Infections needing hospitalisal treatment in early- and mid-life are associated with an increased subsequent risk of Alzheimer’s and Parkinson’s diseases, according to a population-based, case control study by published in PLOS Medicine. No such increase was seen for amyotrophic lateral sclerosis (ALS), however.
The study used Swedish data on individuals diagnosed with Alzheimer’s disease, Parkinson’s disease or ALS, from 1970–2016, as well as five matched controls per case. The analysis included more than 290 000 Alzheimer’s disease cases, 100 000 Parkinson’s disease cases and 10 000 ALS cases.
The results show that a hospital-treated infection five or more years before diagnosis was associated with a 16% increased risk of Alzheimer’s disease and a 4% higher risk of Parkinson’s disease. The associations only applied to individuals diagnosed before the age of 60, whereas no association was found for those diagnosed later in life.
Individuals with multiple hospital treatments for infections before age 40 was associated with the highest risk of disease, with more than doubled risk of Alzheimer’s disease and more than 40% increase in the risk of Parkinson’s disease.
No association was observed for ALS, regardless of age at diagnosis. Due to the observational nature of the study, no causal link could be established.
“These findings suggest that infectious events may be a trigger or amplifier of a pre-existing disease process, leading to clinical onset of neurodegenerative disease at a relatively early age,” said Jiangwei Sun, the study’s first author and postdoctoral researcher at Karolinska Institutet.
Research reports for the first time a pathway that begins in the gut and ends with a potent pro-inflammatory toxin in brain cells contributing to the development of Alzheimer’s disease (AD). Results are published in Frontiers in Neurology, where the researchers also report a simple way to counter the process.
The researchers, led by Drs Yuhai Zhao and Walter J Lukiw, found evidence that a molecule containing a very potent microbial-generated neurotoxin (lipopolysaccharide or LPS) derived from the Gram-negative bacteria Bacteroidesfragilis in the human gastrointestinal (GI) tract generates a neurotoxin known as BF-LPS.
“LPSs in general are probably the most potent microbial-derived pro-inflammatory neurotoxic glycolipids known,” explained Dr Lukiw. “Many laboratories, including our own, have detected different forms of LPS within neurons of the Alzheimer’s disease-affected human brain.”
The researchers detailed the pathway of BF-LPS from the gut to the brain and its mechanisms of action once there. BF-LPS leaks out of the GI tract, crosses the blood brain barrier via the circulatory system, and accesses brain compartments. Then it increases inflammation in brain cells and inhibits neuron-specific neurofilament light (NF-L,) a protein that supports cell integrity. A deficit of this protein leads to progressive neuronal cell atrophy, and ultimately cell death, as is observed in AD-affected neurons. They also report that adequate intake of dietary fibber can head off the process.
The novel features of this newly described pathological pathway are threefold. The AD-stimulating pathway begins in the gut microbiome and therefore is very “locally sourced” and active throughout our lives. The highly potent neurotoxin BF-LPS is a natural by-product of gut-based microbial metabolism. Bacteroides fragilis abundance in the microbiome, which is the source of the neurotoxin BF-LPS, can be regulated by dietary fiber intake.
“Put another way, dietary-based approaches to balance the microorganisms in the microbiome may be an attractive means to modify the abundance, speciation, and complexity of enterotoxigenic forms of AD-relevant microbes and their potential for the pathological discharge of highly neurotoxic microbial-derived secretions that include BF-LPS and other forms of LPS,” Dr Lukiw explained.
The researchers conclude that an improved understanding of the interaction between the Gut–Brain axis and the gut microbiome and Alzheimer’s disease has considerable potential to lead to new diagnostic and therapeutic strategies in the clinical management of Alzheimer’s disease and other lethal, progressive, and age-related neurodegenerative disorders.
The fields of Alzheimer’s disease and cancer research have both been shaken by recent investigations which have revealed image falsification and plagiarism. These findings call into question specific avenues of research which have received considerable funding.
Neuroscientist Matthew Schrag, a junior professor studying Alzheimer’s, had already ruffled some feathers criticising the FDA approval of the Alzheimer’s drug Aduhelm when he was approached by an attorney to investigate Simufilam, another Alzheimer’s drug under development.
According to Science, he used funding given to him by the attorney to investigate the data behind the drug’s development. The research focuses on amyloid beta (Aβ) plaques, long thought to be the culprit behind Alzheimer’s.
Schrag identified apparently altered or duplicated images in dozens of journal articles, and sent them to the National Institutes of Health (NIH), which had funded tens of millions of dollars.
The investigation drew him towards a bedrock of modern Alzheimer’s research, a 2006 Nature study by Sylvain Lesné of the University of Minnesota in the laboratory of Karen Ashe, which identified an amyloid beta protein.
Schrag avoids describing the suspicious data as fraud, since that would require unfettered access to the original material. “I focus on what we can see in the published images, and describe them as red flags, not final conclusions,” he said. “The data should speak for itself.”
The work focused on ‘toxic oligomers’, subtypes of Aβ that dissolve in some bodily fluids, a potential Alzheimer’s cause that had gained traction in the early 2000s partly due to their discovery in autopsied Alzheimer’s patients.
Using transgenic mice, the UMN team discovered a previously unknown oligomer species, Aβ*56. They isolated Aβ*56 and injected it into young rats, causing a reduction in cognitive ability.
This discovery, the first to show a direct cause, resulted in an explosion in related research, with related studies receiving $287 million in National Institutes of Health funding in 2021, compared to no funding in 2006.
In concert with molecular biologist Elisabeth Bik, no less than 20 of Lesné’s papers were flagged, 10 of which related to Aβ*56. A finding which some Alzheimer’s experts say calls into question 16 years of amyloid beta research. Some had been suspicious and had failed to replicate the findings, but journals are reluctant to publish research which proves a negative or which contradicts a prominent researcher’s findings.
Cancer research has been dogged by its own crisis with fabricated data, according to an investigative report by Nature. For years, a prominent US cancer-research laboratory run by leading cancer geneticist Carlo Croce at the Ohio State University (OSU) had been dogged by allegations of plagiarism and falsified images. To date 11 papers he has co-authored have been retracted, and 21 have needed corrections.
In 2017, The New York Times first reported on allegations of research misconduct against Croce, when OSU opened inquiries into papers from Croce’s lab. These proceeded to formal investigations, Nature learnt, two of which found multiple instances of research misconduct, including data falsification and plagiarism, by scientists Michela Garofalo and Flavia Pichiorri, in papers they’d authored while in Croce’s laboratory.
Garofalo claimed she did not received proper image manipulation training and Pichiorri said she did not understand plagiarism at the time. They have since moved on from OSU.
OSU declined to charge Croce with misconduct as his involvement did not relate to direct plagiarism or image fabrication, but did note that these cases resulted out of his “poor mentorship and lack of oversight.”
Croce was removed from a number of his positions – for which he attempted to sue – but is still employed by OSU, and many of the papers identified by OSU have not been retracted by their journals.
In a study with nearly 2 million older adults, those who received at least one influenza vaccine were 40% less likely than their non-vaccinated peers to develop Alzheimer’s disease over four years of follow-up, according to a new study from UTHealth Houston.
An early online version of the paper detailing the findings is available in advance of its publication in the Journal of Alzheimer’s Disease in August.
“We found that flu vaccination in older adults reduces the risk of developing Alzheimer’s disease for several years. The strength of this protective effect increased with the number of years that a person received an annual flu vaccine – in other words, the rate of developing Alzheimer’s was lowest among those who consistently received the flu vaccine every year,” said first author Avram S. Bukhbinder, MD. “Future research should assess whether flu vaccination is also associated with the rate of symptom progression in patients who already have Alzheimer’s dementia.”
The study comes two years after UTHealth Houston researchers found a possible link between the flu vaccine and reduced risk of Alzheimer’s disease. This new study analysed a much larger sample than previous research, including 935 887 flu-vaccinated patients and 935 887 non-vaccinated patients.
During four-year follow-up appointments, about 5.1% of flu-vaccinated patients were found to have developed Alzheimer’s disease. Meanwhile, 8.5% of non-vaccinated patients had developed Alzheimer’s disease during follow-up.
These results underscore the strong protective effect of the flu vaccine against Alzheimer’s disease, according to Bukhbinder and Schulz. However, the underlying mechanisms behind this process require further study.
“Since there is evidence that several vaccines may protect from Alzheimer’s disease, we are thinking that it isn’t a specific effect of the flu vaccine,” said Professor Paul. E. Schulz, MD, senior author of the study. “Instead, we believe that the immune system is complex, and some alterations, such as pneumonia, may activate it in a way that makes Alzheimer’s disease worse. But other things that activate the immune system may do so in a different way – one that protects from Alzheimer’s disease. Clearly, we have more to learn about how the immune system worsens or improves outcomes in this disease.”
Past research has uncovered a decreased risk of dementia associated with prior exposure to various adulthood vaccinations, including those for tetanus, polio, and herpes, in addition to the flu vaccine and others.
Additionally, as more time passes since the introduction of the COVID vaccine and longer follow-up data becomes available, Dr Bukhbinder said it seeing if there is a similar link between COVID vaccination and the risk of Alzheimer’s disease.
Scientists publishing in Neuron have described how a newly discovered neuron type may be involved with the formation of memory in the hippocampus, which is marked by high-frequency electrical events.
It is known that memory is represented by changes in the hippocampus. One of the well-established changes in the hippocampus that has been associated with memory is the presence of so-called sharp wave ripples (SWR). These are brief, high-frequency electrical events generated in the hippocampus, and they are believed to represent a major event occurring in the brain in the so-called episodic memory, such as recalling a life event or a friend’s phone number.
However, what happens in the hippocampus when SRWs are generated has not been well understood.
Now a new study sheds light on the existence of a neuron type in the mouse hippocampus that might be a key to better understanding of episodic memory.
Professor Marco Capogna and Assistant professor Wen-Hsien Hou have contributed to the discovery of the novel neuron that is associated with sharp wave ripples and memory.
Possible disruption in dementia and Alzheimer’s
The study describes the novel neuron type in the hippocampus.
“We have found that this new type of neuron is maximally active during SWRs when the animal is awake – but quiet – or deeply asleep. In contrast, the neuron is not active at all when there is a slow, synchronized neuronal population activity called “theta” that can occur when an animal is awake and moves or in a particular type of sleep when we usually dream,” Prof Capogna said.
Because of this dichotomic activity, this novel type of neuron is named theta off-ripples on (TORO).
“How come, TORO-neurons are so sensitive to SWRs? The paper tries to answer this question by describing the functional connectivity of TORO-neurons with other neurons and brain areas, an approach called circuit mapping. We find that TOROs are activated by other types of neurons in the hippocampus, namely CA3 pyramidal-neurons and are inhibited by inputs coming from other brain areas, such as the septum,” Prof Capogna explained.
“Furthermore, the study finds that TOROs are inhibitory neurons that release the neurotransmitter GABA. They send their output locally – as most GABAergic neurons do – within the hippocampus, but also project and inhibit other brain areas outside the hippocampus, such as the septum and the cortex. In this way, TORO-neurons propagate the SWR information broadly in the brain and signal that a memory event occurred,” he concluded.
The team has monitored the activity of the neuron by using electrophysiology – a technique that detects activity of the neurons by measuring voltage versus time, and by using imaging that detects activity by measuring changes in calcium signalling inside the neurons.
Demonstrating a causal link between the activity of TORO-nerve cells and memory will be the next step, and exploring whether inhibition of TORO-neurons and sharp wave ripples occurs in dementia and Alzheimer’s diseases.
Researchers have found that quantifiable changes can be measured in dogs suspected of suffering from cognitive decline: an approach that could serve as a model for evaluating cognitive decline progression in, and treatments for, humans with Alzheimer’s disease.
In dogs there is a similar condition to similar to Alzheimer’s disease in humans, canine cognitive dysfunction syndrome (CCDS). In CCDS, cognitive decline is associated with the development of amyloid plaques as well as cortical atrophy. CCDS is also challenging to diagnose. Traditionally, CCDS is diagnosed based on ruling out any obvious physical conditions and an owner’s answers to a questionnaire.
“One problem with the current approach is that questionnaires only capture a constellation of home behaviours,” explained Professor Natasha Olby, co-senior author of the paper. “There can be other reasons for what an owner may perceive as cognitive decline – anything from an undiagnosed infection to a brain tumour.”
Olby and co-senior author Assistant Professor Margaret Gruen, wanted to see if cognitive function could be accurately quantified in dogs.
“Our goal was to bring together multiple tools in order to get a more complete picture of how CCDS presents in dogs,” A/Prof Gruen said.
To accomplish this, they recruited 39 dogs from 15 breeds. All of them were in the senior and geriatric age range, but in good health overall. A dog is considered ‘senior’ if it is in the last 25% of its expected life span based on breed and size, and geriatric beyond that.
The dogs underwent physical and orthopaedic exams, as well as lab work that included a blood test that is a marker of neuronal death. Their owners filled out two commonly used diagnostic questionnaires, and then the dogs participated in a series of cognitive tests designed to assess executive function, memory and attention.
“The approach we took isn’t necessarily designed to be diagnostic; instead, we want to use these tools to be able to identify dogs at an early stage and be able to follow them as the disease progresses, quantifying the changes,” Prof Olby said.
The team found that cognitive and blood test results correlated well with the questionnaire scores, suggesting that a multi-dimensional approach can be used to quantify cognitive decline in aging dogs.
“Being able to diagnose and quantify CCDS in a way that is clinically safe and relevant is a good first step toward being able to work with dogs as a model for Alzheimer’s disease in humans,” Prof Olby said. “Many of the current models of Alzheimers disease – in rodents, for example – are good for understanding physiological changes, but not for testing treatments.”
“Dogs live in our homes and develop naturally occurring disease just like we do,” A/Prof Gruen said. “These findings show promise for both dogs and humans in terms of improving our understanding of disease progression as well as for potentially testing treatments.”
A University of Cambridge study appears to show that older adults who received lithium were less likely to develop dementia. The findings, which appear in the journal PLOS Medicine, are in agreement with other recent studies and could pave the way for larger investigations.
Dementia, the most common form of which is Alzheimer’s, currently represents the leading cause of death in elderly Western populations, but there are no preventative treatments available.
“The number of people with dementia continues to grow, which puts huge pressure on healthcare systems,” said Dr Shanquan Chen from Cambridge’s Department of Psychiatry, the paper’s first author. “It’s been estimated that delaying the onset of dementia by just five years could reduce its prevalence and economic impact by as much as 40 percent.”
In previous studies have proposed, lithium was proposed as a possible treatment for those with a dementia diagnosis or early cognitive impairment, but it is unclear whether it can delay or even prevent the development of dementia altogether, as these studies were limited in size.
Lithium is a mood stabiliser usually prescribed for conditions such as bipolar affective disorder and depression. “Bipolar disorder and depression are considered to put people at increased risk of dementia, so we had to make sure to account for this in our analysis,” said Dr Chen.
The researchers analysed data from 29 618 NHS patients who accessed mental health services between 2005 and 2019. Patients were all over 50 years of age, with a mean age just under 74, had received at least a one-year follow-up appointment, and had not been previously diagnosed with either mild cognitive impairment or dementia.
Of these patients, 548 had been treated with lithium and 29 070 had not. For the group that had received lithium, 53, or 9.7%, were diagnosed with dementia. For the group that had not received lithium, 3,244, or 11.2%, were diagnosed with dementia.
After controlling for factors such as smoking, other medications, and other physical and mental illnesses, lithium use was associated with a lower risk of dementia, both for short and long-term users. However, since the overall number of patients receiving lithium was small and this was an observational study, larger clinical trials would be needed to establish lithium as a potential treatment for dementia.
Another limitation of the study was the number of patients who had been diagnosed with bipolar disorder, which is normally associated with an increased risk of dementia. “We expected to find that patients with bipolar disorder were more likely to develop dementia, since that is the most common reason to be prescribed lithium, but our analysis suggested the opposite,” said Dr Chen. “It’s far too early to say for sure, but it’s possible that lithium might reduce the risk of dementia in people with bipolar disorder.”
Additional research is now needed to see if lithium really does have a benefit in these conditions.
Researchers at the National Robotarium in the UK, are developing an artificial intelligence (AI) ‘storytelling’ companion that will aid memory recollection, boost confidence and combat depression in patients suffering from Alzheimer’s disease and other types of dementia.
The idea for the ground-breaking ‘Agent-based Memory Prosthesis to Encourage Reminiscing’ (AMPER) project came from Dr Mei Yii Lim, a co-investigator of the project and an experienced memory modelling researcher.
In Alzheimer’s patients, memory loss occurs in reverse chronological order, with pockets of long-term memory remaining accessible even as the disease progresses. Rehabilitative care methods currently focus on physical aids and repetitive reminding techniques, but AMPER’s AI-driven user-centred approach will instead focus on personalised storytelling to help bring a patient’s memories back to the surface.
Dr Lim explained the project: “AMPER will explore the potential for AI to help access an individual’s personal memories residing in the still viable regions of the brain by creating natural, relatable stories. These will be tailored to their unique life experiences, age, social context and changing needs to encourage reminiscing.”
Having communication difficulties and decreased confidence are commonly experienced by people living with dementia and can often lead to individuals becoming withdrawn or depressed. By using AI to aid memory recollection, researchers at the National Robotarium hope that an individual’s sense of value, importance and belonging can be restored and quality of life improved.
The project’s long-term vision is to show that AI companions can become more widely used and integrated into domestic, educational, health and assistive-needs settings.
Professor Ruth Aylett from the National Robotarium is leading the research. She said: “One of the most difficult aspects of living with dementia can be changes in behavior caused by confusion or distress. We know that people can experience very different symptoms that require a range of support responses. Current intervention platforms used to aid memory recollection often take a one-size-fits-all approach that isn’t always suitable to an individual’s unique needs.”
“AI technology has the potential to play a pivotal role in improving the lives of people living with cognitive diseases. Our ambition is to develop an AI-driven companion that offers patients and their caregivers a flexible solution to help give an individual a sustained sense of self-worth, social acceptance and independence.
“Through projects like AMPER, we’re able to highlight the many ways AI and robotics can both help and improve life for people now and in the future. At the National Robotarium, we’re working on research that will benefit people in adult care settings as well as across a wide range of other sectors that will make life easier, safer and more supported for people.”
Once developed, the AI technology will be accessed through a tablet-based interface to make it more widely accessible and low-cost. The National Robotarium team will also investigate a using the AI in a desktop robot to see if a physical presence has any benefit.
A study in the journal Neurologyhas shown that a less expensive blood test to detect Alzheimer’s is highly accurate at early detection, providing further evidence that the test should be considered for routine screening and diagnosis.
“Our study shows that the blood test provides a robust measure for detecting amyloid plaques associated with Alzheimer’s disease, even among patients not yet experiencing cognitive declines,” said senior author Professor Randall J. Bateman, MD.
“A blood test for Alzheimer’s provides a huge boost for Alzheimer’s research and diagnosis, drastically cutting the time and cost of identifying patients for clinical trials and spurring the development of new treatment options,” Prof Bateman said. “As new drugs become available, a blood test could determine who might benefit from treatment, including those at very early stages of the disease.”
Developed by Prof Bateman and colleagues, the blood test assesses whether amyloid plaques have begun accumulating in the brain based on the ratio of the levels of the amyloid beta proteins Aβ42 and Aβ40 in the blood.
The gold standard PET scan evaluation requires a radioactive brain scan, at an average cost of $5000–$8000 (R75 000–R120 000) per scan. Another common test, which analyses levels of amyloid-beta and tau protein in cerebrospinal fluid, costs about $1000 (R15 000) but requires a spinal tap process.
This study estimates that prescreening with a $500 (R7500) blood test could halve both the cost and the time it takes to enrol patients in clinical trials that use PET scans. Using only blood testing for screening could be done in under six months, a tenth or less of the cost. The test is currently only available in the US and Europe.
The current study shows that the blood test remains highly accurate, even when performed in different labs following different protocols, and in different cohorts across three continents.
Scientists didn’t know if small differences in sampling methods (such as anticoagulant use) could have a big impact on test accuracy because results are based on subtle shifts in amyloid beta protein levels in the blood. Subtle interfernece in these amyloid protein ratios could have triggered a false negative or positive result.
To confirm the test’s accuracy, researchers tested blood samples from current Alzheimer’s studies in the United States, Australia and Sweden, each of which uses different protocols for the processing of blood samples and related brain imaging.
Findings from this study confirmed that the Aβ42/Aβ40 blood test using a high-precision immunoprecipitation mass spectrometry technique developed at Washington University provides highly accurate and consistent results for both cognitively impaired and unimpaired individuals across all three studies.
When blood amyloid levels were combined with another major Alzheimer’s risk factor – the presence of the genetic variant APOE4 – the blood test accuracy was 88% compared to brain imaging and 93% when compared to spinal tap.
“These results suggest the test can be useful in identifying nonimpaired patients who may be at risk for future dementia, offering them the opportunity to get enrolled in clinical trials when early intervention has the potential to do the most good,” Prof Bateman said. “A negative test result also could help doctors rule out Alzheimer’s in patients whose impairments may be related to some other health issue, disease or medication.”
A large UK study found that use of menopausal hormone therapy (MHT, also known as hormone replacement therapy, HRT) is not associated with increased dementia risk.
The study, published in the BMJ, found within the subgroup of women with a specific diagnosis for Alzheimer’s disease, a slight increasing risk association was found with use of oestrogen-progestogen treatments, but only seen for long-term usage (5 years or more).
This study “brings clarity to previously inconsistent findings and should reassure women in need of menopausal hormonal therapy,” said the researchers.
MHT relieves menopausal symptoms such as hot flushes, sleep disturbance, mood swings, memory losses and depression. Treatment includes oral tablets with oestrogen only, or oestrogen and progestogen combined, as well as patches, gels and creams.
Early signs of dementia are similar to some menopausal symptoms. Research has shown a beneficial link between oestrogen and age-related brain decline. However, in the largest trial of MHT, the Women’s Health Initiative Memory Study, an increased dementia risk was found among users of oestrogen-progestogen treatments. A recent study picked up a possible link to Alzheimer’s disease among users of both oestrogen-only and oestrogen-progestogen treatments, though the study has some issues.
To address this uncertainty, researchers set out to investigate the risks of developing dementia for women using commonly available menopausal hormone therapy treatments.
They used two UK primary care databases to analyse MHT prescriptions for the 118 501 women aged 55 and older diagnosed with dementia between 1998 and 2020 (cases), and 497 416 matched women without dementia (controls).
After adjusting for confounding factors, no overall associations were found between use of hormone therapy and risk of dementia, regardless of hormone type, application, dose, or duration of treatment. Only a slightly decreased risk of dementia was found in one subgroup: those under 80 years who had been taking oestrogen-only therapy for 10 years or more. Analysis of cases with a specific diagnosis of Alzheimer’s disease showed a slight increase in risk associated with oestrogen-progestogen therapy. This rose gradually with each year of exposure, reaching an average 11% increased risk for use of between 5 and 9 years and an average 19% for use of 10 years or more, equivalent to, respectively, five and seven extra cases per 10 000 woman years.
As this is an observational study it cannot establish cause, and some limitations include incomplete recording of menopausal symptoms, particularly for women registered after their menopause. However, its large size counts in its favour. According to the researchers, this study provides the most detailed estimates of risk for individual treatments, and their results are in line with existing concerns in guidelines about long term exposures to combined hormone therapy treatments.
“The findings will be helpful to policy makers, doctors, and patients when making choices about hormone therapy,” they concluded.
The findings do not change the recommendation that menopausal hormone therapy should not be used to prevent dementia, US researchers commented in a linked opinion article. However, it is helpful for providers to put dementia findings in context for patients, they added.
“The primary indication for hormone therapy continues to be the treatment of vasomotor symptoms, and the current study should provide reassurance for women and their providers when treatment is prescribed for that reason,” they concluded.
