#399 ‒ The evolution of Alzheimer’s disease and dementia care: how early detection, personalized treatment, new therapies, and a multimodal approach are changing the landscape | Gayatri Devi, M.D.

Gayatri’s training and clinical focus, why dementia is a spectrum disease, and how personalized treatment is changing Alzheimer’s care [A: 3:45, V: 0:11]

• Alzheimer’s disease is a topic discussed a number of times on the podcast 
• Gayatri is a physician that is near and dear to Peter’s practice
  • She co-manages a number of high risk patients
  • Peter has always been impressed by the way she has taken a very personalized approach to managing this condition

Gayatri is both a neurologist and a psychiatrist 

• She is board certified in multiple specialties: neurology, psychiatry, brain injury medicine, pain medicine, and behavioral neurology
• But her subspecialty is really memory disorders primarily from a neurological perspective

All these other areas allow her to better handle people with cognitive impairment 

As you think about the evolution of your career when you started (which is not that many years ago, you’re still quite young), to where you are today, what has been the biggest shift in your understanding of the dementing conditions that we’re going to talk about today? 

• 1 – Over the years of her practice, she has come to realize that pretty much all dementing conditions and particularly Alzheimer’s disease can present variably depending on the person who has the condition and also depending on comorbidities

“There really is a spectrum aspect to Alzheimer’s and dementias, which people don’t recognize.”‒ Gayatri Devi

• People think of it as an all or nothing disease and that’s NOT true 
• Much like autism, it really can span the spectrum from very mild impairment that doesn’t get worse to severe impairment that kind of deteriorates rapidly
• 2 – What’s really exciting is that the field now almost feels as if she was an infectious disease doctor who is practicing medicine before and after penicillin was discovered.

There are now so many different ways that we can treat dementias, we can personalize our treatment 

• We can give each person the right cocktail of medications that would best benefit them 
• And we now have drugs that can alter the course of the disease, which is absolutely fantastic
• We still have a ways to go, but Gayatri feels like we’re on the threshold of something really grand
• And that’s what Peter wants to talk most about today, but first there’s some groundwork he’d like to lay to bring the listeners along with us 

How Alzheimer’s disease fits within the broader spectrum of dementia: diagnosis, biomarkers, and early pathophysiology [A: 7:15, V: 3:55]

 We are not dealing with binary diseases 

• It’s not like you have vascular dementia or you don’t, or you have Lewy body dementia or Alzheimer’s disease or you don’t

Can you go a little deeper into this idea of what the spectrum of Alzheimer’s disease looks like? 

Define Alzheimer’s disease within the broader context of dementia 

And then walk us through the different subtypes and how a clinician is able to arrive at that diagnosis 

• Dementia is the umbrella term

A dementation of the brain means that there is loss of connectivity between the brain cells that results in a loss of function and it’s a progressive condition 

• There are several different types of dementia, Alzheimer’s being the most common

Gayatri explains, “Alzheimer’s is defined as is a loss of synaptic connections or synaptic connectivity that results in a loss of function that is driven by the presence of extraneuronal amyloid plaques, intraneuronal or intracellular tangles (neurofibrillary tangles), and increasingly what we now know to be inflammation in the supporting microglial cells and other glial cells of the brain substrate that cause cognitive impairment that progresses.”

So the question is, how do you make this diagnosis in a person? 

• And that’s really difficult because you have to really have a high index of suspicion, particularly with people who are very intelligent, people who are very functional, people who are able to compensate very well
  • So that you can have someone who has moderate pathology and even severe pathology, and they can still perform very well in many areas because they have a good brain reserve
  • They have a resilience in their brain that prevents the kind of cognitive and functional deterioration that someone who has less reserve and less brain resilience doesn’t have

And there are many different subtypes of Alzheimer’s disease depending on the part of the brain that’s affected 

• You can have an Alzheimer’s disease that primarily affects memory versus Alzheimer’s that can affect more the visuospatial system
• So it depends on the area of the brain where the pathology tends to predominate and it also depends on secondary conditions
  • Comorbid brain conditions that are present such as Lewy body disease, TDP-43 pathology, argyrophilic grain disease—all of which can inform how the person presents

When you’re looking at Alzheimer’s disease, first of all, you want to establish that the person has these plaques and tangles 

• And that’s something we can get into later because there are 2 groups of thought on that
  • 1 – There are people who will diagnose Alzheimer’s based on biological biomarkers alone
  • 2 – There is another group that says you need to have biomarkers plus clinical symptoms (a functional deficit) to make the diagnosis

⇒ The biomarkers are amyloid, tau, and increasingly neuroinflammation 

Other genetic conditions that are dispositive in their prediction of a person developing Alzheimer’s disease 

• We have talked about the APOE genotype, which is probably one of the most common genetic predisposing factors, although not the strongest

What starts this process? Pathophysiologically, what is the order of operations? 

• Peter wonders if it starts with inflammation?
  • If it starts with the deposition of amyloid?
  • If it starts with the tangles?
  • If it is different in every person?
  • If it is different by location in the brain?
• Generally speaking, it used to be thought that amyloid was the first abnormality that begins in the brain up to 2-3 decades even before the onset of clinical symptoms 
• But now we’re beginning to understand that changes in the inflammatory pathways may predate amyloid deposition by quite some time

So it may be that first neuroimmunological changes, then amyloid, and then eventually down the road tau 

• And that ultimately causes synaptic dysfunction where the synapses, the connections between the nerve cells start to go awry and the person then develops cognitive changes

And that process takes decades 

Gayatri explains, “The whole point, I think with with Alzheimer’s and other dementias is if you can intervene early enough (even as early as your 30s into your 40s) by incorporating anti-inflammatory methodology, anti-inflammatory activities into your lifestyle, then perhaps you can prevent the whole cascade from being triggered.”

The emerging role of neuroinflammation and viral infections in Alzheimer’s disease [A: 13:30, V: 10:45]

One thing Peter has become much more aggressive in his practice is around managing 2 viruses: herpes simplex virus and varicella zoster

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