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Why sex and gender matter in Alzheimer’s research

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An international panel of experts has issued a “consensus statement” on sex and gender disparities in resilience to Alzheimer’s disease; which they hope will help to shape future research.

Based on a review of a large body of literature, the panel identified sex and gender differences in dementia risk and identified a gap in the understanding of specific risk and resilience pathways.

While women tend to have an initial cognitive advantage, they decline faster than men as the disease progresses. This may be due to differential development of pathologies, known as resistance to Alzheimer’s disease, or different ability to maintain normal functioning over time and cope with pathology once this is present, known as cognitive resilience to Alzheimer’s disease.

In fact, women initially show greater resilience, coping better with brain pathology and atrophy and maintaining cognitive function. The greater initial resilience in women is supported by animal research showing a protective role of the X-Chromosome in Alzheimer’s disease (females typically have two X chromosomes, while males have one).

However, this initial resilience fades away as they progress towards a clinical diagnosis of mild cognitive impairment and Alzheimer’s disease, when they show greater vulnerability. Indeed, studies suggest that women are more likely to have an abnormal build-up of tau protein in the brain and show a higher burden of vascular pathologies, particularly after the menopause.

The authors propose various mechanisms explaining the difference in risk and resilience between women and men, including a higher prevalence of physical inactivity and affective disorders in women, but also biological factors. In this regard, genetic evidence suggests that resilience might be associated with immune pathways in females and cardiovascular pathways in men.

The panel was led by the Barcelona Institute for Global Health (ISGlobal), a centre supported by the “la Caixa” Foundation, under the umbrella of the Alzheimer’s Association International Society to Advance Alzheimer’s Research and Treatment. Its work has been published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

Eider Arenaza-Urquijo, first author of the study, said: “Assessing how sex and gender interact is crucial to understanding the mechanisms that maintain cognitive function and reduce the accumulation of pathologies in ageing and Alzheimer’s disease, i.e. resilience and resistance factors.”

According to the research team, studies of resilience in Alzheimer’s disease have mainly focused on individual behaviour, without taking into account how social and cultural factors, such as gender, influence behaviour and therefore risk and resilience. Importantly, differences in cognitive function between men and women may be decreasing as gender inequalities also decrease due to more opportunities for women in education, workforce participation, and improvements in their economic status and living conditions.

“Protective factors, such as education, may have different effects in men and women. We need to understand the complexity of interactions between biological and social factors to understand resilience to Alzheimer’s disease”, argues Arenaza-Urquijo.

For this reason, the authors call for a sex- and gender-sensitive approach to resilience to better understand the complex interplay of biological and social determinants. “Focusing more on the differential effects of modifiable factors will help to determine whether a particular factor has a greater impact on cognitive or brain resilience in men or women”, remarks Arenaza-Urquijo.

To improve our understanding of how sex and gender affect cognitive resilience to ageing and Alzheimer’s disease, the researchers recommend several directions for future studies. First, they stress the need to explore how sex and gender factors interact across cultures, taking into account the demographic, genetic, social and clinical differences that influence dementia risk.

They point out that sex/gender differences in brain characteristics, such as brain connectivity, remain understudied as resilience factors for Alzheimer’s disease that may minimise the impact of pathologies on cognition.

The authors also argue that publishing negative results is crucial to avoid bias and that all studies should include sex-disaggregated results.

Finally, they point out the importance of considering sex and gender in a non-binary way, and of including LGTBIQ+ populations, who are often underrepresented and face a higher burden of chronic disease.

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On a mission to show that hearing loss is not inevitable

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The world’s largest investigation into the effectiveness of hearing training kicks off this week – as part of a movement to prove that hearing loss is not an inevitable part of ageing.

The research project aims to attract a minimum of 10,000 participants to better understand how hearing training impacts auditory processing skills like speech comprehension and the ability to locate where sounds are coming from.

Researchers are interested in the impact of hearing training on users who start training with different hearing ability levels, as well as training adherence in groups with different attitudes to smartphone technology.

Their aim is to find new ways to deliver and improve auditory training at scale and for a wider range of hearing skills; and to measure factors which influence training engagement.

The research is led by health tech firm Eargym. Co-founder Andy Shanks says:  Contrary to popular belief, hearing loss is not an inevitable consequence of ageing. We can take steps to improve and protect our hearing throughout our lives, yet preventative measures like hearing training have traditionally been under-researched.

“Our data shows the transformative impact hearing training can have on our ability to process sounds. Now, we want to deepen and widen our research and use our platform to make hearing training even more effective and accessible. Imagine improving and maintaining your hearing by up to 20% or more: it could make a big difference to the lives of so many people.”

The games on the Eargym app include a “busy barista” exercise, where users must discern speech over a cafe’s bustling background noise; and a “sound seeking” exercise, where users make their way through forests, jungles and oceans to locate the sources of different sounds. Each game is designed to be immersive and to help users practise specific auditory processing skills regularly.

Eargym was set up by former NHS CEO Amanda Philpott and DJ Andy Shanks in 2020, after they were both diagnosed with hearing loss. Amanda has moderate age related hearing loss, whilst Andy has “notch” or noise-induced hearing loss due to DJ-ing. Both found hearing loss isolating and it impacted their ability to socialise and communicate. They created eargym to empower others to better understand their hearing health and take proactive steps to protect it.

Hearing loss currently affects 18 million adults in the UK, with around one billion young people at risk of developing hearing loss due to increased use of headphones. Hearing loss is closely associated with increased dementia risk. Despite this, people wait an average ten years before seeking help for hearing loss.

Eargym plans to publish the findings of its research in early 2025.

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Interview: Exploring electrical stimulation for Parkinson’s disease

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The STEPS II study is investigating functional electrical stimulation (FES) in people with Parkinson’s disease to help improve their walking. Dr Paul Taylor, co-founder and Clinical Director of Odstock Medical Ltd (OML), spoke to Agetech World to tell us more.

Bradykinesia – slowness of movement which can lead to difficulty walking – affects many people living with Parkinson’s disease. The symptom can cause Parkinson’s patients to walk or move slowly, increasing the risk of falls, leading to a reduced quality of life and an increased dependence on others. 

Funded by the National Institute for Health and Care Research, sponsored by Salisbury NHS Foundation Trust, and managed by the University of Plymouth’s Peninsula Clinical Trials Unit, the STEPS II study is exploring the use of an FES device in Parkinson’s patients to help improve bradykinesia. 

The FES device, which has been pioneered by Salisbury researchers as a drop foot treatment for stroke and MS patients, is attached to the patient’s leg and produces small electrical impulses that improve movement.

“If you have Bradykinesia you’re moving slowly. The predominant treatment for Parkinson’s is medication and these can be very effective, but they have the problem of not working all the time,” explains Taylor, co-founder of Odstock Medical Ltd, a company owned by Salisbury NHS Foundation Trust.

”The effects of the drugs will wear off and after a period of time they become less effective, so, there’s a need for improvement.”

Taylor explains that deep brain stimulators are currently available, however, they are very invasive, expensive and can be risky. 

“We’re trying to do something which is a bit simpler and cheaper, which may possibly be able to help people at an earlier stage of Parkinson’s,” Taylor says.

“We’re stimulating the common peroneal nerve, which is the nerve that goes down the leg to the muscles, using a device called a drop foot stimulator. The device is commonly used for stroke and multiple sclerosis.”

A small feasibility study has already been conducted, which showed that FES can help patients walk faster and reduce some symptoms of Parkinson’s. 

In the STEPS II study, researchers hope to confirm the long-term effects of FES on walking speed and daily life with 234 participants at sites across Salisbury, Birmingham, Prestwick, Leeds, Swansea and Carlisle.

Taylor continues: “Our original idea was that we could use electrical stimulation to overcome freezing – which is the effect where people with Parkinson’s will stop walking, particularly when they come to doorways or very narrow areas. It’s to do with the processing of information from the outside world. 

“We wanted to see if we could use electrical stimulation to overcome that freezing and, to a certain extent, we did find that is the case for some patients, but more commonly and with a greater number of patients FES affected bradykinesia – speeding up their movement and helping with more effective walking.”

For the STEPS II study, participants will be randomised into a care as normal group, or a care as normal plus FES group. They will use the stimulator if they are in the FES group for 18 weeks, then the stimulator is taken away, with patients followed up one month later to see if the effects are continued.

Measurements of walking speed and movement will be analysed, along with sensory perception, balance, coordination, muscle strength, as well as secondary effects such as how the device impacts daily living and quality of life.

OML has established clinics around the country with trained therapists where the device will be used if the study is successful. 

“There’s a network of clinics already experienced in using the treatment so we plan to reach those clinics to include Parkinson’s patients in their cohorts,” says Taylor. “Then we’ll work with our contacts to see if we can get it overseas as well.”

OML is currently recruiting participants for the study, to find out more please visit: https://www.plymouth.ac.uk/research/penctu/steps-2 

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Quit Googling to stave off dementia onset, expert urges

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Resisting the temptation to search the web for information that could otherwise be recalled be exercising your brain could help to reduce the risk of dementia.

That is according to Canadian academic Professor Mohamed I. Elmasry who believes simple daily habits such as afternoon naps, memory ‘workouts’ and not reaching for a smartphone can increase the odds of healthy aging.

His new book, iMind: Artificial and Real Intelligence, says the focus has shifted too far away from RI (natural, or real) intelligence in favour of AI (machine, or artificial) intelligence. Elmasry instead calls us to nurture our human mind which, like smartphones, has ‘hardware’, ‘software’ and ‘apps’ but is many times more powerful – and will last much longer with the right care.

Professor Elmasry, an internationally recognised expert in microchip design and AI, was inspired to write the book after the death of his brother-in-law from Alzheimer’s and others very close to him, including his mother, from other forms of dementia.

Although he says that smart devices are ‘getting smarter all the time’, he argues in iMind that none comes close to ‘duplicating the capacity, storage, longevity, energy efficiency, or self-healing capabilities of the original human brain-mind’.

He writes that: “The useful life expectancy for current smartphones is around 10 years, while a healthy brain-mind inside a healthy human body can live for 100 years or longer.

“Your brain-mind is the highest-value asset you have, or will ever have. Increase its potential and longevity by caring for it early in life, keeping it and your body healthy so it can continue to develop.

“Humans can intentionally develop and test their memories by playing ‘brain games,’ or performing daily brain exercises. You can’t exercise your smartphone’s memory to make it last longer or encourage it to perform at a higher level.”

In iMind: Artificial and Real Intelligence Professor Elmasry shares an anecdote about his grandchildren having to use the search engine on their smartphones to name Cuba’s capital—they had just spent a week in the country with their parents.

The story illustrates how young people have come to rely on AI smartphone apps instead of using their real intelligence (RI), he says, adding: “A healthy memory goes hand-in-hand with real intelligence. Our memory simply can’t reach its full potential without RI.”

Published by Routledge, iMind: Artificial and Real Intelligence includes extensive background on the history of microchip design, machine learning and AI and their role in smartphones and other technology.

The book also explains how both AI and human intelligence really work, and how brain function links the mind and memory. It compares the human mind and brain function with that of smartphones, ChatGPT and other AI-based systems.

Drawing on comprehensive existing research, iMind aims to narrow the knowledge gap between real and artificial intelligence, to address the current controversy around AI, and to inspire researchers to find new treatments for Alzheimer’s, other neurodegenerative conditions and cancer.

It argues that current or even planned AI cannot match the capabilities of the human brain-mind for speed, accuracy, storage capacity and other functions. Healthy aging, Professor Elmasry notes, is as important as climate change but doesn’t attract a fraction of the publicity.

He calls for policymakers to adopt a series of key reforms to promote healthy aging. Among such changes, he suggests that bingo halls could transition from their sedentary entertainment function to become active and stimulating learning centers.

As well as napping to refresh our memories and other brain and body functions, he also outlines a series of practical tips to boost brain power and enhance our RI (Real Intelligence).

These include building up ‘associative’ memory – the brain’s ‘dictionary of meaning’ where it attaches new information to what it already knows. Try reading a book aloud, using all of your senses instead of going on autopilot and turning daily encounters into fully-lived experiences.

Other techniques include integrating a day for true rest into the week, reviewing your lifestyle as early as your 20s or 30s, adopting a healthy diet, and eliminating or radically moderating alcohol consumption to reduce the risk of dementia.

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