A new form of deep brain stimulation offers hope for an alternative treatment option for dementia, without the need for surgery.
Researchers at Imperial College London are leading the development of the technique, known as temporal interference (TI). This non-invasive method works by delivering electrical fields to the brain through electrodes placed on the patient’s scalp and head. Their initial findings, which are published in the journal Nature Neuroscience, could lead to an alternative treatment for brain diseases such as Alzheimer’s, and its associated memory loss.
Temporal interference
By targeting the overlapping electrical fields researchers were able to stimulate an area deep in the brain called the hippocampus, without affecting the surrounding areas – a procedure that until now required surgery to implant electrodes into the brain.
The approach has been successfully trialled with 20 healthy volunteers for the first time by a team at the UK Dementia Research Institute (UK DRI) at Imperial and the University of Surrey.
Their initial results show that when healthy adults perform a memory task whilst receiving TI stimulation it helped to improve memory function.
The team is now conducting a clinical trial in people with early-stage Alzheimer’s disease, where they hope TI could be used to improve symptoms of memory loss.
Dr Nir Grossman, from the Department of Brain Sciences at Imperial College London, who led the work said: “Until now, if we wanted to electrically stimulate structures deep inside the brain, we needed to surgically implant electrodes which of course carries risk for the patient, and can lead to complications.
“With our new technique we have shown for the first time, that it is possible to remotely stimulate specific regions deep within the human brain without the need for surgery. This opens up an entirely new avenue of treatment for brain diseases like Alzheimer’s which affect deep brain structures.”
Reaching deep brain regions
TI was first described by the team at Imperial College London in 2017 and shown to work in principle in mice.
This latest work, funded and carried out through the UK Dementia Research Institute, shows for the first time that TI is effective at stimulating regions deep within the human brain.
According to the researchers, this could have broad applications and will enable scientists to stimulate different deep brain regions to discover more about their functional roles, accelerating the discovery of new therapeutic targets.
In a study published in Current Biology, people with early Alzheimer’s disease were found to have difficulty turning when walking. The new study used virtual reality and a computational model to further explore the intricacies of navigational errors previously observed in Alzheimer’s disease.
Researchers, led by Professor Neil Burgess and colleagues in the Space and Memory group at the UCL Institute of Cognitive Neuroscience, grouped participants into three categories: healthy younger participants (31 total), healthy elderly participants (36 total) and patients with mild cognitive impairment (43 total). They then asked them to complete a task while wearing virtual reality goggles, which allowed them to make real movements.
In the trial, participants walked an outbound route guided by numbered cones, consisting of two straight legs connected by a turn. They then had to return to their starting position unguided.
The task was performed under three different environmental conditions aimed at stressing the participant’s navigational skills: an unchanged virtual environment, the ground details being replaced by a plain texture, and the temporary removal of all landmarks from the virtual reality world.
The researchers found that people with early Alzheimer’s consistently overestimated the turns on the route and showed increased variability in their sense of direction. However, these specific impairments were not observed in the healthy older participants or people with mild cognitive impairment, who did not show underlying signs of Alzheimer’s.
This suggests that these navigational errors are specific to Alzheimer’s disease – rather than an extension of healthy ageing or general cognitive decline – and could help with diagnosis.
Joint first author, Dr Andrea Castegnaro (UCL Institute of Cognitive Neuroscience), said: “Our findings offer a new avenue for the early diagnosis of Alzheimer’s disease by focusing on specific navigational errors. However, we know that more work is needed to confirm these early findings.
Dr Castegnaro added, “Cognitive assessments are still needed to understand when the first cognitive impairments develop, and when it comes to existing spatial memory tests used in clinics, those often rely on verbal competence. Our tests aim to offer a more practical tool that doesn’t rely on language or cultural background.”
A study published in The Lancet Healthy Longevity shows that brain metabolism, detected with advanced imaging techniques, declines more sharply in middle-aged people with a sustained high cardiovascular risk over 5 years
Cardiovascular disease and dementia frequently occur together in elderly people. Nevertheless, few longitudinal studies have examined how atherosclerosis and its associated risk factors affect brain health from middle age. Now, a new study by scientists at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid provides new data on this relationship; the results confirm the importance of controlling traditional cardiovascular risk factors, such as hypertension, cholesterol, diabetes, smoking, and a sedentary lifestyle, not only to preserve cardiovascular health, but also to prevent Alzheimer’s disease and other dementias.
The CNIC study shows that atherosclerosis (accumulation of fatty deposits in the arteries) and its associated risk factors, in addition to being the main cause of cardiovascular disease, are also implicated in the cerebral alterations typically found in Alzheimer’s disease, the most frequent cause of dementia.
According to study author Dr Valentín Fuster, CNIC General Director, the new findings are important because they open up the possibility of treating a modifiable disorder, ie cardiovascular disease, to prevent the development a presently untreatable disease – dementia. “The sooner we act to control cardiovascular risk factors, the better it is for our brain health,” said Dr. Fuster.
“Everybody knows that a healthy lifestyle and controlling cardiovascular risk factors are important for preventing a heart attack,” continued Dr Fuster. “Nevertheless, the additional information linking the same risk factors to a decline in brain health could further increase awareness of the need to acquire healthy habits from the earliest life stages.”
In 2021, CNIC scientists discovered that the presence of cardiovascular risk factors and subclinical (presymptomatic) atherosclerosis in the carotid arteries (the arteries that supply the brain) was associated with lower glucose metabolism in the brains of apparently healthy 50-year-old participants in the PESA-CNIC-Santander study. Glucose metabolism in the brain is considered an indicator of brain health.
The PESA-CNIC-Santander study directed by Dr Fuster is a prospective study that includes more than 4000 asymptomatic middle-aged participants who have been exhaustively assessed for the presence and progression of subclinical atherosclerosis since 2010.
Dr Fuster’s team, led by Drs Marta Cortés Canteli and Juan Domingo Gispert, have continued to monitor the cerebral health of these participants over 5 years. Their research shows that individuals who maintained a high cardiovascular risk throughout this period had a more pronounced reduction in cerebral glucose metabolism, detected using imaging techniques such as positron emission tomography (PET).
“In participants with a sustained high cardiovascular risk, the decline in cerebral metabolism was three times greater than in participants who maintained a low cardiovascular risk,” commented Catarina Tristão-Pereira, first author on the study and INPhINIT fellow.
Glucose is the main energy source for neurons and other brain cells. “If there is a sustained decline in cerebral glucose consumption over several years, this may limit the brain ability to withstand neurodegenerative or cerebrovascular diseases in the future,” explained Dr Gispert, an expert in neuroimaging at the CNIC and Barcelonaβeta Research Center.
Through a collaboration with Drs Henrik Zetterberg and Kaj Blennow, world experts in the identification of new blood biomarkers at the University of Gothenburg in Sweden, the CNIC team discovered that the individuals showing this metabolic decline already show signs of neuronal injury. “This is a particularly important finding because neuronal death is irreversible”, said Dr. Cortés Canteli, a neuroscientist at the CNIC and a Miguel Servet fellow at the Fundación Jiménez Díaz Health Research Institute.
The CNIC team also discovered that the progression of subclinical atherosclerosis in the carotid arteries over five years is linked to a metabolic decline in brain regions vulnerable to Alzheimer’s disease, in addition to the effect of cardiovascular risk factors. “These results provide yet another demonstration that the detection of subclinical atherosclerosis with imaging techniques provides highly relevant information,” said Dr Fuster, who is the principal investigator on the PESA study. “The interaction between the brain and the heart is a fascinating topic, and with this study we have seen that this relationship begins much earlier than was thought.”
The scientists conclude that, “carotid screening has great potential to identify individuals at risk of cerebral alterations and cognitive decline in the future.” In the published article they write, “this work could have important implications for clinical practice since it supports the implementation of primary cardiovascular prevention strategies early in life as a valuable approach for a healthy cerebral longevity.”
“Although we still don’t know what impact this decline in cerebral metabolism has on cognitive function, the detection of neuronal injury in these individuals shows that the earlier we start to control cardiovascular risk factors, the better it will be for our brain,” concluded Dr Cortés Canteli.
Circadian disruption is a hallmark of Alzheimer’s disease, affecting nearly 80% of patients with issues such as difficulty sleeping and worsening cognitive function at night. Currently there are no treatments for Alzheimer’s that target this aspect of the disease.
A new study in Cell Metabolism from researchers at University of California San Diego School of Medicine has shown in mice that it is possible to correct the circadian disruptions seen in Alzheimer’s disease with time-restricted feeding, a type of intermittent fasting focused on limiting the daily eating window without limiting the amount of food consumed.
In the study, mice that were fed on a time-restricted schedule showed improvements in memory and reduced accumulation of amyloid proteins in the brain. The authors say the findings will likely result in a human clinical trial.
“For many years, we assumed that the circadian disruptions seen in people with Alzheimer’s are a result of neurodegeneration, but we’re now learning it may be the other way around – circadian disruption may be one of the main drivers of Alzheimer’s pathology,” said senior study author Paula Desplats, PhD, professor at UC San Diego School of Medicine. “This makes circadian disruptions a promising target for new Alzheimer’s treatments, and our findings provide the proof-of-concept for an easy and accessible way to correct these disruptions.”
People with Alzheimer’s experience a variety of disruptions to their circadian rhythms, including changes to their sleep/wake cycle, increased cognitive impairment and confusion in the evenings, and difficulty falling and staying asleep.
“Circadian disruptions in Alzheimer’s are the leading cause of nursing home placement,” said Desplats. “Anything we can do to help patients restore their circadian rhythm will make a huge difference in how we manage Alzheimer’s in the clinic and how caregivers help patients manage the disease at home.”
Boosting the circadian clock is an emerging approach to improving health outcomes, and one way to accomplish this is by controlling the daily cycle of feeding and fasting. The researchers tested this strategy in a mouse model of Alzheimer’s disease, feeding the mice on a time-restricted schedule where they were only allowed to eat within a six-hour window each day. For humans, this would translate to about 14 hours of fasting each day.
Compared to control mice who were provided food at all hours, mice fed on the time-restricted schedule had better memory, were less hyperactive at night, followed a more regular sleep schedule and experienced fewer disruptions during sleep. The test mice also performed better on cognitive assessments than control mice, demonstrating that the time-restricted feeding schedule was able to help mitigate the behavioral symptoms of Alzheimer’s disease.
The researchers also observed improvements in the mice on a molecular level. In mice fed on a restricted schedule, the researchers found that multiple genes associated with Alzheimer’s and neuroinflammation were expressed differently. They also found that the feeding schedule helped reduce the amount of amyloid protein that accumulated in the brain. Amyloid deposits are one of the most well-known features of Alzheimer’s disease.
Because the time-restricted feeding schedule was able to substantially change the course of Alzheimer’s in the mice, the researchers are optimistic that the findings could be easily translatable to the clinic, especially since the new treatment approach relies on a lifestyle change rather than a drug.
“Time-restricted feeding is a strategy that people can easily and immediately integrate into their lives,” said Desplats. “If we can reproduce our results in humans, this approach could be a simple way to dramatically improve the lives of people living with Alzheimer’s and those who care for them.”
New Alzheimer’s research suggests that enhanced light sensitivity may contribute to ‘sundowning’, which is the worsening of symptoms late in the day, thereby spurring sleep disruptions thought to contribute to the disease’s progression.
Published in Frontiers in Aging Neuroscience, these new insights from UVA Health into the disruptions of the biological clock seen in Alzheimer’s could lead to new treatments and symptom management, the researchers say. For example, caregivers often struggle with the erratic sleep patterns caused by Alzheimer’s patients’ altered circadian rhythms. Light therapy, the new research suggests, might be an effective tool to help manage that.
Better understanding Alzheimer’s effects on circadian rhythms could have implications for prevention. Poor sleep quality in adulthood is a risk factor for Alzheimer’s, as brains at rest naturally cleanse themselves of amyloid beta proteins that are thought to form harmful tangles in Alzheimer’s.
“Circadian disruptions have been recognised in Alzheimer’s disease for a long time, but we’ve never had a very good understanding of what causes them,” said researcher Thaddeus Weigel, a graduate student working with Heather Ferris, MD, PhD. “This research points to changes in light sensitivity as a new, interesting possible explanation for some of those circadian symptoms.”
Alzheimer’s hallmark is progressive memory loss, to the point that patients can forget their own loved ones, but there can be many other symptoms, such as restlessness, aggression, poor judgment and endless searching. These symptoms often worsen in the evening and at night.
Ferris and her collaborators used a mouse model of Alzheimer’s to better understand what happens to the biological clock in Alzheimer’s disease. They essentially gave the mice “jet lag” by altering their exposure to light, then examined how it affected their behaviour. The Alzheimer’s mice reacted very differently to control mice.
The Alzheimer’s mice, the scientists found, adapted to a six-hour time change significantly more quickly than the control mice. This, the scientists suspect, is the result of a heightened sensitivity to changes in light. While our biological clocks normally take cues from light, this adjustment happens gradually – thus, jet lag when we travel great distances. Our bodies need time to adapt. But for the Alzheimer’s mice, this change happened abnormally fast.
The researchers initially thought this might be because of neuroinflammation. So they looked at immune cells called microglia that have become promising targets in developing better Alzheimer’s treatments. But the scientists ultimately ruled out this hypothesis, determining that microglia did not make a difference in how quickly mice adapted. (Though targeting microglia might be beneficial for other reasons.)
Notably, the UVA scientists also ruled out another potential culprit: “mutant tau,” an abnormal protein that forms tangles in the Alzheimer’s brain. The presence of these tangles also did not make a difference in how the mice adapted.
The researchers’ results ultimately suggest there is an important role for the retina in the enhanced light sensitivity in Alzheimer’s, and that gives researchers a promising avenue to pursue as they work to develop new ways to treat, manage and prevent the disease.
“These data suggest that controlling the kind of light and the timing of the light could be key to reducing circadian disruptions in Alzheimer’s disease,” Ferris said. “We hope that this research will help us to develop light therapies that people can use to reduce the progression of Alzheimer’s disease.”
A safe treatment against Alzheimer’s progression may be hidden in a common bodybuilding supplement. Researchers recently discovered that a muscle-building supplement called beta-hydroxy beta-methylbutyrate (HMB), may help protect memory, reduce plaques and ultimately help prevent the progression of Alzheimer’s disease. The researchers published their results in the journal Cell Reports.
HMB is a safe over-the-counter supplement, which bodybuilders regularly use to enhance exercise-related muscle strength and growth.
“This may be one of the safest and the easiest approaches to halt disease progression and protect memory in Alzheimer’s disease patients,” said Kalipada Pahan, PhD, at RUSH Medical College.
Studies in mouse models of Alzheimer’s have shown that HMB successfully reduces plaques and increases factors for neuronal growth to protect learning and memory, according to neurological researchers at RUSH.
“Understanding how the disease works is important to developing effective drugs to protect the brain and stop the progression of Alzheimer’s disease,” Pahan said.
Previous studies indicate that a family of proteins known as neurotrophic factors are drastically decreased in the brains of people with Alzheimer’s disease and have been found to help in survival and function of neurons, which are cells that receive and send messages from the body to the brain and vice versa.
“Our study found that after oral consumption, HMB enters into the brain to increase these beneficial proteins, restore neuronal connections and improve memory and learning in mice with Alzheimer’s-like pathology, such as plaques and tangles,” Pahan said.
The study findings indicate that HMB stimulates the nuclear hormone receptor PPARα within the brain that regulates the transport of fatty acids, which is key to the success of HMB as a neuroprotective supplement.
“If mouse results with HMB are replicated in Alzheimer’s disease patients, it would open up a promising avenue of treatment of this devastating neurodegenerative disease,” Pahan said.
With yet a third new Alzheimer’s drug, the monoclonal antibody donanemab, expected to be approved by the Food and Drug Administration (FDA), the field is beginning to show progress in the fight to slow the disease. But the drugs work best for those in the earliest stages of Alzheimer’s, and other therapies will be needed to help those with advanced disease, according to Gil Rabinovici, MD, director of the UCSF Alzheimer’s Disease Research Center.
This is likely “just the opening chapter in a new era of molecular therapies for Alzheimer’s disease and related neurodegenerative disorders,” Rabinovici wrote in an editorial that is being published along with the results of the latest drug, donanemab, in JAMA. Rabinovici was not involved in the trial.
Donanemab is a monoclonal antibody, like the two earlier Alzheimer’s drugs, aducanumab (Aduhelm) and lecanemab (Leqembi). These drugs attack plaques in the brain that are made of a protein called amyloid. They disrupt cell function and lead to the rapid spread of another protein called tau. Both amyloid and tau contribute to the development of Alzheimer’s disease.
The trial showed donanemab slowed cognitive decline by 35% compared with placebo in patients with low-to-intermediate levels of tau in the brain. These results are similar to those reported with Leqembi, which received FDA approval earlier this month. In the donanemab trial, patients also experienced a 40% lower risk of progressing from mild cognitive impairment to mild dementia, or from mild-to-moderate dementia.
Donanemab was better at removing amyloid plaques compared to Aduhelm and Leqembi. It reduced tau concentrations in the blood, but not in a key area of the brain.
While these results are encouraging, Rabinovici said an in-depth analysis still is needed to understand how these findings affect patient outcomes.
Limited benefit in advanced disease
Patients with more advanced disease showed little to no benefit compared to those who received the placebo. Together with the drug’s potentially serious side effects, this should push experts to “aim higher in developing more impactful and safer treatments,” wrote Rabinovici, who is affiliated with the UCSF Memory and Aging Center, departments of Neurology, Radiology and Biomedical Imaging, as well as the Weill Institute for Neurosciences.
Donanemab should be restricted to patients with low-to-intermediate levels of tau, which indicates mild disease. Other trials are evaluating how well monoclonal antibodies work in the earliest phase of the disease before symptoms appear.
Like the two other new Alzheimer’s drugs, donanemab was associated with ARIA, amyloid-related imaging abnormalities that may include brain swelling and microbleeds. Serious ARIA occurred in 3.7% of patients, including three deaths. Risks were higher among patients with the APOE4 gene, which is related to an increased risk for Alzheimer’s. For that reason, Rabinovici said, genetic testing should be recommended prior to monoclonal antibody treatment.
While ARIA has generally been managed safely in clinical trials, Rabinovici urged caution as these drugs enter into real-world practice. He suggested limiting access to patients with normal pre-treatment MRIs, repeating MRIs at regular intervals and stopping or suspending treatment when ARIA occurs.
Lack of racial and ethnic diversity was a major limitation of the trial. Just 8.6% of the 1,251 U. S. participants were non-white. Rabinovici said this raises ethical concerns about the “generalisability of results to populations at highest risk,” noting studies that have shown higher rates of dementia in Black and Latino populations.
Given the anticipated high cost of donanemab and high patient demand, Rabinovici said it might make sense to limit the treatment duration to the time needed to clear amyloid plaques from the brain, which is the approach pioneered in the trial. He said this could “greatly enhance the feasibility of treatment for patients, clinicians, insurers and health systems.”
New research published in Nature Communications has found that in a mouse model mimicking Alzheimer’s Disease (AD) pain signals are not processed in the same way as in healthy mice. The research, from King’s College London, suggests that the perception of pain in people with Alzheimer’s Disease may be altered, and asks whether changes in management of pain in people with AD could improve their quality of life.
While chronic musculoskeletal pain is common in individuals with AD, it remains largely untreated as it can go unreported due to the cognitive deficits attached to the disease.
In this study, the researchers sought to explore whether there is also an alteration in the body’s response to pain by the nervous system in people with AD.
In healthy mice, pain signals are transmitted from the point of origin to the central nervous system to initiate an immune response. The protein Galectin-3 has been demonstrated to be responsible for pain signal transmission to the spinal cord. Upon reaching the spinal cord, it binds to another protein, TLR4, to initiate the immune response.
In this study, researchers used an AD mice model and gave them rheumatoid arthritis, a type of chronic inflammatory disease, through blood transfer. They observed an increase in allodynia, pain caused by a stimulus that doesn’t normally provoke pain, as a response to the inflammation. They also saw increased activation of a microglia in the spinal cord. They determined that these effects were regulated by TLR4.
Researchers found that the mice with AD lacked TLR4 in the immune cells of their central nervous system and were therefore unable to respond to pain in the typical way as the signals were not being perceived.
This resulted in the mice with AD developing less joint inflammation related pain, and a less powerful immune cell response to the pain signals received by the central nervous system.
Professor Marzia Malcangio, Professor of Neuropharmacology at King’s IoPPN and the study’s senior author said, “Nociceptive pain – pain which is the result of tissue damage – is the second most prevalent comorbidity in individuals with Alzheimer’s disease. Our study has shown that, in mice with Alzheimer’s, the body’s ability to process that pain is altered due to the lack of TLR4; a protein vital to the immune response process in the central nervous system.
“These are important findings, as untreated pain can contribute to the psychiatric symptoms of the disease. Increasing our understanding of this area could, with more research, lead to more effective treatments and ultimately improve people’s quality of life.”
George Sideris-Lampretsas, a PhD student at King’s IoPPN and the study’s first author said, “The results of this study have the potential to make an impact, not only by identifying Galectin-3/TLR4 as a potential therapeutic target for chronic pain, but most importantly by raising awareness around the underreported and untreated pain experienced by patients with AD.”
The Bacillus Calmette-Guérin (BCG) for tuberculosis vaccine has a number additional beneficial effects, and is currently a recommended therapy for non–muscle-invasive bladder cancer. In a new study published in JAMA Network Open, treatment with the BCG vaccine was associated with a reduced risk of Alzheimer’s disease and related dementias.
Although previous research has suggested a link between the BCG vaccine and a lower risk of dementia, studies were limited by size, study design, or analytical methods. To conduct a more robust study, researchers followed 6467 individuals for up to 15 years after they were diagnosed with non–muscle-invasive bladder cancer.
The group included 3388 patients who underwent BCG vaccine treatment and 3079 who served as controls, matched by factors such as age, sex, and medical co-morbidities.
During follow-up, 202 patients in the BCG vaccine group and 262 in the control group developed Alzheimer’s disease and related dementias. The incidence was 8.8 per 1000 person-years and 12.1 per 1000 person-years in the respective groups.
Analyses revealed that treatment with the BCG vaccine was associated with a 20% lower risk of Alzheimer’s disease and related dementias. The protective association was greater in patients aged 70 years or older. Additionally, during follow-up, 751 patients in the BCG vaccine group and 973 in the control group died. Thus, treatment with BCG vaccine was associated with a 25% lower risk of death.
Study leader Marc Weinberg, MD, Ph.D., an Instructor in Psychiatry at MGH, said: “A vaccine like BCG, if proven effective, is a perfect example of a cost-effective, population-health–based solution to a devastating illness like Alzheimer’s disease. We are shifting our focus towards studying the potential benefits of BCG vaccination of older adults in Alzheimer’s disease–related clinical trials.”
If a causal link is found, it will be important to understand the mechanisms involved. Weinberg and his colleagues note that the BCG vaccine’s effects on the immune system may play a role.
Women are about twice as likely as men to be diagnosed with Alzheimer’s disease. Some of that is age: women outlive men in most countries, and advanced age is the strongest risk factor for Alzheimer’s. But not all of it explains the excess risk.
One such factor may be stress may be one such reason. A study published in Brain shows that the effect stress has on the brain differs by sex, at least in mice. In stressful situations, levels of the Alzheimer’s protein amyloid beta rises sharply in the brains of females but not males. In addition, the researchers identified a molecular pathway that is active in brain cells from female mice but not male mice, and showed that it accounts for the divergent responses to stress.
The findings, from researchers at Washington University School of Medicine in St. Louis, add to a growing collection of evidence that sex matters in health and disease. From cancer to heart disease to arthritis, scientists have found differences between males and females that could potentially affect how men and women respond to efforts to prevent or treat chronic diseases.
“How women respond to stress versus how men respond to stress is an important area of research that has implications for not just Alzheimer’s disease but other conditions, too,” said co-corresponding author Carla M. Yuede, PhD, an associate professor of psychiatry. “In recent years, the National Institutes of Health (NIH) has prioritized understanding sex differences in medicine. Stress is one area in which you can clearly see a difference between males and females. This study shows that reducing stress may be more beneficial for women than men, in terms of lowering the risk of Alzheimer’s disease.”
Stress falls into the category of socioeconomic risk factors, along with factors such as depression and social isolation, that together account for an estimated 8% of the risk of developing Alzheimer’s. That risk calculation, however, doesn’t take sex into account. Women consistently report higher levels of stress than men, and it affects them differently.
Corresponding author John Cirrito, PhD, an associate professor of neurology; Yuede; and first author Hannah Edwards, a graduate student in Cirrito’s lab, reasoned that stress also may affect women’s brains differently than men’s, and these differences may help explain the sex imbalance in Alzheimer’s disease.
To find out, they measured levels of amyloid beta in the brains of mice every hour for 22 hours, beginning eight hours before the mice experienced stress. The experience was equally stressful for male and female mice, as measured by the levels of stress hormones in their blood. But the responses in their brains were not the same.
In female mice, amyloid beta levels rose significantly within the first two hours and stayed elevated through the end of the monitoring period. In male mice, brain amyloid levels did not change overall, although about 20% of them did show a delayed and weak rise in amyloid levels.
Further experiments revealed that the difference comes down to a cellular stress response pathway in brain cells. Stress causes the release of a hormone known as corticotropin releasing factor. Neurons from female rodents take up the stress hormone, triggering a cascade of events that results in increasing levels of amyloid beta in the brain. In contrast, neurons from male rodents lack the ability to take up the stress hormone. It is not known whether there are similar sex differences in how human neurons take up stress hormones.
“There’s a fundamental biological difference between males and females in how they respond to stress at the cellular level, in both mice and people,” Cirrito said. “We don’t think that stress is the sole factor driving the sex difference in Alzheimer’s disease. There are many other differences between men and women – in hormones, lifestyle, other diseases they have – that undoubtedly contribute in some way. But that stress is driving one aspect of this sex difference I think is very likely.”
