The study shows for the first time that Chlamydia pneumoniae can reach the retina—the tissue lining the back of the eye—where it triggers immune responses linked to inflammation, nerve cell death and cognitive decline.

“Seeing Chlamydia pneumoniae consistently across human tissues, cell cultures and animal models allowed us to identify a previously unrecognized link between bacterial infection, inflammation and neurodegeneration,” said Maya Koronyo-Hamaoui, PhD, professor of Neurosurgery, Neurology, and Biomedical Sciences at Cedars-Sinai Health Sciences University and the leading, senior author of the study. “The eye is a surrogate for the brain, and this study shows that retinal bacterial infection and chronic inflammation can reflect brain pathology and predict disease status, supporting retinal imaging as a noninvasive way to identify people at risk for Alzheimer’s.”

To conduct the study, researchers used advanced imaging, genetic testing and protein analysis to examine retinal tissue from 104 individuals, some with normal cognition, some with mild cognitive impairment and some with Alzheimer’s disease.

They found significantly higher levels of Chlamydia pneumoniae in the retinas and brains of people with Alzheimer’s disease than they found in people with normal cognition. The higher the bacterial levels detected, the more severe the brain changes and cognitive decline investigators found.

Higher levels of the bacterium were more common in people who carried the APOE4 gene variant, a known risk factor for Alzheimer’s disease.

Investigators also studied human neurons in the lab and in laboratory mice with Alzheimer’s disease. In both, infection with Chlamydia pneumoniae increased inflammation, nerve cell death and cognitive decline, showing the bacterium can accelerate disease processes. The infection also triggered production of amyloid-beta, the protein that accumulates in the brains of people with Alzheimer’s.

The findings were driven by co-first authors Bhakta Gaire, PhD, and Yosef Koronyo, MSc.

“This discovery raises the possibility of targeting the infection-inflammation axis to treat Alzheimer’s,” said Timothy Crother, PhD, co-corresponding author of the study and research professor at Cedars-Sinai Guerin Children's and the Department of Biomedical Sciences at Cedars‑Sinai.

The findings suggest that targeting chronic bacterial infection—and the inflammation it triggers—could represent a new treatment strategy. The research also supports potential use of the retina as a noninvasive way to help diagnose and monitor the disease.

Additional Cedars-Sinai authors include Bhakta Gaire, Yosef Koronyo, Jean-Philippe Vit, Alexandre Hutton, Lalita Subedi, Dieu-Trang Fuchs, Natalie Swerdlow, Altan Rentsendorj, Saba Shahin, Daisy Martinon, Edward Robinson, Alexander V. Ljubimov, Keith L. Black, Jesse Meyer, and Moshe Arditi.

Other authors include Julie A. Schneider, Lon S. Schneider, Debra Hawes, Stuart L. Graham, Vivek K. Gupta, and Mehdi Mirzaei.

Funding: This work has been supported by the NIH/NIA grants R01AG056478, R01AG055865, and AG056478-04S1 (M.K.H.), R01AG075998 (M.K.H. and T.R.C.), and Alzheimer’s Association grant AARG-NTF-21-846586 (T.R.C.). MKH is also supported by The Goldrich and Snyder Foundations. ER has been supported by The Ray Charles Foundation.

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“Previous studies have shown that transfusions of blood or plasma from young mice improved cognitive decline in older mice, but that is difficult to translate into a therapy,” said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute and senior author of the study. “Our approach was to use young immune cells that we can manufacture in the lab—and we found that they have beneficial effects in both aging mice and mouse models of Alzheimer’s disease.”

The immune cells, called mononuclear phagocytes, circulate throughout the body disposing of harmful substances, but become less effective as we age.

The investigators used human induced pluripotent stem cells, which are adult cells that have been taken “back in time” to an early embryonic state, to generate young mononuclear phagocytes. When the young cells were infused into aging mice or a mouse model of Alzheimer’s disease, investigators noted several important changes.

First, the mice receiving the young cells performed better on memory tests than mice without cell treatment. These mice were also found to have more “mossy cells” in the hippocampus, a brain region critical for learning and memory.

“The numbers of mossy cells decline with aging and Alzheimer’s disease,” said Alexendra Moser, PhD, a project scientist in the Svendsen Lab and lead author of the study. “We did not see that decline in mice receiving young mononuclear phagocytes, and we believe this may be responsible for some of the memory improvements that we observed.”

Mice receiving the young mononuclear phagocytes also had healthier immune cells, called microglia, in their brains. These microglia use long thin branches to detect and clear debris and damaged cells. The branches shrink and retract due to aging and Alzheimer’s disease, but they remained long and healthy in mice receiving the therapy.

The mechanism behind the effects in the brain remain to be established. As the young mononuclear phagocytes did not appear to enter the brain, investigators believe the cells may have worked indirectly.

The cells could have released antiaging proteins or even tiny particles called extracellular vesicles, which are small enough to enter the brain. Or they could have absorbed pro-aging factors from the blood to keep them out of the brain. The mechanism of protection is the focus of ongoing studies to determine the most effective way to turn these findings into a therapy that could be used in a clinical trial in patients. 

“Because these young immune cells are created from stem cells, they could be used as personalized therapy with unlimited availability,” said Jeffrey A. Golden, MD, executive vice dean for Education and Research. “These findings show that short-term treatment improved cognition and brain health, making them a promising candidate to address age- and Alzheimer’s disease-related cognitive decline.”

Additional authors include Luz Jovita Dimas-Harms, Rachel M. Lipman, Jake Inzalaco, Shaughn Bell, Michelle Alcantara, Erikha Valenzuela, George Lawless, Simion Kreimer, Sarah J. Parker, and Helen S. Goodridge.

Funding: This work was supported by the Universal Sunlight Foundation, the Cedars-Sinai Center for Translational Geroscience, and the Cedars-Sinai Board of Governors Regenerative Medicine Institute.

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Still, more than 90% of Alzheimer’s disease trials do not yield the hoped-for result, said Mitzi Gonzales, PhD, director of Translational Research in the Jona Goldrich Center for Alzheimer’s and Memory Disorders. There is still something to learn from each study, Gonzales said.

“Even trials that aren’t considered successful are incredibly important in shaping our scientific knowledge,” Gonzales said. “Trials that show us that one pathway isn’t working can push us in new directions.”

That was the case with recently published results of a trial Gonzales led testing a drug called rapamycin. In preclinical studies, rapamycin was associated with increased longevity and reduction in many age-related symptoms and conditions.

“Data from preclinical studies showed rapamycin reduced buildup of amyloid beta and tau proteins in the brain, which we know are associated with Alzheimer’s disease,” Gonzales said. “We were hoping to see similar results in humans.”

Instead, levels of amyloid and tau increased, Gonzales said.

“That result has raised its own scientific questions and led to some other avenues of research,” Gonzales said. “So it has been helpful for pushing us in new directions, including looking at whether it might be more effective in earlier-stage disease.”

Samples—such as blood and cerebrospinal fluid—taken during unsuccessful clinical trials can also lead to breakthroughs down the road, said Sarah Kremen, MD, director of the Neurobehavior Program.

“The pivotal A4 study tested a drug called solanezumab in cognitively normal people with elevated amyloid,” Kremen said. “The drug did not improve cognition or remove amyloid from the brain, but it was the first time that we'd ever studied anybody who was asymptomatic but at risk. It was a really big deal.”

Studies done with samples from that trial contributed to a larger body of work showing that a biomarker called pTau217 can be an early indicator of Alzheimer’s disease. And that marker is used in the first Food and Drug Administration-approved blood test for the accumulation of amyloid plaques in the brain, Kremen said.

Gonzales and Kremen noted the many reasons Alzheimer’s disease has proved so challenging, including its multiple likely causes, the fact that these factors are present for many years before the disease is detectable, and the complexity of the brain itself.

“The brain is not as well understood as other organs and the processes underlying neurodegenerative disease are complex,” Kremen said. “It will take time—and many more clinical trials—to unravel all the different mechanisms behind Alzheimer’s disease.”

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“We found that by using gene editing to boost ACE in immune cells called microglia, which we believe become exhausted in the brains of patients with Alzheimer’s disease, we supercharged those cells and seemed to restore them to full function,” said Warren Tourtellotte, MD, PhD, professor of Pathology and Laboratory Medicine, Neurology, Neurosurgery, and Biomedical Sciences at Cedars-Sinai, and senior author of the study. “This allowed the microglia to clear the brain of the amyloid plaques associated with symptoms of Alzheimer’s disease and to reverse neurodegeneration and cognitive decline.”

To perform their experiments, investigators used genetic engineering to develop laboratory mice that accumulated amyloid plaques in their brains and overexpressed ACE in their microglia.

“The overexpression of ACE had a profound effect on the Alzheimer’s-related brain changes in these mice,” Tourtellotte said. “Their brains had fewer amyloid plaques and damage to neurons, and the connections between them appeared to be rescued. In addition, when ACE was expressed in microglia in these mice their performance in learning and memory tests was markedly improved.”

The next step in this line of research is to show that this same biology exists in human microglia, Tourtellotte said. While more studies are needed, these findings might eventually lead to creation of a cell-based therapy that would work either independently or along with other Alzheimer’s disease treatments.

“Scientific discovery is the key to developing treatments that will help us overcome Alzheimer’s disease, which affects more than 7 million people in the U.S. and those who love them,” said Nancy L. Sicotte, MD, chair of the Department of Neurology at Cedars-Sinai. “These findings, from the first pilot project to receive funding from the Jona Goldrich Center for Alzheimer’s and Memory Disorders at Cedars-Sinai, point to a promising new direction for future work and possible new treatments.”

Additional authors include Andrew R. Gomez, Hyae Ran Byun, Shaogen Wu, A. K. M. Ghulam Muhammad, Jasmine Ikbariyeh, Jaelin Chen, Alek Muro, Lin Li, Kenneth E. Bernstein, and Richard Ainsworth.

Funding: This study was supported by NIH grant nos. RF1-AG074365 and R01-AG074365 to W.G.T., NIH grant no. R01-AI164519 to K.E.B. and a Cedars-Sinai Goldrich Alzheimer’s Center grant to W.G.T. and K.E.B.

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Although the APOE gene is known to influence Alzheimer’s risk, experts emphasize that genetics alone cannot predict whether someone will develop the disease. Instead, experts recommend making healthy lifestyle choices to help maintain brain health.

Tan, the Carmen and Louis Warschaw Chair in Neurology and director of the Maxine and Bernard Platzer Lynn Family Memory and Healthy Aging Program, told Prevention engaging the brain in new and different activities is one of the best ways to reduce dementia risk.

“Brain games, crossword puzzles and Sudoku are meant to challenge specific areas of the brain, but our minds are complex, and different areas serve different functions,” he said. “Think of it like cross-training for the brain, because different activities give you a better chance of having the totality of your mind stimulated and engaged.”

Tan told Prevention regular physical exercise also stimulates the brain and “undoubtedly reduces the risk for heart disease, stroke and other vascular phenomena.”

He said certain vitamin deficiencies can affect memory and recommended speaking with a physician about whether supplements could help.

“If your vitamin B12 is low, it needs to be supplemented, because brain cells need B12 to function,” he said. “And there is a link between lack of vitamin D and dementia, so it can be good to take a supplement.”

Other ways to help reduce Alzheimer’s risk include managing stress, eating plant-based and lean proteins, improving sleep and staying socially connected.

Click here to read the complete article from Prevention.

“In older adults, higher levels of amyloid beta and tau have been associated with poorer memory and cognition," said Mitzi Gonzales, PhD, director of Translational Research in the Jona Goldrich Center for Alzheimer’s and Memory Disorders at Cedars-Sinai and lead author of the study. “Our study found that this was also true in adults age 55 and younger—a period thought to be important for prevention. We also found higher levels in individuals with a higher genetic risk for Alzheimer's disease. Future studies should examine memory and cognitive changes over time and look at why some individuals remain mentally sharp despite having high levels of these proteins, to provide important clues about maintaining cognitive health over the lifespan.”

The findings highlight the importance of understanding the effects of amyloid beta and tau proteins on memory and thinking abilities at earlier ages. The work could also help focus dementia-prevention efforts in younger at-risk populations.

Additional authors: Adrienne O’Donnell, Saptaparni Ghosh, Emma Thibault, Georges El Fakhri, Sudha Seshadri, Jeremy Tanner, Claudia L. Satizabal, Charles S. Decarli, Keith A. Johnson, Alexa S. Beiser, Matthew Pase.

Funding: National Institutes of Health, Grant/Award Numbers: N01-HC-25195, HHSN268201500001I, 75N92019D00031; National Institute on Aging, Grant/Award Numbers: RF1AG059421, R01AG054076, R01AG049607, R01AG033090, R01AG066524, R01NS017950, R01AG077472, P30AG066546; National Health and Medical Research Council of Australia Investigator, Grant/Award Number: GTN2009264. 

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“The retina, a layer of tissue at the back of the eye, is part of the central nervous system and is directly connected with the brain,” said Maya Koronyo-Hamaoui, PhD, professor of Neurosurgery, Neurology and Biomedical Sciences at Cedars-Sinai and senior author all three studies. “It has similar cell types and vascular structures to the brain, but is not shielded by bone, so it is more accessible to noninvasive imaging. Our latest research unearths new details about the eye-brain connection.”

Tau

Tau is a protein that helps stabilize the structure of nerve cells in the brain and the retina and is one of the key markers of Alzheimer’s disease. When tau disengages from nerve cells it can form tangles that interfere with cellular function and contribute to cognitive decline.

In a study published in the peer-reviewed journal Acta Neuropathologica, Koronyo-Hamaoui and fellow investigators compared retinal tissue from 45 patients diagnosed with Alzheimer’s-related cognitive impairment or dementia with tissue from 34 individuals with normal cognition or non-Alzheimer’s forms of dementia.

Investigators found that higher levels of abnormal tau in the retina corresponded to levels of tau in the brain, other brain changes related to Alzheimer’s disease, and cognitive decline.

Vessels and amyloid plaques

Clumps of a protein called beta-amyloid, also known as amyloid plaques, are another hallmark of Alzheimer’s disease.

In a study published in the peer-reviewed journal Acta Neuropathologica Communications, Koronyo-Hamaoui and co-investigators used leading-edge imaging and image-processing technology to compare amyloid plaques in the retinas of living patients who had early-stage cognitive impairment with those in individuals who had normal cognition.

Thirty-four patients underwent retinal and brain imaging, and cognitive testing. Analysis in 28 patients revealed two to three times as many plaques clustered near blood vessels in the retinas of patients with mild cognitive impairment or Alzheimer’s disease when compared with individuals with normal cognition. The numbers and position of the plaques correlated with cognitive decline and physical changes in the brain.

Diagnosis in development

Koronyo-Hamaoui’s team also published a review article in the peer-reviewed journal Progress in Retinal and Eye Research that detailed additional Alzheimer’s disease biomarkers that have been identified in the retina.

These include reduced blood flow, deposits of amyloid-beta proteins inside blood vessel walls, damage to the barrier that prevents harmful substances from entering retinal tissue, inflammation, and damage to nerve cells.

“Imaging technology now being developed will allow us to see these changes in patients in clinical settings,” said Keith L. Black, MD, chair of the Department of Neurosurgery and the Ruth and Lawrence Harvey Chair in Neuroscience at Cedars-Sinai and co-author of these studies. “This technology, which is noninvasive and affordable, allows us to see changes in the cells and blood vessels in tremendous detail.”

Black and Koronyo-Hamaoui envision this technology as a tool to screen patients in primary care settings, with those who show features suggestive of Alzheimer’s disease referred for additional testing, such as a PET brain scan or cerebrospinal fluid or blood test. The technology could also assess disease progression and the effectiveness and safety of new treatments.

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The study detailed how the tool, a free and publicly available software platform, analyzes and compiles data and information—including new peer-reviewed studies—to answer researchers’ queries. The key to the tool’s success is a new type of large language model, said Jason H. Moore, PhD, professor and chair of the Department of Computational Biomedicine at Cedars-Sinai and senior and corresponding author of the study.

Large language models are a specific type of AI programs that can distill large amounts of data—like medical studies, books, articles and interviews—and use that data to create new content.

“The large language model approach we developed uses knowledge stored in a special database, called a knowledge graph, that specializes in capturing the relationships between entities such as drugs and genes,” Moore said.

Historically, the main challenge in using large language models to generate content is ensuring quality, accuracy and reliability of the generated responses.

The Cedars-Sinai technique, however, moved past this challenge by using the graph-of-thoughts technique—a framework that allows investigators to break down a problem into subproblems, and turn the information generated by the large language models into a visual graph.  

The Cedars-Sinai tool also incorporates retrieval augmented generation, or RAG, which augments large language models with external data sources that provide relevant facts and context. Together, this powerful tool unearths efficient and accurate data and information about varying conditions and diseases, including Alzheimer’s disease, which was the focus of the research study published in Bioinformatics.

The open-source software, called Knowledge Retrieval Augmented Generation ENgine—or KRAGEN—is publicly available on GitHub, a cloud-based platform that helps developers collaborate and manage code. To date, the software has received more than 400 endorsements from users.

To demonstrate the usability of the database, Moore and team used KRAGEN to generate data on Alzheimer’s disease, including data on genes, drugs and other aspects related to the condition. Investigators asked the database questions like, “What drugs bind to the proteins APOE and PTAU?” And “Which are genes associated with Alzheimer’s disease?”

Instead of receiving a list of data points for their question, investigators received a synthesized summary of information.

“This AI approach is a step toward fully automating the analysis of Alzheimer’s disease data by incorporating knowledge generated from previous biomedical research studies,” Moore said.

As a next step, investigators are working on ways to integrate KRAGEN into Cedars-Sinai’s AI software for automated machine learning analysis of complex biomedical data.

“This advance is a big step toward allowing users to issue spoken commands to perform analyses in minutes, that otherwise could take weeks or months,” said Craig Kwiatkowski, PharmD, senior vice president and chief information officer at Cedars-Sinai, who was not involved in the study. “It’s encouraging to see the potential of this tool to impact AI-driven programs at Cedars-Sinai.”

Other authors involved in the study include Nicholas Matsumoto, Jay Moran, Hyunjun Choi, Miguel E. Hernandez, Mythreye Venkatesan, and Paul Wang.

This work is supported in part by funds from the Center for AI Research and Education at Cedars-Sinai Medical Center and grants from the National Institutes of Health USA (U01 AG066833 and R01 LM010098).

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“After several decades of research, we understand that Alzheimer’s disease is not going to be easy to conquer,” said Zaldy Tan, MD, MPH, director of The Maxine and Bernard Platzer Lynn Family Memory and Healthy Aging Program. “There is no magic infusion, injection or pill that will cure it, but there are tactics to prevent or reduce one’s risk for it. While we continue to search for a viable path for stopping this disease in its entirety, prevention is of the utmost importance.”

An estimated 6.7 million Americans are living with Alzheimer’s disease, according to the National Institutes of Health. As advances in medicine and disease prevention are helping more people live longer and reach the age—65 and older—at risk for developing Alzheimer’s disease and dementia, Cedars-Sinai’s healthy aging program focuses on personalized risk profiling using clinically validated tools.

Risk factors for developing Alzheimer’s disease or dementia include family history of the disease, a gene called APOE4, diabetes, high blood pressure, sleep apnea, unhealthy weight, history of traumatic brain injury or head trauma, and social isolation.

The Cedars-Sinai program is open to anyone 40 to 60 years old with at least two of these risk factors, and anyone 60 or older who doesn’t have signs of Alzheimer’s disease or dementia but wants to protect their brain health.

Prior to their first clinic visit, patients complete a questionnaire that delves into their physical activity, diet, social networking, history of physical and emotional trauma, and level of education, among other things.

During the clinic visit, Tan and colleagues perform a detailed physical and neurological exam and cognitive tests. They also assess each patient’s grip strength, how many times they can sit in a chair and stand up again unsupported in 30 seconds, their level of frailty and risk of falling. Some patients are sent home with digital devices to continuously measure blood pressure, sleep patterns and oxygenation during sleep.

“These are things that are not necessarily asked about in primary care, or even in general neurology clinics,” said Tan, who is also medical director of the Jona Goldrich Center for Alzheimer’s and Memory Disorders and the Carmen and Louis Warschaw Endowed Chair in Neurology at Cedars-Sinai. “We use clinically validated tools to evaluate each individual’s risk and resilience factors. And based on that information, we teach them strategies to reduce their risk and maintain brain health.”

The team includes a dietitian to help participants improve their eating habits, a health psychologist who assists with behavior change issues such as smoking cessation, sleep specialists, and an occupational therapist who helps participants understand how their brains work and offers cognitive training to improve memory habits. Patients also can be referred to other specialists, including those from the Smidt Heart Institute at Cedars-Sinai, as brain and heart health are closely linked, Tan said.

“Studies show that as many as 40% of cases of Alzheimer’s disease and related dementias can be prevented or delayed with the right clinical guidance,” said Nancy L. Sicotte, MD, chair of the Department of Neurology and the Women’s Guild Distinguished Chair in Neurology at Cedars-Sinai. “We launched this program to help our patients optimize their brain health throughout life, and also to push the science forward through continued translational research.”  

Tan noted that recommendations and referrals are personalized and specific to each patient. He said that everyone is different, and while some people have more areas to improve on and others have fewer, everyone has something.

“We want to help people take preventive action as early as possible,” Tan said. “Delaying the onset of Alzheimer’s disease for even five to eight years is tantamount to a cure for many people, because the greatest risk is in those ages 80 and up. Those who delay onset until their late 80s might avoid it altogether.”

Read more on the Cedars-Sinai Blog: When Should I Be Concerned About Memory Loss?

in the Department of Neurology at Cedars-Sinai. She will treat patients with Alzheimer’s disease and related dementias as well as lead research programs aimed at preserving cognition across the lifespan.

“Dr. Gonzales will be instrumental in strengthening our research infrastructure that follows individuals through the cognitive continuum so that we can more fully understand the biology of Alzheimer’s disease,” said Zaldy Tan, MD, MPH, medical director of the Jona Goldrich Center for Alzheimer’s and Memory Disorders. “She will also help us expand our research diversity so that our discoveries more closely represent the broad spectrum of communities we serve.”

Gonzales is also part of the Center for Translational Geroscience at Cedars-Sinai, a multidisciplinary effort that focuses on preventing age-related disease and improving health and wellness for older adults.

“Innovative research and integrated clinical care are key to our mission to enable a life free from significant disease or disability,” said Sara Espinoza, MD, director of the Center for Translational Geroscience. “Dr. Gonzales’ neuropsychology background and expertise in research and patient care will be an important contribution to these efforts.”

Neuropsychologists study how the biology of the brain and nervous system relate to behavior and cognition. 

“Biology is extremely important to our cognitive trajectory in life and whether we decline faster as we age,” Gonzales said. “But our environment is also crucial in shaping synaptic plasticity—the ability of our brain cells to form new connections—throughout the lifespan. My interest is in exploring the role of biology and environment in age-related brain changes.” 

Gonzales comes to Cedars-Sinai from The University of Texas Health Science Center at San Antonio, where she was an assistant professor in the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases and the Department of Neurology. She earned her PhD in clinical psychology from the University of Texas at Austin. She completed her pre-doctoral internship at the University of Illinois at Chicago and postdoctoral fellowship in clinical neuropsychology at the VA Northern California Health Care system.

“A multidisciplinary approach is critical for diagnosing and treating complex neurodegenerative disorders,” said Nancy Sicotte, MD, chair of the Department of Neurology at Cedars-Sinai. “As the Jona Goldrich Center for Alzheimer’s and Memory Disorders and the Center for Translational Geroscience continue to grow, the addition of clinician-scientists such as Dr. Gonzales puts us in the best possible position to offer innovative memory care to our patients.” 

Gonzales finds patient care an important element in her work.

“I love the fact that neuropsychology offers me the opportunity to work directly with individuals grappling with the changes associated with cognitive decline, and to conduct research that moves the science forward and brings better care to these patients,” Gonzales said. “That one-on-one patient contact keeps the urgency of the work that we're doing in focus.”

Gonzales helps patients and families understand the opportunity presented by clinical trials and the need for long-term planning to ensure that patients’ wishes are communicated and the necessary supports are in place to accommodate changes that might be on the horizon.

“I tell patients and families that this is going to be a journey together,” Gonzales said, “and I try to always give a message of hope.”

She predicts significant innovation and transformation in the landscape of Alzheimer’s disease diagnosis and treatment over the next decade.

“One of the most exciting developments that I think will come to full fruition within the next few years is the validation of an inexpensive blood-based screening test for Alzheimer's disease,” Gonzales said. “This will help us engage people in research at earlier stages, before disease symptoms show up, and to detect very early changes that might lead to new therapeutic targets.”

Read more on the Cedars-Sinai Blog: How to Help a Loved One With Alzheimer’s or Dementia

is designed to help medical staff tailor care to best serve these patients.

“People with dementia or cognitive impairment can be especially vulnerable in the hospital if their care team is unaware,” said Zaldy Tan, MD, MPH, medical director of the Jona Goldrich Center for Alzheimer’s and Memory Disorders at Cedars-Sinai and first author of the study. “Our study is the first to investigate the feasibility of utilizing the electronic health record to identify these patients and alert the hospital team to help guide clinical care.”

If a patient with dementia is hospitalized for an unrelated condition, such as a fall or infection, they might not be able to accurately describe their medical history or safely make decisions about their medical care, Tan said. Patients with dementia might also need help to understand discharge instructions or just to stay calm in the hospital environment.

“Diagnoses such as Alzheimer’s disease, dementia or cognitive impairment are often not documented in a patient’s medical records,” said Tan, who is also director of the Memory and Healthy Aging Program and the C.A.R.E.S. Program at Cedars-Sinai. “And if providers are not aware that their patient has dementia, they may not call a loved one who can provide critical information, help with decision-making, and provide support.”

To identify these patients, investigators created a secure algorithm to search patients’ electronic health records for a diagnosis of dementia and for prescriptions for medications approved by the Food and Drug Administration to treat dementia.

“The biggest challenge in creating the algorithm was the variety of clinical scenarios that led to a potential diagnosis of dementia,” said Cameron Escovedo, MD, MS, physician leader of Enterprise Information Services at Cedars-Sinai and co-author of the study. “We had to account for multiple scenarios to ensure the algorithm was complex enough to capture everyone.”

When the algorithm detects a patient with possible dementia, a yellow banner pops up on the patient’s chart to make hospital staff aware.

“Given the poor patient outcomes currently associated with dementia care in the hospital setting—including increased risks for falls, use of restraints, and prescription of antipsychotic medications—there was a need for a method to accurately identify these patients,” said Nancy Sicotte, MD, chair of the Department of Neurology at Cedars-Sinai and senior author of the study. “Our algorithm alerts the hospital team to the presence of cognitive impairment so that they can employ targeted interventions and ultimately improve outcomes for vulnerable hospitalized patients.”

To help ensure that medical staff understand how to respond to these patients once identified, a team of nurses and physicians at Cedars-Sinai created and tested a training program and published their results in the peer-reviewed journal Geriatric Nursing.

“About 25% of the nursing staff on the units where we tested this training felt they had not previously received comprehensive training in the care of persons with dementia,” said nurse practitioner Deana Rhinehart, DNP, first author of the study. “Our goal was to help bridge the gap in knowledge and confidence within our nursing teams.”

The training was conducted over multiple 45-minute virtual sessions led by Rhinehart and nurse practitioner Dyane Gatmaitan, NP, a co-author of the study. Sessions included interactive case studies and question-and-answer segments.

“Topics included effective communication, documentation of behaviors, delirium versus dementia, refusal of medications, general behavior management and patient advocacy,” said Gatmaitan. “We are finalizing a rollout plan to expand this training to additional units in March.”

Tan said that the identification system will be expanded to all medical and some surgical units, and that the system and the training—currently in use only at Cedars-Sinai—could easily be deployed at other institutions as well.

Learn more on the Cedars-Sinai Blog: When Should I Be Concerned About Memory Loss?

In July, the first direct-to-consumer blood test designed to assess a user’s risk for developing Alzheimer’s disease hit the market. The test, which has not undergone Food and Drug Administration (FDA) review, measures the level of a protein called beta amyloid, a key component of plaques that form in the brains of Alzheimer’s disease patients, disrupting brain function.

Zaldy Tan, MD, MPH, medical director of the Jona Goldrich Center for Alzheimer’s and Memory Disorders and the Carmen and Louis Warschaw Endowed Chair in Neurology at Cedars-Sinai, sat down with the Cedars-Sinai Newsroom to answer questions about the test, as well as similar blood tests that are in development.

What do these new blood tests measure?

Blood tests for Alzheimer's disease provide a convenient way for patients to see whether they might be developing Alzheimer's-type changes or pathology in their brain years before memory issues even begin. The challenge here is that these brain changes do not necessarily mean that they have Alzheimer's disease, which is a clinical diagnosis. What blood tests do is to look at traces of certain proteins that are known to develop in patients with Alzheimer's disease.

Who should take this type of blood test?

First, it is important to remember that the test currently on the market has not been evaluated or approved by the FDA. Neither have any of the other, similar tests that are in development. And these blood tests should really be reserved for people who are at risk or are having early symptoms of memory issues. These types of blood tests do not have a place for people who do not have significant risk factors for developing memory problems, or are not having any functional or social issues related to cognitive change.

Does a blood test alone provide enough information to diagnose potential memory issues?

A blood test will not answer that question. Only a trained clinician can. So, for people who are interested in these kinds of blood tests, I would suggest that patients first speak with their healthcare professional to see if these tests are right for them.

Alternatives to these newer-on-the-market tests are things like cognitive testing, a neurologic examination, or consultation with memory specialists. These blood tests provide just one data point or piece of information among many that need to be collected to know if someone is having early signs of Alzheimer's disease.

Do these blood tests help patients qualify for some of the new Alzheimer’s disease treatments such as lecanemab?

Currently, we confirm the presence of amyloid beta in the brain and qualify patients for these treatments through a PET scan of the brain or a lumbar puncture to test cerebrospinal fluid. These blood tests will need to be tested further and will need to be cleared by the FDA to make sure that they are reliable before they can be used to qualify patients for these new treatments. 

What are the risk factors for Alzheimer’s disease?

Age is one of the main risk factors for developing dementia later in life. Others include family history, especially having dementia diagnosed in a first-degree relative. People who have had traumatic brain injury or have had a stroke or have Parkinson's disease or other neurologic conditions may also be at increased risk of developing dementia.

What can people do to reduce their risk of Alzheimer’s disease?

So, what we need to do is to make sure that our brains get the blood supply that they need, and that is best assured by a healthy lifestyle: good diet, good sleep, exercise, increased socialization to make sure those connections between brain cells are nice and healthy. And of course, protecting your brain from trauma by wearing a helmet when you cycle or skate, wearing a seatbelt when you're driving, is important. So, it's really a combination of things in order to reduce the overall risk. Just like we do for our hearts and our bodies, we need to have a multimodal approach to risk reduction of brain disease, including Alzheimer's disease.

Read more on the Cedars-Sinai Blog: Am I at Risk for Dementia? What You Need to Know

“This is the most promising therapy yet for Alzheimer’s disease, but delivering the treatment to patients is far from simple,” said Sarah Kremen, MD, who leads the Alzheimer’s Disease Clinical Trial Program in the Department of Neurology at Cedars-Sinai. “We want to be sure that potential patients understand the treatment process and risks, and are clear about what type of real-world gains it might deliver.”

Lecanemab, marketed under the brand name Leqembi, isn’t a perfect solution, but it is a positive step forward, said Zaldy Tan, MD, MPH, medical director of the Jona Goldrich Center for Alzheimer’s and Memory Disorders in the Department of Neurology at Cedars-Sinai.

“More than 6 million people in the U.S. are diagnosed with Alzheimer’s disease, and this is the most effective treatment we have available,” Tan said. “We have to start somewhere.”

Kremen and Tan sat down with the Cedars-Sinai Newsroom to explain the screening and treatment process for patients interested in receiving lecanemab, and its risks and benefits.

How does lecanemab work—and how well?

Kremen: Clinical trial data showed that the treatment can pull amyloid—a protein that forms plaques and disrupts brain function—out of the brain in a significant way. Patients receiving lecanemab during clinical trials also showed moderately less decline on tests of memory and functional ability. Lecanemab also seems to decrease accumulation of tau protein, which forms tangles inside neurons of Alzheimer’s patients, particularly in the memory centers of the brain. That being said, treatment takes 18 months and only slows cognitive decline by about six months.

When will Cedars-Sinai start administering lecanemab to patients?

Tan: Cedars-Sinai hopes to begin offering this treatment in the next few months. Our multidisciplinary team—including experts in cognitive testing, brain imaging, pharmacy, infusion therapy and patient care coordination—has been working to create a robust process that will support patients from pre-treatment screening through follow-up care and account for every anticipated challenge that might present itself.

Who can be treated with lecanemab?

Kremen: This treatment is designed for people who have either mild cognitive impairment or mild dementia due to Alzheimer’s disease. This is not for people with moderate or severe dementia, where their memory and other cognitive functions are so impacted that they need to rely on other people for help with daily living. It is also not for people at risk for Alzheimer’s disease but who have normal memory and thinking. The medication isn’t recommended for anyone taking blood thinners or who has significant brain bleeds, brain swelling, aneurysms, vascular malformation, brain tumors, or an uncontrolled bleeding disorder.

What kind of real-world benefits might the drug have for patients?

Tan: We don’t yet know how many people will have observable benefits from this medication. We’re hopeful that it’s going to prolong our patients’ ability to function, but that might be a difference of as little as three months’ delay in disease progression. Still, three more months of better thinking and participating in activities of daily life may be meaningful to some of our patients and their families as they navigate this condition.

What are the risks associated with treatment?

Kremen: Risks include brain bleeding and brain swelling, which is also true of other, similar Alzheimer’s disease treatments that haven’t made it this far in clinical research tests. The side effect we’re most concerned about is large brain bleeds, which are fairly rare but can happen. So people need to go into this with eyes open, because we’re not going to be able to completely mitigate this risk.

What is the treatment process like?

Tan: The medication is given by IV infusion over one hour, every two weeks—so the time commitment is something to consider. And patients will need to have an MRI before the fifth, seventh and 14^th infusions, according to FDA guidelines, so that we can monitor for brain swelling and brain bleeds. We will also have to monitor for infusion reactions, such as low blood pressure or difficulty breathing, which could happen during any type of IV infusion. We will monitor for three hours after the patient’s first dose, two hours after the second and third doses, and 30 minutes after the remaining doses for patients who do not have infusion-related reactions.

What types of pre-treatment testing will patients need?

Kremen: Patients will need a diagnostic evaluation to confirm that their dementia or cognitive impairment is due to Alzheimer’s disease and not something else. This evaluation can be done by a primary care doctor, geriatrician, neurologist or psychiatrist. They will also need testing to confirm the presence of amyloid, which is what the medication is designed to treat. This can be done via specialized brain imaging—which is not widely available or covered by insurance—or through spinal fluid tests. Patients will also need genetic testing, because those with one or two copies of a gene called APOE4 are at increased risk of brain bleeds and swelling and will need to take this into account when deciding whether to be treated.

What costs are associated with treatment?

Tan: According to lecanemab’s manufacturer, Eisai, the drug itself will cost around $26,500 per year, and there are additional costs for required pre-treatment testing and monitoring during treatment. The Centers for Medicare & Medicaid Services has stated that if lecanemab receives full FDA approval, Medicare will cover the treatment in “appropriate settings.” It is still unclear whether Medicare or private insurers will cover testing and monitoring, and the out-of-pocket cost to patients is uncertain.

Read more on the Cedars-Sinai Blog: How to Help a Loved One With Alzheimer's or Dementia