Anton P. Porsteinsson, MD:
In my experience as a psychiatrist in a geriatric psychiatry clinic, my colleagues in psychiatry often refer patients who are in mid or late life and have anxiety, depression, or bipolar disorder and are beginning to experience some cognitive changes.

Prompting this conversation about brain health is an increase in the interest of patients and our colleagues in this topic. I see that every day, not only in the media and online but also in professional communications and educational opportunities. Professional groups like the American Association of Neurology and World Health Organization have published position statements and papers highlighting that paying attention to brain health across the lifetime is critically important.¹

I believe that health across a lifetime is something that we pay attention to in psychiatry, but we may not think as much about brain health and cognition as part of that. We certainly are very interested in early life experiences and early life events because they increase patients’ risk of depression, anxiety disorders, psychosis, and suicide risk. I think that cognition is also very important.² In the practice setting, as one works with people in middle adulthood and older, this becomes very relevant. Our patients often complain about their attention, concentration, short-term memory and that they are not as quick or as sharp as they used to be.

Anton P. Porsteinsson, MD:
When we think about the current and emerging brain health crisis as it relates to dementia, we have almost 7 million Americans living with Alzheimer’s disease and related dementia right now. We expect that to double to almost 14 million by 2060.³ Psychiatry has to keep an eye out for this tsunami just as us in the Alzheimer's disease field. I know you've been very active in that area and very focused on prevention, Dr. Atri.

Alireza Atri, MD, PhD:
As a cognitive neurologist, I agree with your assessment, Dr. Porsteinsson. Lifespan is increasing. However, the increasing longevity does not correspond with an increase in quality of life. There needs to be vital brain aging, the process of maintaining and optimizing brain health as we age despite changes that occur over time. People are seeing a lot more issues in their own families as they get older. The scourge of dementia is something that takes an incredible economic toll, but it also takes a personal toll on people.

What we appreciate is that, as Dr. Porsteinsson said, throughout the life course, we can modify our risk. Although physical exercise demonstrates potential protective benefits, it does not guarantee immunity from neurodegenerative conditions like Alzheimer’s disease, even among individuals who engage in rigorous athletic pursuits like marathon running. However, as with many aspects of health and lifestyle, engaging in regular physical activity represents a proactive strategy for risk mitigation.

Accumulating data suggest that we can increase not only our cognitive reserve but also our behavioral and emotional reserves through life, and we will talk a little bit about some of that data. 

Yes, psychiatry is on the front lines because, often, psychiatry follows along with cognitive issues that go undetected. Some of the first things people notice are changes in behavior, mood issues, anxiety, and sleep issues. This requires a concerted effort among numerous disciplines to bring it to the forefront.

To appreciate that, these lifestyle interventions have biological effects that can decrease neuroinflammation and improve metabolic changes and energy utilization in the brain. These interventions can affect the pathophysiology of Alzheimer’s disease and how it develops, how it spreads, and what kind of impact it has.

Anton P. Porsteinsson, MD:
When I started in the field, we primarily focused only on the later, full dementia stage of Alzheimer’s disease. However, we now recognize that mild cognitive impairment (MCI) represents an earlier stage in the disease progression. The full dementia stage is characterized by significant cognitive impairment—not only in short-term memory, but also in at least 1 other area of higher cognitive function, such as language, executive function, or visual-spatial function.⁴ These impairments have to be severe enough to lead to functional impairment in quality of life.

Alireza Atri, MD, PhD:
This is where psychiatry, as a specialty, is particularly important because we know the lead time before cognitive symptoms are noticed. Some of the shared risks and symptoms that are caused by Alzheimer’s disease and related conditions manifest themselves very early on and are recognized early on as changes in behavior, mood, sleep, anxiety, and so on.

Anton P. Porsteinsson, MD:
But right now, we are looking at Alzheimer’s disease as a continuum. We have a preclinical stage with no apparent cognitive impairment and this stage may last a couple of decades for those who are having progressive changes in the brain consistent with the pathophysiology of Alzheimer’s disease, that is, increased amyloid-β plaque initiates the pathologic process, followed by tau hyperphosphorylation forming neurofibrillary tangles, which destabilizes neuronal structures. Neuroinflammation driven by microglial activation compounds the amyloid and tau pathologies, ultimately leading to synaptic loss and neuronal destruction.⁵

When that damage is significant enough, the clinical symptoms emerge first as part of MCI, where patients may have isolated impairment in short-term memory that is above the normal changes seen with aging. Then, slowly, they may expand to other areas of cognitive function.

However, people with MCI retain their functional independence. After a duration of approximately 4 years (the mean duration in the MCI stage), things have progressed to a point where patients meet diagnostic criteria for dementia. On average, people with Alzheimer’s disease live between 3 and 11 years after diagnosis, but some can live 20 years or more. My clinical observation is that the mean duration of life after the diagnosis of Alzheimer’s disease dementia is approximately 6 years until death.⁶

This recognition that pathophysiologic changes start early has made a major impact on and caused a certain argument within the field as to how define Alzheimer’s disease.⁷ I know that you have some opinions on that, Dr. Atri.

Alireza Atri, MD, PhD:
Opinions, yes. But, it is complex. Everything you said, Dr. Porsteinsson, is true regarding the lead time. We have an opportunity, in many ways, to recognize the biology that is changing in the brain. There are arguments about what is exactly the cause of Alzheimer’s disease.

We know that elevated amyloid species are toxic and plaques are necessary, as they are part of the definition of Alzheimer’s disease and there is strong evidence from genetics that implicates amyloid, but plaques are not sufficient. As you mentioned, individuals are diagnosed at a later stage, approximately 6 years from diagnosis to death because often, people are not diagnosed in the MCI or even mild dementia stages. It is really in moderate dementia stages that they are usually diagnosed. So, we have this lead time opportunity both for timely diagnosis but also changing the course. Anything related to the brain—whether it's mood changes, sleep disturbances, anxiety, brain fog, or other concerns—is an opportunity to discuss brain health strategies with a psychiatrist. These conversations can help mitigate risks at any stage of life and pave the way for a healthier, better path forward.

The other part that is very interesting is why some people have not only more cognitive reserve. But, even given the same amount of observed pathology in the brain, some have very different manifestations in their abilities, how they are functioning, and even their lifespan.

Some individuals can live 12, 15, or more years even in the symptomatic stages of Alzheimer’s disease.⁸ What gives others that extra something to be able to ward off symptoms and functional decline longer? I think of brain health strategies as, pardon the pun, a no-brainer. It is something that has low risk, can improve people’s quality of life, and can mitigate many kinds of symptoms they may have.

Anton P. Porsteinsson, MD:
Before we talk more about the specifics of how to address some of those risk factors, let me talk a little bit about how Alzheimer’s disease is currently defined.

There are 2 main schools of thought. One is more research oriented and looks at Alzheimer's disease as defined by the presence of biomarkers, whether there are clinical symptoms or not. If a patient has elevated amyloid plaque burden, tau tangles, or other pathophysiologic changes but no clinical symptoms, that patient has Alzheimer’s disease.

There have been significant changes in how we define Alzheimer’s disease during the past couple of decades. The Alzheimer’s Association have revised the criteria for Alzheimer’s disease first in 2011, then 2018, and then again last year.^9,10 The disease is defined by pathophysiologic changes as realized by biomarkers. We see many of our colleagues who push back against that. This biomarker definition is the Alzheimer's Association criteria, previously referred to as the NIA for the National Institute of Aging, so the NIA-AA criteria.

The International Working Group disagreed with the Alzheimer’s Association criteria, where they said that although understanding the pathophysiology and the presence of that through biomarkers is important, not everyone who has those pathophysiologic changes will develop clinical MCI or Alzheimer’s dementia during their lifetime.¹¹

So, do they have a disease or are clinical symptoms a requirement before we can say that someone has Alzheimer’s disease? As I operate on a day-to-day basis in the clinic, I adhere more to the International Working Group, whereas in the research area, I adhere more to the Alzheimer’s Association criteria.

Anton P. Porsteinsson, MD:
Both you, Dr Atri, and I are currently involved in clinical trials with medications to bend the curve, particularly through amyloid-targeting therapies. The AHEAD study (NCT04468659), also referred to as the A3-45 study, evaluates lecanemab, a humanized monoclonal antibody targeting β-amyloid plaques, in patients who have somewhere between intermediate to more significant elevation in amyloid burden. Individuals who are cognitively intact are treated for several years and symptom progression is tracked through cognitive testing and amyloid PET.¹²

Donanemab, which is another humanized monoclonal antibody against a pyroglutamate form of β-amyloid, is being looked at in the Trailblazer-ALZ-3 study (NCT05026866) in a similar way.¹³ Trailblazer-ALZ-3 is treating, for an extended time, people with no cognitive symptoms who have elevation in the phosphorylated tau217 blood biomarker, looking at progression of symptoms and time to clinical dementia as the outcome.

Alireza Atri, MD, PhD:
Even now, in the early symptomatic stages of Alzheimer’s disease, we have 2 drugs that are approved by the FDA for the removal of amyloid plaques: lecanemab and donanemab. Both are approved for adults with MCI or mild dementia due to Alzheimer’s disease who have confirmed elevated β-amyloid levels in the brain. You mentioned that prevention will be even more important with the lecanemab AHEAD studies and Trailblazer-ALZ-3 with donanemab and the remternetug study, DIAN-TU-002 (NCT06647498). In these prevention clinical trials, the treatments to slow clinical decline all target amyloid plaques.

Those are focused on what we call secondary prevention. These are people who have no cognitive impairment yet but have elevated or could have elevated amyloid in their brain, or they have major risk factors, including, for example, dominant risk genes. That is a different area of study, but it does not preclude the fact that lifestyles can really decrease inflammation in the body. Lifestyles can change blood flow, metabolism, and the efficiency of how we clear toxic proteins, including amyloid, tau, and their cousins. 

Anton P. Porsteinsson, MD:
This brings us to the conversation of Alzheimer’s disease biomarkers and what role they might have in psychiatry. Obviously, we often talk about Alzheimer’s disease in different terms than neurology. In psychiatry, the diagnostic terms are minor neurocognitive disorder and major neurocognitive disorder.¹⁴ In some ways, this might be close to the thinking that I just discussed in terms of the syndromal staging of disease.

The FDA-approved biomarkers for Alzheimer’s disease diagnosis are either the amyloid PET scans or the cerebrospinal fluid analyses, which tend to look at ratios between A-beta 42/40, A-beta 42 to total tau or A-beta 42 to p-tau.¹⁵ But we are rapidly seeing blood biomarkers come to the forefront. A lot of these biomarkers are looking at understanding the different aspects of neuropathology, such as amyloid tau, neurodegeneration, loss of synapses, and neuroinflammation. Although these biomarkers are mainly used in research right now, they may become part of disease staging as we move forward.

But still, we are seeing increasing availability of blood biomarkers. And p-tau217 looks like it is rising to the top as a sensitive blood biomarker that reflects, interestingly enough, amyloid plaque burden.

I often get questions from colleagues about the best way to consider biomarkers within clinical practice. I still think that biomarkers are best used as part of a comprehensive evaluation for those patients with cognitive complaints. 

Alireza Atri, MD, PhD:
Thanks, Dr Porsteinsson. I will bridge from what you were just asking to the DETeCD-ADRD criteria, which gives us a framework in every practice setting for older individuals, who may have symptoms or complaints that could be related to the brain, including mood, behavior, thinking, and so on, and then how the biomarkers fit in. Of interest, for the first time, we recently published the Alzheimer’s Association DETeCD-ADRD Clinical Practice Guidelines for evaluation and disclosure of cognitive and behavioral changes and impairments in somebody who is older and in whom we may suspect the impairments are caused by a neurogenerative condition.

This framework is for any practice setting, primary care or subspecialty care.^16,17 It incorporates this new age of biomarkers, how to use it, in whom, and when, into the foundations of good practice of medicine, including taking an appropriate history, and thinking about risk factors.

In other patients, there should be a review of systems not only related to those conditions, but also related to domains of cognition, behavior, and daily function. These practice guidelines formalize a structured interview with the patient and potentially a care partner, what risk factors, including brain health, to focus on, and what standardized instruments could be used for the assessment of these domains.¹⁸ There are lists of assessments that are provided, along with links. Also outlined is how to think about tiers of testing, including standardized kinds of screening instruments, and what first-tier blood work to order and when to add others. What about MRI? When to refer for neuropsychology? In which patients do you want to move on to biomarkers and which ones: FDG-PET, cerebrospinal fluid, or amyloid PET? We know the tau PET and blood biomarkers are still emerging, and they are not quite there for clinical use in a broad population, but they will be in the future. From this perspective, psychiatry and psychiatrists are very well positioned to evaluate and counsel individuals who are older with potentially related symptoms. It is very high yield when there is a mood or other issue to think about cognition.

The counseling pathway is always involved. If there is a relevant condition or a diagnosis, then discussion of brain health and the strategies that can mitigate risk is always relevant.

Anton P. Porsteinsson, MD:
When you say “mitigate,” I think that it is important for us to think about the fact that there have been some very solid publications. The Lancet Commission reviews data on a regular basis. The American Heart Association also has addressed the main risk factors that greatly contribute to dementia risk.¹⁹

Being a psychiatrist myself, I want to highlight some of the things that really increase one’s lifetime risk of developing dementia.

Alireza Atri, MD, PhD:
As a cognitive disorder specialist, brain health strategies, changes, and interventions are always part of my plan. Being a neurology subspecialist does not mean I will become an expert in cardiovascular issues. But I always tell my patients and their care partners that I will partner with them. Let’s think about realistic goals of what things are, maybe, not optimal and can be improved, and how we can move the needle little by little to get there. Occasionally that's smoking or exercise. I could tell them what the ideals at groups levels may be, but what's really important is the exercise that they're willing to start and do. At least to start with, what’s going to be safe and practical for them.

Anton P. Porsteinsson, MD:
Both of us are memory disorder specialists, but there are not nearly enough of us. We can only see a small portion of the people who have concerns about their cognition. We have to very much depend on our colleagues who may have a broader practice, be that in psychiatry or in neurology, to be sensitive to brain health discussions because the wait times to see a brain disorder specialist, even in the most optimal setting, is 6 months and can be a year and a half in some of the more rural or less resourced areas.

Anton P. Porsteinsson, MD:
Some risk factors are sensory impairments—hearing loss, visual impairment—which we often see in our patients. But untreated depression is more significant factor in brain health. We know that stress matters. We know that traumatic brain injury can increase risk as can physical inactivity, smoking, obesity, excessive alcohol use, and social isolation.

The criteria from the Lancet Commission often omit sleep quality.²⁰ Disrupted sleep can have a very negative impact as well.²¹ These are all things that we see very frequently in psychiatry. Some of the things that we know matter are basically reducing or stopping smoking and alcohol use, treating depression, helping improve sleep disruptions, and helping deal with and manage anxiety.

Alireza Atri, MD, PhD:
The same things that apply to sleep hygiene also apply to diet changes; there is always a place for gradual, sustainable modifications rather than drastic overhauls that are difficult to maintain. To have these discussions on diet in a framework that is referrable to the brain — there's always an opportunity for brain health education, appreciation, and planning.

Anton P. Porsteinsson, MD:
A healthier diet would be something like a Mediterranean diet or the MIND diet, that avoids red meat, high-fat food groups like butter or stick margarine, cheese, sweets, pastries, fried or fast food and focus more on vegetables, nuts, berries, beans, whole grains, seafood, poultry, olive oil, and possibly wine.^22,23

Anton P. Porsteinsson, MD:
We can also encourage people to focus on lifelong cognitive stimulation—be it at work or school—because, over a lifetime, this truly matters.²⁴ This can affect one’s leisure activities as well and can lay the foundation for some cognitive interventions.

Anton P. Porsteinsson, MD:
What is often overlooked is the incredible impact of social isolation and the fact that dementia is much higher in socially isolated individuals.²⁵ This is a chronic problem for our patients. Mental disorders push people quite a bit toward social isolation, especially older individuals. I think that the move toward social isolation is changing a little bit among the younger generation.

Social isolation is truly toxic.²⁶ Helping people reintegrate into their community and improving their social activity is tremendously important.

Anton P. Porsteinsson, MD:
The questions really are: What is the process here? What do we do? Where do we focus our attention? I applaud the psychiatrists who have been actively exploring with their patients if there are changes in their cognitive behavior.

A sticky issue that can emerge in psychiatry, especially working with adults, is that we characteristically work with individual patients, and confidentiality is incredibly important. Nevertheless, family members may need to become involved but choosing the right time and moment is often a challenge. When is the right time? Are the patients okay with that? Or do they see that as a breach of the relationship between the psychiatrist and them. It is something that we need to be aware of.

In memory disorders, having outside input in terms of the symptoms or functional decline that someone is experiencing is pivotal. That is not always easy and must be handled in a sensitive manner. One has to ask the patient permission to bring in outside parties. I think that that is even more sensitive in psychiatry than in other fields of medicine., but it is difficult to do the right sort of assessment without it.

Family may be really interested in what the modifiable risk factors are and how can they help ensure that those modifications take place. But, because of patient confidentiality, I think that it is critical to have a conversation and to be very transparent about whom you're communicating with and making sure that everyone is in agreement with basically who's in the room.

Alireza Atri, MD, PhD:
I would also add that one of the major strategies is to always partner with and have goal-setting with the patient: Put it in the setting of education about brain health and how it could affect their life span and also the condition they are seeing you for, such as mental fog, memory issues, attention issues, and so on.²⁷ Helping from the very beginning to set goals together on how someone who can be a partner with them is going to be important in improving their brain health, and to engage them to get that buy-in. It may take a while. There's that knowledge and then there's that appreciation. Bringing them to an appreciation that these brain health strategies apply to them and how they could affect their goals in the short-term, intermediate-term, and long-term. Ultimately, it comes to people knowing about what their changes are and what can be done about them. The pillars of medical ethics include autonomy, respect for persons, and justice.

The data show that people generally want to know about their brain health. As healthcare professionals, we can help them appreciate why brain health is important because we can always do something about it. I always try to explain to patients and families how treatment can improve their brain health and can affect pathologic change in their brain, their energy, their mood, etc. There is always that opportunity.

Anton P. Porsteinsson, MD:
I agree that people want to know more if there is something they feel they can do about their futures and if you can offer potential positive actions.

Keep your eyes and ears open for symptoms of cognitive change. Think about implementing brain health discussion into your practice. See if your patient is bringing it up. If a family member raises a concern, you can proactively screen for this by embedding questions about cognition within the standard medical review of systems. For psychiatry, some of these positive lifestyle modifications that are applicable to the risk factors identified by the Lancet Commission can work not only to bend the curve on cognitive health, but also enhance compliance with the treatment of depression, anxiety, and other conditions that we deal with on a regular basis. Linking brain health to wellness is an important strategy.

Finally, this takes time and effort. It is important to be able to bill for this and get appropriate reimbursement. I think that there are 3 main ways to do that. You can, as appropriate, bill based on the problem-focused visit relevant to the patient’s diagnosis. If you are mainly focused on counseling and care, you can bill for that as relevant to the patient's diagnosis. Finally, what I use in my kind of narrow specialty setting, my colleague and I bill a lot with time-based coding as relevant to the patient diagnosis.

Alireza Atri, MD, PhD:
I agree, brain health for our specialties of psychiatry and neurology is really an essential pillar that we have to probe. They should be part of our standard review of systems because the conditions that we are addressing are often cognitive behavioral impairments.²⁸ They really are part of and relevant to how we manage it.

I think there will be many opportunities, hopefully, in the decade to come for us to be able to even do more of this as the evidence base increases.