Spring 2025

Spring 2025 Issue

Cognitive Function and Autoimmune Disorders
By Lindsey Getz
Today’s Geriatric Medicine
Vol. 18 No. 2 P. 18

Exploring the Developing Research

When patients experience a sudden onset of confusion or memory loss, it can be scary for caregivers and family members to witness. Patients might be not only misplacing items but also putting them in nonsensical locations, losing track of their thoughts, or starting to forget important details. When this occurs suddenly, it is important to determine why, and in some cases, it could even be related to an autoimmune disease.

There are more than 100 different known autoimmune conditions in which the immune system mistakenly attacks one’s own body. It’s thought that because the immune system weakens as one ages, many autoimmune conditions become less active. But, because of this, autoimmune conditions might be overlooked or missed entirely in the aging population. This is concerning as autoimmune conditions can lead to a variety of potential symptoms—including even potential inflammation in the brain, resulting in cognitive dysfunction. Researchers are trying to better understand the intersection between autoimmune conditions and cognitive health.

“There is indeed a link between the immune system and the brain,” says Paula V. Barreras, MD, a neurologist with Cedars-Sinai in Los Angeles. “We know that they influence each other. While the immune system is supposed to keep everything regulated, when it is exposed to certain stimuli or that regulation fails, we know those cells can take the wrong signal to the brain and either directly cause damage or alter how the brain cells behave. This can manifest as cognitive changes.”

Barreras says that this includes a family of autoimmune conditions that are not directly associated with brain inflammation like lupus, sarcoidosis, type 1 diabetes, Graves’ disease, and rheumatoid arthritis (RA). While some disorders like multiple sclerosis directly cause brain lesions, these other autoimmune conditions usually do not. There are also cases of autoimmune encephalitis, where there is direct inflammation of the brain driven by the immune system.

“We are realizing that some of these patients do have cognitive symptoms, which is why there is a growing interest in investigating the link between the immune system and brain health,” she explains. “Brain fog is the most common cognitive symptom that we see, but there can also be a more dramatic decline in cognition—and that can be quite distressing for patients. An MRI and spinal fluid can also look normal despite these symptoms, and overall, this is not very well understood.”

Brain fog is typically described as confusion, forgetfulness, or difficulty concentrating. It’s critical to keep in mind that pain, stress, and sleep issues, which are often associated with autoimmune conditions, can also sometimes lead to brain fog.

Of course, it’s the dramatic decline in cognitive health that is most concerning of all. This can have a significant impact on daily life. These patients might suddenly lose their independence due to the rapid decline in their cognition.

Unfortunately, there is very little discussion around how autoimmune conditions can impact the brain, says Eoin P. Flanagan, MB, BCh, an autoimmune neurologist at Mayo Clinic in Rochester, Minnesota.

“Many people understand, for instance, that if you have dermatitis and rub a steroid cream on it, it will go away. Or, if you have RA, it will attack the joints, but steroids will help make the joints feel better,” he explains. “But people rarely talk about the immune system’s impact on the brain. When the immune system attacks the brain, it can manifest itself in a few different ways. One is memory difficulty or cognitive dysfunction. This is typically seen as a rapid-onset symptom with noticeable memory loss or confusion occurring seemingly overnight.”

Autoimmune Symptoms and Neurodegenerative Disease
Diagnosing autoimmune-related cognitive decline is not always easy, particularly in patients who do not have an already-diagnosed autoimmune condition. If patients initially present with the onset of cognitive symptoms, it can be misleading.

When the cognitive decline is severe, patients may be mistakenly diagnosed with a neurodegenerative condition like Alzheimer’s-related dementia, Flanagan says. In fact, up to one-third of people with autoimmune etiologies initially receive a diagnosis of a neurodegenerative condition, he says. But this can send patients down the wrong path.

“It can be devastating for patients to be labeled with a neurodegenerative disease but actually have an immune-mediated dementia because they’re missing out on a treatment that can reverse their symptoms,” Flanagan explains. “If treatment is delayed, patients tend not to respond as well. It’s important to recognize this condition because you might miss your opportunity for treatment.”

Coined “autoimmune dementia,” or autoimmune encephalitis, the condition can mimic a neurodegenerative disease, but symptoms typically come on much more rapidly. Flanagan says that while a condition like Alzheimer’s would progress relatively slowly, with the decline happening over a period of many months, autoimmune dementia could lead to cognitive decline in a matter of days.

“Rapid decline in memory—over a matter of days—is a red flag that this might not be a neurodegenerative condition,” Flanagan says. “We know that in a disease like Alzheimer’s, the memory loss trickles in slowly. But autoimmune patients might literally be fine one day and then suddenly experience a rapid decline, noticeable to family and friends.”

Some of these patients may also experience seizures.

“Autoimmune dementia can be accompanied by twitches that are actually seizures,” Flanagan says. “This can happen many times a day—where a patient may suddenly drop something. These twitches come and go away but are a marker of an autoimmune condition.”

Barreras says that seizures are a key symptom to watch for—and they can be subtle.

“These seizures are not always the grand mal ones that are accompanied by body shaking,” she says. “Sometimes it’s just a behavioral pause or a moment of confusion. If the family reports something like this, it’s important to explore whether there could be anything further that would suggest seizures. While it’s true that seizures can occur with neurodegenerative conditions, that is generally much later on, whereas these seizures are occurring early on.”

Flanagan adds that another marker for seizures is unexplained goosebumps. Clinically, this is known as ictal piloerection. This occurs when the seizures originate from the temporal lobe of the brain.

Other possible symptoms that could be clues for autoimmune dementia include headaches and even psychosis.

Knowing that autoimmune conditions can have this type of impact on the brain, Barreras says that it’s important for primary care physicians to be careful not to assume all cognitive decline is automatically neurodegenerative in nature. Doctors need to further screen patients who have some of these red flags.

“Certainly not every patient who comes in with cognitive decline needs to be screened for an autoimmune condition, but these red flags are important to look for,” she adds. “Missing this diagnosis can be a significant setback for the patient.”

What makes proper diagnosis so critical is the fact that autoimmune dementia is reversible, whereas a neurodegenerative disease is not, Flanagan explains. But that window of reversibility is only about six to 12 months, he adds. If a proper diagnosis is not made, there could be irreversible brain damage. The initial treatment of autoimmune dementia typically involves using high-dose steroids.

For the less serious cognitive effects of autoimmune conditions, treating the autoimmune condition itself also typically leads to improved brain function.

“Even though it’s much less common, making the proper diagnosis of an autoimmune-related cognitive problem can be life-changing,” Flanagan says. “I just had a patient in my office who had symptoms for three or four months, had seen other doctors, and had not gotten the right answers. Now, he’s at the Mayo Clinic and receiving immediate immunotherapy treatment. While we do not have any treatments that can reverse neurodegenerative conditions, with autoimmune conditions, immunotherapy could make a difference in cognition after just one treatment.”

Testing and Treatment
Making the diagnosis of an autoimmune-related condition is not always simple. Sometimes the MRI report can come back as normal, but Barreras says to make sure the MRI is done with contrast as this can make brain inflammation more visible.

Flanagan agrees that an MRI with contrast can be useful as in around one-third to even one-half of patients, brain inflammation is noticeable.

“With Alzheimer’s, we just see loss of brain tissue, but we don’t see inflammation,” he continues. “With a brain MRI, we are also always ruling out brain tumors as a cause for cognitive decline.”

“If you’re sending out spinal fluid for markers of Alzheimer’s—which we can do now—we can also look for markers of inflammation,” Barreras says. “Sometimes the antibodies that are associated with autoimmune encephalitis do not show up in blood but show up in spinal fluid. If we’re already looking into Alzheimer’s, it may also be worth looking into an autoimmune condition just in case it’s mimicking neurodegenerative dementia.”

Flanagan agrees that looking into whether an autoimmune condition might be attacking the brain can definitely start by looking for antibody biomarkers in the blood or spinal fluid.

“We have now identified around 70 different markers of autoimmune dementia, so we really can make a more definitive diagnosis with an antibody test these days,” he says. “Here at Mayo Clinic, we test over 200,000 samples per year, looking for these. They are rare, but it’s so important to find them. It’s also important to note that sometimes an underlying cancer is the cause of the problem, which the patient may not even know that they have.”

“When the immune system is trying to fight cancer, it can get confused and attack the brain,” Barreras says. “So, if we’re finding cognitive symptoms that we suspect are related to the immune system, we do need to look for cancer. Cancer in the older adult population is also more common. If a patient presents. with cognitive symptoms, it may be worth prescreening for signs of cancer. Has the patient been losing weight or experiencing night sweats? These may point to cancer. Sometimes, when we identify the cancer and treat that, the cognitive symptoms also improve.”

Flanagan says that for autoimmune dementia, a high dose of steroids is the first step of treatment. He adds that the Mayo Clinic has found that 64% of patients with autoimmune dementia respond to first-line therapy.

In addition, there are other treatments that can go further and prevent relapses. This includes plasmapheresis (or plasma exchange), which involves removing the antibodies from the blood. There is also intravenous immunoglobulin, which can deliver antibodies that will help neutralize the unwanted antibodies. In most cases, Flanagan says that patients can be weaned off of immunotherapy treatments in two to five years.

“In general, we have made great progress in the last 20 years, having discovered new antibodies but also understanding how specific pathways of the immune system can go awry,” Flanagan continues. “We can now give treatments that are more targeted and dampen down the immune system but not so broadly like chemotherapy does.”

Seeking More Answers
Since a primary care practitioner is often the first stop a patient and their family make when new symptoms emerge, it’s important that doctors keep an open mind when presented with cognitive decline. There are times when this can require some out-of-the-box thinking.

“Caregivers are important, too, in recognizing the red flags of possible autoimmune causes of decline and advocating for testing if there are concerns,” Barreras says. “It is important for doctors to ask caregivers about these symptoms and not only ask the patient. Caregivers may notice subtle seizures, goosebumps, personality changes, and have a better sense of the temporal evolution of symptoms.”

In some cases, a specialist may be warranted. Sometimes, referring to a neurologist is the next step. “If there is concern that an autoimmune condition may be the cause of cognitive decline, a neurology referral and work-up is a reasonable next step,” Barreras says. “There are neurologists who specialize in dementia along with those who are well-versed in autoimmune conditions like neuroimmunologists.”

Of course, finding the right specialist can be a challenge of its own. The link between autoimmune conditions and cognitive health continues to be researched and is not universally well understood so missed diagnoses are likely common.

“Just being aware that not every cognitive symptom in an older patient is always related to Alzheimer’s disease is an important consideration,” Barreras says. “In talking about autoimmune diseases, it’s also important to mention that when a patient is taking a treatment to suppress their immune system, they will be at higher risk of infections in the brain. For instance, progressive multifocal leukoencephalopathy is a rare but very serious brain infection.”

Barreras says that any time there is a significantly rapid decline in a patient’s cognitive health, it requires some extra questions and screening.

Flanagan agrees. “If a patient and their family is seeking care for a rapid progression of cognitive symptoms, it warrants a referral to a neurologist or in some cases, going through the emergency room,” he says. “That rapid onset is a big red flag, and you may need to send the patient to the hospital to at least get the process started in figuring out what’s going on.”

— Lindsey Getz is an award-winning freelance writer in Royersford, Pennsylvania.