuebrich, NP: I’ve also used just a simple graphic, a graph that essentially has a progressive downward trend so that you can kind of point, “Here’s where I think you are now.” I think that just really helps emphasize that this is a chronic progressive disease that will get worse over time and that they’ll need more help with past and daily life. And I like that a lot of those tools really focus on function, so that we know what somebody’s able to do and how those things may change over time.

Dr. Nick Villano: That reminds me of how, in episode one, Dr. Perry likened dementia to aging in reverse. You acquire skills as you age, and then if you have a diagnosis of dementia, sadly, you start to lose them in the reverse order. I think knowing this, just having some expectation of what might be to come, can really be valuable for patients and their families. Although isn’t it true that how fast someone’s going to progress through those stages isn’t very predictable?

Dr. Indu Partha: It really isn’t. And I wish there was a template we could follow for all patients to let them know exactly how it’s going to go for them, but that’s just not realistic. I just also want to touch on one other poignant question Ms. Wise’s daughter asked us, Nick. She asked us what this diagnosis meant for her. After seeing a loved one suffering from dementia, I think it’s only normal to wonder and worry if you’re going to be next.

Dr. Gad Marshall: So I would say a very common question or belief that patients and families have when they come in is, did I get this because my family history is this, my mother had Alzheimer’s disease, I’m doomed, that’s it. I have it. There is that belief may be a strong word. And my response depends on what information I have for the patient. So the easiest thing to say, which is almost always true, is age is the biggest risk factor, and that’s what’s driving your condition here. Most forms of dementia are not directly inherited. For Alzheimer’s disease, for example, only 1% of cases have an autosomal dominant mutation that causes it. I mean, there are a number of mutations, but altogether, they account for only about 1%.

Dr. Nick Villano: That’s neurologist, Dr. Gad Marshall.

Dr. Indu Partha: So to summarize, when telling a patient they have dementia, we need to find out what they know and what they want to know. We need to give them a clear message of what is going on so they and their caregivers have an understanding of what to expect over time, the inevitable loss of ADLs, IADLs, and also how to prepare for those functional losses.

Dr. Nick Villano: Right. And when asked about risk to family, we can say, yes, mom has Alzheimer’s, but it’s very rarely genetic. The biggest risk factor is just getting older. So okay, let’s say that we have a patient and her family, and they understand the disease, and now we’re trying to talk about next steps, right? I mean, I know we said we don’t have a perfect medication to fix this, but there are treatments for dementia, right?

Dr. Indu Partha: There sure are. And Ms. Wise’s daughter had gone to Dr. Google and had seen some press releases about new medications that had been approved for Alzheimer’s, and she came to us wanting to know more. She was really hoping they would be the right fit for her mom, but I knew I needed to know more before I could make any clear recommendations. And that leads us to

Deep Dive 2: Prescribing medications for cognitive decline. 

Dr. Indu Partha: Nick, before we go too much further, I just want to point out that we are not talking about treatment for other dementia like Parkinson’s and vascular type today. We’re just going to be talking about treatment for Alzheimer’s disease since that’s what Ms. Wise had.

Dr. Gad Marshall: So three of the medications are cholinesterase inhibitors, donepezil, galantamine, and rivastigmine. They’re all approved for Alzheimer’s disease at the stage of dementia, primarily mild to moderate dementia. Danepezil also at the stage of severe dementia. None of them are approved for mild cognitive impairment.

Dr. Indu Partha: So we have donepezil, galantamine, and rivastigmine, which are indicated for mild to moderate dementia, but not for mild cognitive impairment.

Dr. Nick Villano: Okay. So, as a throwback to episode one, let me just remind myself. Mild cognitive impairment describes patients who have some functional impairment, but are still able to do what they need to live independently. On the other hand, dementia or major neurocognitive disorder at any level is when patients have true dependence on others functionally.

Dr. Indu Partha: Exactly. Those are the folks who can’t do everything for themselves.

Dr. Nick Villano: Okay. But with that in mind, isn’t it kind of interesting that these medications aren’t indicated for mild cognitive impairment? I mean, that seems counterintuitive. Wouldn’t we want to get them on medications and intervene ASAP?

Dr. Gad Marshall: Patients certainly ask for treatment as soon as they can, but to say that it works better earlier is not based on data. So I go with the data, and there have been multiple trials at the stage of mild cognitive impairment with these drugs that have not shown benefit. And for these drugs, earlier is not necessarily better.

Dr. Indu Partha: Yeah. I have to admit, it was a bit disappointing to hear about, and I agree it’s counterintuitive, but just because we want something to work earlier doesn’t change the fact that the evidence isn’t there, at least not right now.

Dr. Nick Villano: Okay. Yeah, that’s a fair point. Maybe earlier on, we’re just really focusing on de- prescribing medications and optimizing the regimen. But we did say that Ms. Wise was having her IADLs impacted, right? And she’s starting to move beyond myocognitive impairment into actual major neurocognitive disorder, dementia territory. So would she qualify for treatment with one of these medications?

Dr. Indu Partha: Yeah, Nick, you’re right. She did qualify, but remember how this all started. She was already inconsistent with her anti-hypertensive regimen, and so pill burden worries were real and she hadn’t come to us with any complaints of feeling unwell. So after discussing this with her and her daughter, we recognized that we didn’t want to make her potentially feel sick with a new medication like one of the cholinesterase inhibitors at that moment.

Dr. Gad Marshall: All three of these have the most common side effect is diarrhea. And so I always mention that first, it could be 15 to 20% of patients develop diarrhea. There are other megastrointestinal side effects as well, and they’re muscle aches, joint aches, vivid dreams. And so I go over the side effect profile. It’s usually pretty well tolerated. Rarely you can have bradycardia. There are really not significant side effects from this. And if you stop the medication, things resolve pretty quickly.

Dr. Nick Villano: Okay. So we’re saying that these medications can have side effects, and we should probably be really vigilant because in a population that’s already vulnerable to falls, things like diarrhea, muscle aches, joint aches could definitely be a risk. But the risks don’t sound terrible. It really makes me wonder, what are the benefits? What are the trade-offs that we’re expecting from these medications?

Dr. Gad Marshall: And almost all the trials were six-month trials. And so you saw this improvement by three months, and then it wore off by six months. Some of the trials were one year; very few were longer than that. So I usually say you get maybe 6 or 12 months of modest improvement, and then it wears off. Not slowing of decline, not stopping of symptoms. That’s what you get: a modest improvement, and then they wear off. That’s how I phrase it in terms of what to expect. And it’s not necessarily better at mild versus moderate dementia. These drugs have been tested across that severity, and it’s not necessarily better earlier than later in that severity. And for donepezil, including with severe dementia.

Dr. Nick Villano: I see patients on these medications for so long, so I think it’s really good to repeat what we’re saying here. For patients on these medications, we’re expecting possibly 6 to 12 months of modest improvement, not slowing of the decline, not stopping of symptoms, potentially 6 to 12 months of modest improvement. With the potential risk for cholinergic side effects that we already discussed.

Dr. Indu Partha: And then there’s Memantine, which is an NMDA receptor antagonist, which is approved for moderate to severe Alzheimer’s disease. And it really is well tolerated and tends to have more benefit on behavioral than cognitive symptoms without causing a lot of side effects. So clinically, if your patient is responding to memantine as monotherapy, or in addition to cholinesterase inhibitors that we talked about, again, you’re basically going to see some modest temporary improvement of symptoms for about six months.

Dr. Nick Villano: Yeah. And from what we heard, that means they might gain a point on their MMSE score. They may show less irritability or agitation with themantine, but after that, the decline can start again.

Dr. Indu Partha: Yeah. And Dr. Perry, again, made a good point when she was reviewing this episode that the brief symptom improvement with cholinesterase inhibitors are more cognition-related versus with memantine, we’re expecting more behavioral symptom improvement.

Dr. Nick Villano: Got it. It’s really good to finally clarify all that. But we’ve talked a lot about adding these medications, but personally, my favorite pastime is actually getting rid of medications, especially ones we don’t need, especially in patients who are older and have cognitive issues. So I guess when I see a patient in the hospital whose dementia’s progressed, I’m looking at Donepezil like, “Is that still worth continuing?”

Dr. Indu Partha: You are always two steps ahead, Nick. I actually talked about this with our experts about when do you stop these medications?

Dr. Gad Marshall: So basically, if past a year, we don’t really see any more obvious benefit. I often will bring it up with patients and families. We can consider tapering the medication because why have another medication if it’s not clearly helpful?

Dr. Indu Partha: So that’s definitely one approach, but another one of our consultants, Mary Beth, actually says that she often continues these medications for longer if the patient is tolerating them.

Dr. Nick Villano: But why would we continue a medication if we’re only expecting benefit for a short period of time?

Dr. Indu Partha: While some feel that there may be a potential benefit to mood or behavior, there was a meta-analysis that found that discontinuing cholinesterase inhibitors may have a negative effect on cognition and neuropsychiatric symptoms, but there are others who argue that the effect wasn’t as clinically significant, and the trials really weren’t convincing to continue the medications.

Dr. Nick Villano: Sounds like we need to remember that these medications have not been shown to provide long-term stabilization for dementia. We don’t really have a lot of evidence of benefit after a year. So it’s understandable that practice patterns start to diverge here on exactly how long to continue therapy.

Dr. Indu Partha: Yeah. There’s going to be basically three scenarios where we’re going to be talking to our patients about coming off of these medications. One, if the medications never really helped; two, if the medications are causing side effects; and three, if the medications did initially help, but it’s been over 6 to 12 months, and we’re not really sure if they are still helping. But to be honest, Nick, it seems like there’s going to be a lot of differing opinions between clinicians about if we decide to discontinue the medications immediately after a year or keep going for a little bit longer to avoid exacerbating any underlying neuropsychiatric or cognitive symptoms.

Dr. Nick Villano: Okay. So these are all the medications that I’ve heard of for dementia, but there’s also a whole new class of medications for Alzheimer’s disease, right? I don’t know too much about them, but I assume they probably end in an AB and probably require prior auth.

Dr. Gad Marshall: These are anti-amyloid monoclonal antibodies, so work very differently. They reduce amyloid plaque in the brain, and these are very specific for either mild cognitive impairment or mild dementia due to Alzheimer’s disease worth evidence of amyloid pathology. So these are the first drugs that actually got approval for this stage of mild cognitive impairment, and certainly the first drugs that got approval to modify amyloid in the brain.

Dr. Nick Villano: Okay. Wait, so I thought patients with mild cognitive impairment that they didn’t have a lot of options. Is this some hope for these folks?

Dr. Indu Partha: Yeah, but it’s a pretty narrow therapeutic window, Nick. So to be eligible for the anti-amyloid monoclonal antibodies like lecanemab, a patient needs to be caught between mild cognitive impairment and mild dementia due to Alzheimer’s disease.

Dr. Nick Villano: Okay. But can anyone with Alzheimer’s disease in that window be a candidate for these meds?

Dr. Indu Partha: Well, we need to make sure that these medications are going to be effective. So our patients are going to need to have amyloid seen on their PET scan, and then they’re going to need to be able to undergo MRI scanning. A couple of other contraindications to be aware of are things like the use of anticoagulants or immunosuppressants.

Dr. Nick Villano: Okay. So let’s say you have a patient with Alzheimer’s disease, they’re between mild cognitive impairment and mild dementia. You know that they have amyloid on their PET scan, and they don’t have any other specific contraindications. So they’re a candidate for this medication, basically. What kind of benefit are we possibly talking about here?

Dr. Gad Marshall: So the benefits on average of the trials that were 18-month-long trials showed a slowing of decline. So now we’re not seeing an improvement, but rather a slowing. And it’s about a third of the pace slower for both drugs compared to a placebo. And so that’s also arguably modest. So it didn’t stop, decline, certainly didn’t cause an improvement. It slowed things down some. Most of the participants in the trials were on cholinesterase inhibitor and/or memantine, about 80% of them. So in fact, this data is when it’s an add-on, mostly an add-on to the standard drugs that have been out there. So keep that in mind.

Dr. Nick Villano: Interesting. So obviously, one takeaway here is that different medications for dementia can have different effects. We said the colonesterase inhibitors improved symptoms briefly, but didn’t slow progression. On the other hand, here we have the antibody medications that don’t improve symptoms, but they do slow progression.

Dr. Indu Partha: It’s great to see benefit with treatment in the patient on mABS, but that benefit is a little bit controversial. The slowing of decline was largely seen on cognitive and functional testing. It was statistically significant, but there are a lot of people who feel that the effect is nevertheless small, and it’s unclear how clinically significant the impact of these mABs is going to be.

Dr. Nick Villano: I see. So I mean, I could see these patients being interested in all the options when faced with a diagnosis like dementia, but if the benefit isn’t clearly substantial, I guess I’d want to know what the downsides are too. 

Dr. Indu Partha: Well, there is a pretty significant risk of infusion reaction with lecanemab, flu-like symptoms, headache, GI upset.

Dr. Nick Villano: Okay. I mean, not pleasant, but it doesn’t sound like that’s the end of the world if it’s just during infusions. I mean, could that be worth the trade-off for better brain function?

Dr. Indu Partha: Well, those reactions may be tolerable, but that’s not the whole story. Have you heard of something called ARIAEH?

Dr. Nick Villano: I don’t think so. It sounds like what some new app is calling their AI companion.

Dr. Indu Partha: Right? Or the latest oral contraceptive. It is actually a term to describe the side effects that can be caused by these amyloid monoclonal antibodies A.R.I.A.followed by an E or an H. It stands for amyloid-related imaging abnormalities with E for edema and H for hemorrhage.

Dr. Nick Villano: Oof, that does not sound good.

Dr. Indu Partha: No, really does not. But it is reversible swelling, and the hemorrhages are microhemorrhages if that makes you feel better. But if there are enough, they can become a macro hemorrhage.

Dr. Gad Marshall: How frequent are these? So the microhemorrhage is about 10% of the edema. For one of the drugs, it’s a 12.5%. So these are not rare. It’s rare to have them with symptoms, and it’s rare to have them with severe symptoms. So the mild symptoms that are common are things like headache, blurry vision, or dizziness, imbalance, but rare symptoms are things like seizures and stroke-like symptoms or acute delirium.

Dr. Nick Villano: Wow. So 10 to 12% of our patients can have microhemorrhages or edema with lecanemab and donanemab. That is definitely a real risk, but on the other hand, it seems like the microhemorrhages were asymptomatic, and that has to be weighed against the potential benefit of giving these medications, a slowing of cognitive decline. That’s really tough. And if it were my patient or my family member, I don’t think I totally discount these medications, but how are we going to be able to give them safely?

Dr. Indu Partha: Yeah. So these require a lot of monitoring. The presence of a susceptibility gene called APOE increases a patient’s risk for swelling and bleeding. So Dr. Marshall said it’s standard of care to do genetic testing before starting treatment to better understand a patient’s risk. And then there are the MRIs.

Dr. Gad Marshall: In the first six months of treatment, we see the highest frequency of these side effects. And so we do for one of them four more MRI scans during that period, and we need to look for these potential abnormalities.

Dr. Indu Partha: So to just kind of keep this clear, a patient is going to get a pre-mAB MRI, and then we’ll have four additional MRI scans in the first six months of treatment because this is when ARIA happens most commonly. And then if you find ARIA, you’re going to need to repeat the MRI monthly until the edema has resolved or the hemorrhages are stable. And then of course, you may need to obtain a PRN MRI if a patient is having symptoms suggestive of ARIA.

Dr. Nick Villano: That’s a lot of MRIs. Okay. So then, if you find ARIA, is that a hard stop? Once you see the edema and hemorrhages, sorry, no more medications.

Dr. Gad Marshall: The guidance has been that if it’s mild and there are no symptoms, you can continue dosing, but obtain repeated MRI scans monthly to make sure that it goes away with the edema or that it’s stable with the microhemorrhages because they don’t really go away on the sequences that we measure, but we can see that there are not more of them where they don’t evolve in size. However, if there are symptoms or it’s moderate or severe in appearance, you will stop treatment until it goes away. If it’s severe in appearance, we will not reintroduce it, but if it’s not as severe, if it’s mild or moderate, if it goes away, we can reintroduce it. And that’s what was done in recent trials of these drugs and similar drugs.

Dr. Indu Partha: Yeah. I mean, like, follow-up scans can tell you if chemo is working. It’s kind of neat that we can see if the mABs are working with imaging.

Dr. Gad Marshall: And so, a lot of places like ours now at 12 months, where about 60% of the participants in the trials became amyloid negative. We decided 12 months of treatment with donanemab to repeat a PET scan. And then if it’s negative, to say, okay, well, you don’t need to continue treatment.

Dr. Nick Villano: Just to clarify, the endpoint of stopping treatment once amyloid plaque is gone is based on clinical trials done on donanemab specifically. This is really a field of ongoing study, especially in lecanemab, where we have even less data on endpoints of treatment.

Dr. Indu Partha: Yeah, there’s a lot of exciting research going on. So just to kind of summarize, if we see no more plaque at 12 months, we may just stop these antibodies because there is nothing more for the anti-amyloid medications to do, because there is no more plaque. If patients have bad side effects, we may stop them, but unfortunately, it’s also common to develop antibodies to donanumab at 12 to 18 months, which is yet another reason to stop the medication, as obviously they’re much less effective at that point anyway.

Dr. Nick Villano: So these medications sound appealing, but the benefit in mild cognitive impairment or mild dementia seems variable, and we need to really educate the patient on all the follow-up imaging and visits that are required to do this safely. That’s a lot of MRI appointments and then a PET scan after a year.

Dr. Indu Partha: Yeah, this brings up an important point, Nick. The MAB journey is really going to look very different depending on where the patient lives. Access to subspecialty care is so variable across the United States. Patients in rural areas are not going to have the same access to subspecialists and infusion centers as those in large cities with many academic medical centers.

Dr. Nick Villano: Yeah. And even though we found out that if patients are eligible, Medicare can cover quite a bit of these treatments. Even if most of the treatment is covered, and even if that patient does live in a high-resource setting, practically getting four MRIs scheduled and done and all the necessary follow-up appointments in six months sounds just not easy.

Dr. Indu Partha: Yeah, not easy at all. And just to remind us, though, there is promise here, but these medications are new, and it’s uncertain how long-lasting the positive impact is going to be. But Dr. Marshall is excited. There are newer drugs in development that will likely be better in tolerability, burden, and hopefully benefit.

Dr. Nick Villano: Well, I can’t wait to see it, but we have covered a lot in this deep dive, so why don’t we take a moment to review where we’re at?

Dr. Indu Partha: Okay. So just to summarize, we started talking about cholinesterase inhibitors, which we begin for mild to moderate dementia and then can substitute with, if there are side effects, or add on memantine for moderate to severe dementia. For cholinesterase inhibitors, we’re looking for actual improvement in cognitive symptoms, whereas memantine can show benefit in behavioral symptoms. Both show benefit for about 6 to 12 months before the decline resumes, and side effects in cholinesterase inhibitors can be GI-related, joint pain, headache, and vivid dreams.

Dr. Nick Villano: And as for the monoclonal antibodies, these are for folks with mild cognitive impairment to mild Alzheimer’s dementia, and we’re looking to slow disease progression by actually clearing out amyloid plaque. The clinical significance of this benefit is still a little bit unclear, and that really does need to be weighed against the burden of monitoring and trying to prevent side effects. Infusion reactions can occur, but we really need to watch for signs of intracranial hemorrhage or edema with regular MRIs, that ARIA side effect that we talked about. We stop the medications if these findings accumulate or if they cause significant symptoms, or if all the amyloid plaque resolves on imaging.

Dr. Indu Partha: Awesome. So thanks for putting that all together, Nick.

Dr. Nick Villano: No worries, but that reminds me that we talked a lot about medications for dementia, but most patients with dementia are on a lot of other medications too. I often have patients with heart failure and dementia, and I’m sort of just agonizing over what to do with their GDMT. Do I get more aggressive? Should I be de- prescribing? Ugh, that’s a lot.

Dr. Indu Partha: It totally is, but don’t worry, that’s what we get into in…

Deep Dive 3: Patient-centered management for a patient with cognitive decline.

Dr. Indu Partha: As you said, we definitely don’t want to harm our patients by removing essential medications, but we’ve got to be realistic. Is the medication list in the chart the same as what is actually being taken at home?

Dr. Laura Perry: So, to go to the adherence question, let’s start with that. Again, where on the spectrum What is this person? If they’re early on, they may still have the ability to adhere to a med list if we make the med list simpler. If we take off any things that are having only a marginal benefit, maybe we’re not going to have the gold standard of the heart failure regimen. Maybe we’re going to have the silver standard, maybe even the bronze or the tin, and we have to just be okay with that in our cells as a prescriber, knowing that it’s better to have them adhere to one pill than to not adhere to five pills.

Dr. Indu Partha: This is one of the really hard parts for me. There’s this nagging feeling like I should be working towards getting someone on the perfect medication regimen, but I think we kind of forget sometimes what the reality looks like for our patients. Side effects, financial burden, or, in keeping with our conversation today, pill burden, while we are so busy chasing the guidelines.

Dr. Laura Perry: Again, knowing what stage of disease they’re at is going to dictate that. If there are opportunities to change a medicine from the best option that’s twice a day to a lesser option that’s once a day, absolutely do it. The other thing I think about in terms of deprescribing is I start with the meds that have the highest likelihood for side effects, and I use the words side effects constantly.

Dr. Indu Partha: So helpful to have geriatrician, Dr. Laura Perry with us again.

Dr. Nick Villano: Yeah. I mean, I don’t know that I just start cutting all cardiac medications in a patient with cognitive issues. Some of these patients probably tolerate them just fine, but it sounds like once problems arise with adherence or side effects, you just need to look at each medication carefully. If one medication’s hard to take, if the risk of side effects are higher, or if you just don’t think the benefit is going to seem as meaningful anymore, maybe it’s time to question those medications. I know that I’m always looking at diuretics and beta blockers pretty carefully on my patient’s list to ask myself, “Do they still need these?”

Dr. Laura Perry: You build a lot of trust with patients by starting with things that are making them feel bad and by doing a lot of advertising and sales pitch about what you think is going to improve. And then over time, they may be willing to come off of more and more things.

Dr. Nick Villano: You know, that’s such a good point. Of everything I do for a patient, nothing makes them happier than when I say, “Hey, you actually don’t need to take one of your medications anymore,” especially if that was one that was giving them trouble.

Dr. Indu Partha: Right. I mean, even the most elegant medication list is meaningless if our patient isn’t following it. And we need to make sure our patients are taking their medications properly, but how we do this is probably going to change over time as their dementia progresses. At the beginning, all it may take is printing out an updated medication list for our patients.

Dr. Nick Villano: Yeah, that’s a great first step. And then eventually over time, you may need to go to other professionals to go to their home, do a pill box setup, or whatever they may need.

Dr. Indu Partha: Yeah. And Mary Beth reminded me that this doesn’t have to be only the PCP’s job to get medications sorted.

NP Mary Beth Kuebrich: Can we get somebody out there to see them? Can we refer to a home-based primary care? Somebody that can go into the home because I think you learn so much more and have so much more context. And often, occupational therapy I find, is really helpful at setting up practical strategies to help people with medicine management, what would work for them, whether it’s a pill box. I mean, there’s so many more new technologies of timed and autodispensing pill boxes. So I think often they’re really good at working with the person in their environment to find what will work.

Dr. Nick Villano: I feel like so often we’re just trying to get to this steady state with problems. We’d love for them to be on medications. They’re doing well. We’re just monitoring for issues, but most diseases don’t work like that. They change over time, especially degenerative diseases like dementia. So we really just need to keep watching and adapting because there’s not going to be a steady state.

Dr. Indu Partha: Exactly. And as the disease progresses, we need to keep coming back to those other factors that affect cognition that we discussed all the way back in deep dive one of episode one.

Dr. Nick Villano: Right. That’s a great point. I mean, some of the things we should be doing include consolidating any redundant medications, deprescribing higher side effect medications, strategizing how we can optimize adherence to medications that they do really need, but also just continuing to check on sleep health, hearing, and screening for mood issues that could be contributing to these symptoms.

Dr. Indu Partha: And for general deprescribing of medications, remember, focus on what patients are actually taking and create strategies to improve adherence, including having care team members actually go and investigate their home situation and consider removing medications that are harder to take, have higher side effects, or those with diminishing returns.

Dr. Nick Villano: All right. So Indu, what happened to your patient?

Dr. Indu Partha: Well, unfortunately, it turned out she had pretty limited finances and really couldn’t afford to expand her caregiver’s hours very much. So we just basically tried to get creative and looked for ways to get more people to check in on her. Her daughter was fortunately able to adjust her work schedule so that she could come and visit and check in more often, and she called up some of the neighbors to help as well. Of course, we ordered home health.

Dr. Nick Villano: As a hospitalist, I’m usually the one that gets involved when these best laid plans that you just talked about don’t go as expected. A patient submitted because they can’t live at home anymore. The patient’s frustrated and the family so often feel like they saw this coming, but just were powerless to stop it. I mean, it’s really hard and really common.

Dr. Indu Partha: Yeah. I mean, dementia does often feel like a train we just can’t stop. But you know what, Nick? The good news, we have the opportunity to really focus on what we PCPs love doing the best, prevention. So here we go to…

Deep Dive 4: Planning for an uncertain future.

Dr. Laura Perry: The primary care of a person with dementia is largely preventive in terms of thinking about what is likely to go wrong in the next 6 to 12 months, and what can I do about that? I think one of the things we keep emphasizing is having conversations that are looking ahead. Don’t wait to have this conversation until the person needs that help. This is something that should be discussed as part of your advanced care planning early on, shortly after the cognitive impairment has been identified. How will you want to do this so that it’s not a surprise when you’ve gotten to the point where it’s necessary, and that’s not the first time you’re thinking about.

Dr. Nick Villano: And I think it’s so important to say really explicitly that we’re doing this because the time will come that mom can’t make decisions for herself anymore or can’t live alone. And we need to know who’s going to make decisions at that time and what she would want those decisions to be. That’s going to make it so much easier when that time does eventually come.

Dr. Indu Partha: Yeah. And remember, we don’t have to be a lone wolf in all of this. We should look out for other professionals who can help us.

Mary Beth Kuebrich, NP: I’m immediately thinking of who else can help me between visits. So, really leaning on my case management and social work colleagues to start getting to know the patient, talking about, and exploring community resources. Are they eligible for any additional in- home assistance? I think that I really start to think about who can help me on my team when it gets to be tricky situations.

Dr. Nick Villano: Okay. So basically, we know this person’s going to need more and more help, so we want to see what’s available and mobilize the troops early before it becomes an emergency.

Dr. Indu Partha: Yeah. There’s this really uncomfortable Goldilocks zone with dementia where patients still have the capacity to elect to live alone, but they’re really having more difficulty, and family and providers are increasingly worried about their safety.

Dr. Nick Villano: Yeah. I mean, we can’t force these folks to stop living alone, but having a safety net or a backup plan in place made up of services, informed family and friends, neighbors, regular check-ins with providers is huge. I mean, I’ve seen it be the thing that gets patients help when someone in this network sees something as wrong before it turns into an avoidable emergency.

Mary Beth Kuebrich, NP: There’s what we as clinicians think needs to happen, and then there’s what the patient is willing to do. And so I think just keeping that in mind. And another question that I find really helpful when you’re thinking about the need for more care is, how will you know when the plan at home isn’t working anymore? Or what’s kind of your line in the sand where you feel like you can do it? And a lot of times that may be incontinence. So when mom’s incontinent, I’m not going to be able to do it anymore. But knowing that ahead of time, I think really helps them, especially when you’re obsessing their functional status in the stage. As you’re nearing that, you can be talking about this more in kind of planning.

Dr. Nick Villano: Patients often say they want to live alone even as dementia progresses, but I’ve never thought to ask them, when would they no longer feel safe living alone or what quality of life would be acceptable living alone? That would make it a lot easier to know when the time has come to transition to new living situation, like really start that conversation.

Dr. Indu Partha: Yeah. Can you imagine how helpful that would be for their family, for clinicians, if they ever aren’t able to communicate their own wishes to us?

Dr. Nick Villano: Yeah, exactly. I mean, these situations always stress me out. I mean, take COPD, for example. It can definitely be dangerous, but at least someone with worsening shortness of breath usually reaches out for help. I’m not usually sitting and wondering what my COPD patients are doing at home, but dementia can be quietly worsening. We really need alarm bells, eyes on the patient, layers of support to be our warning, our canary in the coal mine.

Dr. Indu Partha: It’s uniquely worrisome territory for clinicians, isn’t it? I mean, who is going to sound the alarm? Who is going to be the bad guy and tell a patient they should move to a facility or stop driving? This really can be so touchy.

Mary Beth Kuebrich, NP: I think these are always hard conversations. And again, we take on a lot of the burden as the PCP and feel like we need to make the most perfect situation.

Dr. Nick Villano: And sometimes I also worry like, am I to blame if I discharge a patient home alone because they refuse the nursing facility that we recommended? If they fall and break a hip and aren’t found for a day or two, I mean, are we at fault?

Dr. Indu Partha: Yeah, you’re not alone in that worry. I feel that sense of dread, too. I wonder if it’s my legal responsibility to get a driver’s license taken away. I think we really do worry so much about patient safety.

Dr. Laura Perry: I think we often find that we’re in this role where we feel like we have to act almost in loco parentis, as though we’re responsible for our patients’ lives. We are not responsible for our patients’ lives, and practically we’re not going to be held responsible for people making bad decisions, even if they have impaired brains, which is what dementias ultimately are, is brain damage. The driving question I think, could be the subject of its own episode of a podcast because it’s really complex and really fraught. And the first thing I want to say about that is probably the most common issue where a patient’s likely to fire their PCP is over a conflict about driving. So the hack that I did when I was in primary care is I had an agreement with my practice partner where I would see all of his patients to have the driving conversation and he would see all of mine so that we could be the bad guy who the patient came back to say, “Can you believe that other jerk of a doctor reported me to the DMV?” and allowed that PCP patient relationship to remain intact. 

Dr. Nick Villano: Sounds like the Geriatrician version of good cop, bad cop.

Dr. Indu Partha: Yeah. The key, though, once again, as Dr. Perry and Mary Beth have already stated, plan ahead, have these conversations before a car accident happens. Outline early on what’s going to be that proverbial straw that breaks the camel’s back that will make someone voluntarily give up their license, invite a caregiver into their home, or move into an assisted living or memory care facility.

Dr. Nick Villano: I feel like I’ve learned so much today Indu, so let’s summarize a little bit. In DeepDive one, we talked about breaking the news of cognitive impairment, how we should find out what our patients understand, and what they’re ready to hear, so we know how to deliver that news. But we should still be very clear about the nature and prognosis of the disease, including that everyone’s trajectory is going to look different, and is going to be hard to predict.

Dr. Indu Partha: And in Deep Dive two, we talked about how cholinesterase inhibitors can provide an actual period of improvement in cognitive symptoms and memantine in behavioral symptoms, but this is in contrast to the monoclonal antibodies, which actually work to slow the worsening of cognitive decline, but the clinical significance of this is still somewhat controversial.

Dr. Nick Villano: And remember that the monoclonal antibodies are approved for mild cognitive impairment and mild dementia. The cholinesterase inhibitors are approved in mild to moderate dementia, and memantine is approved in moderate to severe dementia.

Dr. Indu Partha: And we also have to monitor for side effects. With cholinesterase inhibitors, this can include GI symptoms, muscle pain, joint aches, and the monoclonal antibodies can cause infusion reactions and need regular MRIs to evaluate for edema and microhemorrhages.

Dr. Nick Villano: And in DeepDive three, we talked about deprescribing medications, focusing on those with more side effects that are hard to take, or which may not have as much longitudinal benefit. And ultimately, the best medication list is the one that your patient takes, so strategize what will realistically help them take their medications at home.

Dr. Indu Partha: Well, said, Nick, and a call out back to episode one. Make sure to screen your patients for sleep disturbances, depression, and hearing loss, as they all can have a large impact on brain health. And you are so great at concisely summarizing key points, but I hope you’re okay if I let our experts wrap it up with some key takeaways from Deep Dive 4.

Dr. Nick Villano: Of course, take it away.

Dr. Laura Perry: One is that this really is a longitudinal disease, and you can’t treat the patient well if you’re not looking at where are they now, where are they going to be by following them very regularly, assessing where they’re at and thinking ahead, giving them that information in the bite-size pieces. Point number two, always doing that resources and counseling in the bite-sized pieces that they can handle. I also think of advanced care planning as kind of like this. In some ways, as I think of advanced care planning as a longitudinal process where I’m doing bit by bit at different points depending on their sort of current emotional state of being. Point number three that we really want to take home is that when you’re taking care of a person with dementia, you really have two people that you’re responsible for, your patient, but also their primary caregiver.

Mary Beth Kuebrich, NP: Our overarching goal is to improve the quality of life for the person with dementia and their caregiver. And I think just reinforcing the relationship with the caregiver is so critical, they can be your best teammate in this. And so I think we want to talk to the caregiver and often the caregiver’s the one that has the accurate history that we’re wanting. But I think one thing I always like to practice is that I’m going to talk to the person with dementia first. In all my visits, I’m going to sit and face them. I’m going to ask them questions. They may not give me all of the accurate history, but I want to keep that rapport with my patient and honor them.

Dr. Indu Partha: Wow. It has been a journey, Nick. I guess really app since we’re talking about a disease that requires longitudinal connections and therapeutic relationships between patients, caregivers and clinicians. I hope we’ve helped demystify cognitive disorders just a bit with this episode and the last one. It’s been such a privilege being here with you discussing this really important topic.

Dr. Nick Villano: Thanks to you, Indu, for putting together a great series of episodes. I know we all learned a lot and I’m definitely going to have to listen to this one again. And thanks to our discussants and to the audience for being here and listening. You can all find our show notes, graphics, and more at coreimpodcast.com

References

• Jaqua EE, Tran MN, Hanna M. Alzheimer Disease: Treatment of Cognitive and Functional Symptoms. Am Fam Physician. 2024;110(3):281-293.

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Tags: cognitive screening, dementia, Geriatrics, primary care