Researchers identify biomarker of cognitive fatigue in multiple sclerosis and long Covid

 Have your competent? doctors and hospital get research going on biomarkers of post stroke fatigue, so we can get protocols created that remove that fatigue! My idiot of a doctor just said I needed more cardiovascular fitness, i.e. more exercise.  He never tested my fitness level which was at the kevel of an athlete.

3 years post stroke at a physical I had a resting heart rate of 54 at age 53, level of an athlete. My doctor asked what exercises I was doing; 'I've done no exercises for the past 3 years'.  And now 20 years past the stroke my fitness has declined a bit, ALL BECAUSE MY STROKE MEDICAL 'PROFESSIONALS' COMPLETELY FAILED AT GETTING ME 100% RECOVERED!  Still managed to get to Tiger's Nest in Bhutan at 10,240 feet in 2023

Researchers identify biomarker of cognitive fatigue in multiple sclerosis and long Covid

New work could pave the way for objective assessment of cognitive fatigue across multiple conditions.

For many people with post-Covid-19 syndrome, also known as 'long Covid', the mental exhaustion, difficulties with concentrating, and impaired cognitive performance that characterise cognitive fatigue can be some of the most disabling symptoms. Cognitive fatigue is also commonly reported by people suffering from other post-viral conditions, as well as conditions such as multiple sclerosis (MS).

However, the underlying causes of this kind of fatigue remain elusive, write Stefanie Linnhoff at Otto-von-Guericke University, Germany, and colleagues in a recent paper in Psychological Medicine. That's largely down to its "subjective and often invisible nature", along with a lack of objective diagnostic markers, they write. In their paper, though, they describe what they believe to be a marker — one that they think could be used to monitor cognitive fatigue in people with a range of different disorders.

Linnhoff and her colleagues recruited 119 participants for their study. Of these, 36 were healthy controls, 33 had 'long Covid-related fatigue', and 50 had MS. All completed a questionnaire that asked about cognitive fatigue, and this led the team to identify 23 of the MS group as being fatigued, and the rest as non-fatigued. The team then used EEG to monitor activity in the participants' brains while they spent three minutes at rest with their eyes closed.

When the researchers analysed the EEG data, they were on the look-out for something called 'aperiodic activity' — irregular electrical signals that were once dismissed as a kind of background noise in the brain, but are now recognised as representing the overall balance between excitation and inhibition in neural networks.

Two neurotransmitters are crucial for this balance; the neurotransmitter glutamate increases excitation (meaning signals are more likely to pass between neurons), while GABA does the opposite. Having the right 'excitation/inhibition (E/I) balance' is important for healthy brain function, and, as the team notes, disruptions to this balance have been linked to various neurological and psychiatric disorders, including MS.

When the team compared the subjective fatigue scores from the participants with the EEG recordings, they found that higher fatigue was associated with lower, flatter, aperiodic values, reflecting a shift towards excitatory activity, in the frontal region of the brain. The long Covid and the fatigued — but not the non-fatigued — MS participants had similar aperiodic activity.

This type of activity in one area of the frontal region, in particular, seemed to be especially tied to fatigue scores. This was the left dorsolateral prefrontal cortex, an area that is important for a number of cognitive functions, including sustained attention and cognitive control. The team writes: "This… points to the dlPFC as a potential common hub of vulnerability in fatigue, possibly reflecting a final common pathway of disrupted cognitive control due to impaired E/I balance."

Further work would be needed to explore whether changes to the E/I balance cause cognitive fatigue, or whether the opposite is true and fatigue drives changes in this balance — as well as to explore whether, as the team suspects, these findings will be replicated in people with cognitive fatigue associated with other conditions. Teams elsewhere are also investigating other potential brain markers of cognitive fatigue; in a recent study of groups of people with myalgic encephalomyelitis and long Covid, for example, Maira Inderyas at Griffith University in Australia and her colleagues reported finding reduced connectivity between various brain regions, which they linked to blunted motivation as well as cognition.

Linnhoff and her colleagues now hope that their findings will pave the way for new, objective ways of assessing cognitive fatigue in patients, as well as for evaluating the effectiveness of treatments.

Read the paper in full:
Linnhoff, S., Kadosh, R. C., & Tino Zaehle. (2026). EEG-based frontal excitation/inhibition balance as an objective biomarker for cognitive fatigue across multiple sclerosis and Long COVID. Psychological Medicine, 56, e21–e21. https://doi.org/10.1017/s0033291725103024

A brief fitness test may predict how long you’ll live

 

In the past 19 years my score would always be 1.5 and it will never get better during my next 31 years. It has absolutely nothing to do with my longevity or cardiovascular risk!

A brief fitness test may predict how long you’ll live

The sit-to-rise test assesses your strength, flexibility, and balance, which are important (but sometimes overlooked) aspects of fitness.

October 1, 2025

By Julie Corliss, Executive Editor, Harvard Heart Letter

• Reviewed by Christopher P. Cannon, MD, Editor in Chief, Harvard Heart Letter; Editorial Advisory Board Member, Harvard Health Publishing

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European Journal of Preventive Cardiology

The study included 4,282 people ages 46 to 75 who did the sit-to-rise test as part of a medical evaluation; researchers then tracked them for an average of about 12 years. The test is scored by starting with 10 points and then subtracting one point every time a person uses a hand, knee, or other support, and a half point every time the person is unsteady or wobbly. Compared to people who scored a 10 (no supports or wobbling), those who scored between 4.5 and 7.5 were about three times as likely to die during the follow-up period. And those who scored 0 to 4 had six times the risk of dying of cardiovascular disease.(So, I should have died in the past 19 years! But my cardiovascular fitness 3 years post stroke was the level of an athlete; age 53, resting heart rate was 54.)

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Boost Brain Health by Following Your Heart: Simple Steps for Longevity

 After your stroke your doctor needs to have accomplished 100% recovery for you so you can get cardiovascularly fit.

3 years post stroke at a physical I had a resting heart rate of 54 at age 53, level of an athlete. My doctor asked what exercises I was doing; 'I've done no exercises for the past 3 years'.  And now 19 years past the stroke my fitness has declined a bit, ALL BECAUSE MY STROKE MEDICAL 'PROFESSIONALS' COMPLETELY FAILED AT GETTING ME 100% RECOVERED!

Boost Brain Health by Following Your Heart: Simple Steps for Longevity

Summary: New research highlights that optimal brain health, crucial for maintaining cognitive function as we age, is strongly linked to cardiovascular wellness. The study underscores that dementia and cognitive decline share risk factors with heart disease, suggesting these conditions are largely preventable by managing diet, exercise, cholesterol, blood sugar, and blood pressure.

Following guidelines such as the American Heart Association’s Life Essential 8—eight essential behaviors to improve cardiovascular and brain health—can significantly lower the risk of developing dementia. Experts argue that integrating these heart-healthy habits into everyday life offers a practical strategy for reducing the growing global burden of dementia.

Key Facts:

• Shared Risk Factors: Dementia and heart disease share common modifiable risk factors, such as diet, blood pressure, and cholesterol.
• Rising Burden: Globally, dementia cases have risen 160% since 1990, outpacing cardiovascular disease.
• Preventative Strategies: Adopting the American Heart Association’s “Life Essential 8” could significantly protect brain health and reduce dementia risk.

Source: AHA

The average adult brain only weighs about 3 pounds, yet it is one of the most complex and vital organs of the human body.

Cognition may decline and our brains become prone to disease as we age, so as medical advances and other factors help the world’s population live longer the prevalence of brain disease, including dementia, is on the rise.

However, keeping our brains healthy may be easier than people realize with some helpful guidance from the American Heart Association, a global force changing the future of health of all.

Elkind said following the American Heart Association’s Life Essential 8™ can be as beneficial for brain health as it is for heart health. Credit: Neuroscience News

Optimal brain health includes the functional ability to perform all the diverse tasks for which the brain is responsible – including thinking, moving and feeling.

Many modifiable risk factors for cognitive loss, such as an unhealthy diet and sedentary lifestyle, develop as early as childhood and adolescence. As we age, our ability to remember, problem-solve, think and communicate decreases.

“We now know that many of the same health risk factors that cause heart disease and stroke also contribute to a decline in overall brain health,” said Mitchell S. V. Elkind, M.D., M.S., FAHA, a neurologist and former volunteer American Heart Association president and currently its chief clinical science officer.

“Just like with heart disease and stroke, most brain disease is preventable. However, the combination of an aging population and projected substantial increases in high blood pressure, obesity and diabetes are likely to lead to unprecedented growth in many types of brain disease.”

According to data reported in the 2025 Heart Disease and Stroke Statistics: A Report of U.S. and Global Data From the American Heart Association:

• Alzheimer’s disease is the 7^th leading cause of death in the U.S. and the leading cause of death among all neurological disorders, including stroke.
• More females than males die of dementia each year because of the higher prevalence of elderly females compared with males. Females accounted for 66.7% of U.S. dementia deaths in 2022.
• More than 6.9 million people in the U.S. are living with Alzheimer’s disease.
• An analysis of Medicare data reported in the update estimates that prevalence will more than double to 13.9 million Americans by 2060.

Also reported in the statistical update:

• Worldwide, nearly 57 million people had Alzheimer’s disease and other dementias in 2021, a 45% increase since 2010 and a 160% increase over the past 30 years (1990-2021). For comparison, the prevalence of cardiovascular disease increased 33% over the past decade and 111% over the past 30 years
• The increase in global deaths from Alzheimer’s disease and other dementias is outpacing that of cardiovascular disease even more – dementia deaths increased by nearly 195% since 1990, compared to a 57% increase in cardiovascular deaths during that same time.
• Estimated U.S. healthcare spending on dementia more than doubled from $38.6 billion in 1996 to $79.2 billion in 2016. Spending on dementias was among the top 10 healthcare costs in the United States in 2016.

“The burden of brain disorders is high. Dementia as a cause of death is growing faster than any other disease, including heart disease, the number one cause of death worldwide. Paradoxically, as we get better at treating other conditions, like heart disease, stroke and cancer, dementia as a cause of death increases,” Elkind said.

“Using many of the same tools and information that have helped us successfully address cardiovascular risk factors and reduce the burden of heart disease over the past several decades, we should be able to do the same for brain disorders and promote brain health.”

Elkind said following the American Heart Association’s Life Essential 8™ can be as beneficial for brain health as it is for heart health. These include 4 health behaviors and 4 health factors identified as key measures for improving and maintaining cardiovascular health:

• Health Behaviors: Eat Better
• Health Behaviors: Be More Active
• Health Behaviors: Quit Tobacco
• Health Behaviors: Get Healthy Sleep
• Health Factors: Manage Weight
• Health Factors: Control Cholesterol
• Health Factors: Manage Blood Sugar
• Health Factors: Manage Blood Pressure

“The American Heart Association is committed to advancing brain science through innovative research that will help scientists shed new light on the causes and contributors to cognitive impairment and dementia, particularly as it relates to heart and vascular health,” Elkind said.

“Additionally, we can support individuals and communities in thinking of brain health not only in terms of an absence of disease, but also in a more positive way. We can look at how we optimize brain function to include positive cognitive traits like creativity, adaptability, resilience, empathy and others.”

He said the increasing cost of poor brain health in lives and dollars makes the Association’s ongoing commitment to better understand how brains age and how vascular health impacts brain health and overall well-being even more imperative.

“When people are asked what health conditions they fear the most with aging, dementia tops the list, surpassing even cancer, heart disease and stroke,” Elkind said.

“It’s critical that as a society and as individuals we understand and make the changes needed to improve health outcomes from brain disease and, more importantly, prevent them to begin with.”

About this brain health and longevity research news

Author: Cathy Lewis
Source: AHA
Contact: Cathy Lewis – AHA
Image: The image is credited to Neuroscience News

Fitness Level May Offset Genetic Dementia Risk

 

 3 years post stroke at a physical I had a resting heart rate of 54 at age 53, level of an athlete. My doctor asked what exercises I was doing; 'I've done no exercises for the past 3 years'.  And now 18 years past the stroke my fitness has declined a bit, ALL BECAUSE MY STROKE MEDICAL 'PROFESSIONALS' COMPLETELY FAILED AT GETTING ME 100% RECOVERED!

Fitness Level May Offset Genetic Dementia Risk

      In middle-age and older adults, high cardiorespiratory fitness was linked with better cognition

by Judy George, Deputy Managing Editor, MedPage Today November 19, 2024

Key Takeaways

• High fitness was associated with lower dementia risk, even in people with genetic predisposition.
• Across all age groups between 39 and 70, higher fitness was tied to better cognitive function.
• Cardiorespiratory fitness may a predictor of cognitive health, the researchers suggested.

Genetic risk for Alzheimer's disease and dementia appeared to be partly offset by high levels of cardiorespiratory fitness, U.K. Biobank data suggested.

Overall, high cardiorespiratory fitness was associated with better global and domain-specific cognitive functions and lower risk of dementia in both middle-age and older adults, reported Weili Xu, PhD, of the Karolinska Institute in Stockholm, and co-authors.

The incidence rate ratio (IRR) of all-cause dementia was 0.60 (95% CI 0.48-0.76) for high versus low cardiorespiratory fitness. Dementia onset was delayed by 1.48 years (95% CI 0.58- 2.39) in the high fitness group.

Among people with moderate or high genetic dementia risk scores, high cardiorespiratory fitness attenuated dementia risk by 35% (IRR 0.65, 95% CI 0.52-0.83) compared with low fitness, Xu and colleagues said in the British Journal of Sports Medicine.

"Cardiorespiratory fitness may be used as a predictor of cognitive health," the researchers stated. "Enhancing cardiorespiratory fitness could be a strategy for the prevention of dementia, even among people with a high genetic predisposition for Alzheimer's disease."

No study to date has explored the combined effect of cardiorespiratory fitness and genetic risk on dementia, Xu and colleagues pointed out. "Open questions remain regarding whether and to what extent favorable cardiorespiratory fitness may reduce dementia risk, even in those with a high genetic predisposition for dementia," they noted.

In this analysis, the researchers followed 61,214 dementia-free U.K. Biobank participants ages 39-70 for a median of 11.72 years. Mean baseline age was 56 and 52% of participants were female.

A 6-minute submaximal exercise test on a stationary bike was completed at study enrollment (from 2006 through 2010) to estimate cardiorespiratory fitness. Fitness scores were divided into low, moderate, and high tertiles, standardized by age and sex.

Global and domain-specific cognitive function was evaluated at baseline. Dementia was identified over the follow-up period using medical history and medical records. Genetic predisposition for dementia was estimated using polygenic risk scores for Alzheimer's disease derived from genome-wide association studies.

During the follow-up period which spanned to 12 years, 553 people (0.9%) received a diagnosis of dementia. High cardiorespiratory fitness was associated with a lower risk of dementia and a delay in the onset of dementia across middle and older ages.

In multi-adjusted linear regression models, higher cardiorespiratory fitness was associated with better global cognitive function, prospective memory, verbal/numeric memory, and processing speed in all participants. The association between cardiorespiratory fitness and cognitive function was consistent in different age and genetic risk groups.

"Future research on the relationship between cardiorespiratory fitness and brain health, especially in older adults, is warranted, and the mechanisms by which cardiorespiratory fitness modifies the relationship between genetic risk and dementia deserve further investigation," Xu and colleagues observed.

"As the measurement of cardiorespiratory fitness in clinical settings becomes both important and feasible, cardiorespiratory fitness may be used as a routine health monitoring tool or an indicator of health conditions," they added.

The study was observational and cannot determine causality. Also, U.K. Biobank participants often are healthier than the general population, the researchers acknowledged.

U.K. Biobank participants with certain health conditions -- such as chest pain at rest, high weight, high blood pressure, or a pacemaker -- were excluded from the exercise test, which may have influenced outcomes. The submaximal exercise test used in this study is considered less accurate than maximal exercise testing which requires participants to exercise to exhaustion, Xu and co-authors said.

In addition, incident dementia cases were determined through register information, which might have led to an underestimation. Most participants did not have repeated cardiorespiratory fitness measurements, and relationships between changes in cardiorespiratory fitness and dementia risk could not be determined.

• Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow

Disclosures

This research was supported by the Swedish Research Council, the Swedish Council for Health Working Life and Welfare, and the Karolinska Institutet Research Foundation.

Xu and co-authors reported no conflicts of interest.

Primary Source

British‌ ‌Journal‌ ‌of‌ ‌Sports‌ ‌Medicine‌‌

Source Reference: Wang S, et al "Association of cardiorespiratory fitness with dementia risk across different levels of genetic predisposition: a large community-based longitudinal study" Br J Sports Med 2024; DOI: 10.1136/bjsports-2023-108048.

Cardiovascular health in middle age strongly associated with brain health in later years

 3 years post stroke at a physical I had a resting heart rate of 54 at age 53, level of an athlete. My doctor asked what exercises I was doing; 'I've done no exercises for the past 3 years'.  

Still had a stroke because my dad's doctor didn't tell him to have his children tested for carotid plaque when he was found to have 80% blockage in his 80's. I'm not going to get either dementia or late life depression, there is too much fun yet to be had.

I'm definitely an optimist, will live to 100 because of these two quotes assuming I'm not too reckless; 

Part of my Hunter S. Thompson journey;

“Life should not be a journey to the grave with the intention of arriving safely in a pretty and well preserved body, but rather to skid in broadside in a cloud of smoke, thoroughly used up, totally worn out, and loudly proclaiming "Wow! What a Ride!”

"Your body is not a temple: It's an amusement park. Enjoy the ride." Anthony Bourdain

The latest here:

Cardiovascular health in middle age strongly associated with brain health in later years

Key takeaways:

• Lifestyle habits such as diet and exercise were linked to a higher risk for stroke or dementia later in life.
• More research is needed, including how factors such as race and ethnicity influence the association.

Cardiovascular health of middle-aged adults was significantly associated with the risk of poor brain health later in life, according to a study published in Neurology.

“Brain health is paramount for the optimal well-being of every person, enabling us to function at our highest level and constantly adapt in the world,” Santiago Clocchiatti-Tuozzo, MD, MHS, study author and postdoctoral fellow in geriatric clinical epidemiology and aging-related research in the department of neurology at Yale University, said in a release related to the study.

The latest research into brain and heart health found that ardiovascular health of middle-aged adults was significantly associated with the risk of poor brain health later in life. Image: Adobe Stock

The American Heart Association’s Life’s Essential 8 (LE8) is a compilation of factors that determine cardiovascular health, although its cumulative effect on metrics related to brain health is unknown. The score encompasses eight modifiable cardiovascular risk factors: blood pressure, glucose, cholesterol, BMI, smoking, physical activity, diet, sleep duration. The factors are organized into 3 subcategories: optimal, intermediate and poor.

Clocchiatti-Tuozzo and colleagues investigated the supposition that worse LE8 profiles in middle-aged adults are associated with higher overall risk of the most relevant clinical factors that contribute to poor brain health.

The researchers engaged in a two-stage prospective study that culled data from the U.K. Biobank (UKB) and All of Us (AoU), the former from the United Kingdom that enrolled more than 500,000 individuals between 2006 and 2010 and the latter an ongoing U.S. cohort study being conducted by the NIH since 2018 with 400,000 people currently enrolled. The discovery stage included 316,127 UKB participants (mean age, 56 years; 52% women), while the replication stage included 68,407 AoU participants (mean age, 56 years; 60% women).

LE8 score was calculated for each individual component, then again for overall score for each participant as an unweighted average of the eight component scores; researchers subsequently divided the overall LE8 scores into three subcategories based on total score (less than 20 meaning poor cardiovascular health; 20 to 80 as intermediate and more than 80 representing optimal cardiovascular health).

The study’s primary outcome was a composite of stroke, dementia or late-life depression, with additional covariate analysis including demographic information collected at each study’s baseline interviews.

According to results, over a mean follow-up time of 4.9 years in the discovery stage, the unadjusted risks for composite outcomes were 0.7% (95% CI 0.61–0.74) for optimal, 1.2% (95% CI 1.11–1.22) for intermediate and 1.8% (95% CI 1.70–1.91) for poor cardiovascular health, respectively.

Data further showed that, over a follow-up of 2.9 years for the replication stage, unadjusted risk of composite outcomes was 2.8% (95% CI 2.49–3.05) for optimal, 6% (95% CI 5.76–6.22) for intermediate and 9.7% (95% CI 9.24–10.24) for poor cardiovascular health.

The association remained in comparative analysis of intermediate vs. optimal cardiovascular health (HR = 1.35; 95% CI, 1.21–1.51) and poor vs. optimal cardiovascular health (HR =1.94; 95% CI, 1.72–2.18).

“Our findings highlight the potential brain health benefits of using these eight cardiovascular and brain health factors to guide healthy lifestyle choices,” Clocchiatti-Tuozzo said in the release. “More research is needed to understand this link between lifestyle habits and brain health, as well as how social factors like race and ethnicity can influence this connection.”

Reference:

Live well, think well: Research shows healthy habits tied to brain health. https://www.aan.com/PressRoom/Home/PressRelease/5208. Published Oct. 24, 2024. Accessed Oct. 28, 2024.

Sources/Disclosures

Collapse

Source:

Clocchiatti-Tuozzo S, et al. Neurology. 2024;doi:10.1212/WNL.0000000000209990.

Disclosures: The authors report no relevant financial disclosures. The study was supported by the NIH.       

Does Increased Cardiorespiratory Fitness Decrease Alzheimer’s Risk? The Impact of Physical Fitness on Neurodegeneration

I was never tested for cardiovascular fitness while in hospital.

3 years post stroke at a physical I had a resting heart rate of 54 at age 53, level of an athlete. My doctor asked what exercises I was doing; 'I've done no exercises for the past 3 years'. 

I know that 17 years post stroke my fitness level has dropped considerably because my doctor and therapists didn't get me close to full recovery so I could keep my fitness level up.

 Does Increased Cardiorespiratory Fitness Decrease Alzheimer’s Risk? The Impact of Physical Fitness on Neurodegeneration

Dementia is a worldwide public health concern. There are 35.6 million people worldwide with dementia; by 2030, estimates are that 75.6 million people worldwide will have dementia. Dementia prevalence doubles every 5 years after age 65, and by age 90, nearly 1 in 3 adults will meet the diagnostic criteria for dementia.¹ 

Hallmarks of aging include chronic low-grade inflammation, mitochondrial dysfunction, and neurodegenerative changes. The concept of “inflammaging,” introduced in 2000 by Claudio Franceschi, correlates aging with elevated inflammatory markers, which make older individuals more susceptible to chronic morbidities, including Alzheimer disease (AD).² Oxidative stress and mitochondrial dysfunction in AD perpetuate an imbalance in neuronal cell function, generating further malfunction. In AD, brain atrophy and reduction in cerebral perfusion are significant, with a yearly hippocampal volume reduction of 3.5% in people with mild cognitive impairment compared with 1% to 2% in healthy controls aged 55 and older.^3,4 Cerebral blood flow is decreased up to 40% in patients with AD compared to healthy controls.⁵   

Cardiorespiratory fitness, as measure by VO₂max (volume of oxygen per kilo of body weight per minute) is affected by age, gender, genetics, exercise type, and training intensity. After age 20, it is estimated that VO₂max decreases by 3% to 6% each decade, with a jump to more than 20% decline per decade after age 70.⁶ Several studies correlate higher VO₂max with lower inflammation, reduced oxidative stress, improved mitochondrial function, and improvement in brain structure and functional connectivity.^5,6,7

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Effective treatments for Alzheimer disease (AD) are lacking, which is shifting the focus to disease prevention. While the benefits of exercise are frequently noted, reported measurements of physical fitness are inconsistent across studies, and many participants self-report their physical activity. Recommended guidelines for exercise are also vague. Considering the effects of cardiorespiratory fitness on inflammation, mitochondrial structure, and cerebral anatomical changes will aid in providing future recommendations for dementia prevention, including AD, and overall cognitive health. 

Cellular Aging and Inflammation as a Cause of Dementia

A number of cellular changes are associated with chronic low-grade inflammation and impairment in immune function. Shrinking of the thymus is one of the most dramatic changes that occurs in an aging immune system. Naïve T-cells leave the thymus to circulate in the blood and lymphatic system to protect against pathogens. Memory T-cells form after antigen exposure. With age, T-cells develop underlying defects and decline in activity, contributing to chronic inflammation and decreased immunity. Naïve T-cell production (CD4 and CD8) also declines with age, and memory T-cell production increases. In older individuals, memory CD4 T-cells show impaired mitochondrial function and increased production of reactive oxygen species.⁸ During chronic inflammation associated with age, pro-inflammatory cytokines, such as interleukin (IL)-6, tumor necrosis factor (TNF), and IL-1β, cross the blood-brain barrier, triggering microglia and astrocytes to produce pro-inflammatory cytokines over anti-inflammatory cytokines.⁹  

Increased dementia risk is noted with comorbid neuropsychiatric and cardiovascular conditions and high systemic inflammation. Apolipoprotein E gene variant APOEε4 is the strongest genetic risk factor for dementia. APOEε4 is also linked to atherosclerosis and the modulation of inflammatory cytokines through promoting innate immune response.¹⁰ Beeri et al noted that having 2 or more cardiovascular risk factors in midlife predicted an increase in amyloid aggregation later in life.¹¹ The researchers noted that midlife risk factors outweigh late-life risk factors in the development of dementia. Gottesman et al found that 2 or more cardiovascular risk factors (BMI ≥30, smoking, hypertension, diabetes, hypercholesterolemia) in midlife had an odds ratio of 2.88 for later-life brain amyloid deposition.¹² This is important to note since the neurodegenerative changes of dementia begin decades before clinical symptoms are evident.

Neuroinflammation is evident in the progression of AD through increasing amyloid plaques and neurofibrillary tangles (NFTs).¹³ Overactivation of the immune response is more pronounced in AD because of the accumulation of amyloid β protein (Aβ).⁵ So-called proteinopathies, which occur due to misfolding of toxic proteins, produce extracellular Aβ plaques and intracellular NFTs. When amyloid beta precursor protein (APP) is cleaved by gamma-secretase, an Aβ-peptide forms containing 42 amino acids, known as Aβ₄₂, which is the most toxic variant.⁹ In addition to tau and phosphor-tau, Aβ₄₂ is a biomarker for AD that can be measured in cerebrospinal fluid via lumbar puncture.⁹ The accumulation of pathologic Aβ₄₂ in the AD brain is attributed in part to impaired mitophagy.¹⁴  

The presence of Aβ plaques contributes to the hyperphosphorylation of tau. The functioning of tau, the major microtubule-associated protein in neurons, is regulated by its degree of phosphorylation. Increased tau phosphorylation decreases microtubule stability and is correlated with neurotoxicity. In AD, tau is noted to be 3 to 4 times more phosphorylated, accounting for the increased formation of NFTs.¹⁴

In aging, prolonged immune activation causes impairment of phagocytosis by microglia and degradation of astrocytes.⁵ An essential role for microglia and macrophages in the central nervous system is to discard cellular debris, while astrocytes aid neuronal stability by modulating the blood-brain barrier.⁵ The phagocytic role of microglia in the central nervous system to degrade Aβ is compromised, which leads to the release of pro-inflammatory products. As a result, inflammatory cytokines, including ILIβ and TNF-α, pass the blood-brain barrier. Proinflammatory production of cytokines, reactive oxygen, and reactive nitrogen species furthers the production of Aβ and tau hyperphosphorylation through a positive feedback loop leading to more toxicity, as shown in Figure 1.⁵

Figure 1. Progression of amyloid β protein causes microglia inefficiency, and produces pro-inflammatory species (cytokines, reactive oxygen species [ROS], reactive nitrogen species [RNS]), causing further amyloid β production, and tau hyperphosphorylation, ultimately leading to neurodegeneration and cell death. 

Effects of Exercise on Inflammation

Over the past 3 decades, several studies have correlated decreased inflammation with decreased AD risk. The Baltimore Longitudinal Study of Aging showed a 60% reduction in dementia in patients using NSAIDs for over 2 years. Zhang et al found a 19% risk reduction in AD with NSAID use from 16 cohort studies.¹⁵  

Lack of physical activity is associated with elevated inflammatory biomarkers. For example, abdominal adipose tissue secretes TNF-α and other inflammatory markers.¹⁶ Conversely, physical activity increases hormones with immunomodulatory effects, increases anti-inflammatory myokines, decreases visceral fat, and decreases expression of toll-like receptors in immune cells.¹⁷ Exercise enhances immunocompetence by circulating immune cells to peripheral tissue. A study by Lavin et al showed that lifelong exercisers had significantly lower levels of IL-6 and higher levels of anti-inflammatory markers IL-10, TNF-α, TNF-β, and EP4.¹⁸ Repeated moderate intensity exercise is shown to have antioxidative effects, decrease oxidative stress, improve mitochondrial efficiency, and improve the immune function response.¹⁸ All of these factors result in a cumulative reduction in inflammation.   

Dougherty et al studied 86 older adults at risk for AD, comparing cardiorespiratory fitness, hippocampal volume measured by magnetic resonance imaging (MRI), and memory measured by Rey Auditory Verbal Learning Test (RAVLT).¹⁹ The results differed based on gender, showing that VO₂max was associated with increased hippocampal volume in women and improved RAVLT memory scores in men. Increased age and decreased physical activity correlate with impaired thymus function, impaired mitochondrial function, decreased VO2max, and increased inflammatory markers IL-6 and IL-1. An increase in physical activity in advancing age is associated with a reduction in IL-6 and increases in anti-inflammatory markers, VO₂max, and mitochondrial capacity (Figure 2).¹⁹

Figure 2. Increased physical activity improved inflammatory markers, correlating to improved memory scores.

Effects of Exercise on Mitochondrial Function

Mitochondria generates adenosine triphosphate (ATP) through oxidative phosphorylation. Additionally, calcium homeostasis, apoptosis, and reactive oxygen species (ROS) production are mitochondrial functions. The accumulation of amyloid β peptide within mitochondria is associated with the progression of AD; study findings show amyloid-β protein precursor and Aβ in mitochondria in AD patients before the formation of senile plaques.²⁰ 

Mitochondria use oxygen to produce energy during metabolism. If ROS levels are unusually elevated, neurodegeneration occurs through the oxidation of proteins that causes damage to their structure. The ROS levels are regulated by mitophagy, a process by which damaged organelles are engulfed by vesicles and degraded by specialized proteins. With aging, the decreased efficiency of antioxidants and the increase in ROS cause toxicity, leading to cellular dysfunction and apoptosis.²¹ 

Postmortem brain studies of individuals with AD show that mitochondrial dysfunction occurs early in the disease process and is especially pronounced in the entorhinal-hippocampal system located in the medial temporal lobe. Cortical neurons in the entorhinal-hippocampal system layer II are thought to be where initial AD pathology occurs.¹⁴ Postmortem studies have also shown a decrease in the number and quality of mitochondrial DNA (mtDNA).²⁰

Mitochondrial biogenesis, the creation of new, functioning mitochondria, is thought to be facilitated by physical activity.²² In 1965, the research of John O. Holloszy, MD, showed that endurance exercise training resulted in the doubling of mitochondria in rodent skeletal muscle. Endurance exercise training improves mitochondrial capacity, which enables protective antioxidant effects.²² He noted that mitochondrial biogenesis occurs with repeated bouts of exercise at sufficient intensities over a period of time. 

Ding et al reported that regular exercise caused increased mitochondrial tricarboxylic acid enzymes and the synthesis of neurotrophins, including brain-derived neurotrophic factor (BDNF).²³ BDNF is a mediator in PGC-1α-induced mitochondrial biogenesis and regulates antioxidant enzymes that reduce ROS seen in AD. A positive correlation between mitochondrial volume and VO₂max has been noted since the 1970s.²⁴ While VO₂max is typically used to measure cardiorespiratory fitness, it depends on mitochondrial efficiency.²³ In addition to mitochondria volume, endurance exercise and higher VO₂max are associated with improvement in mitochondria respiratory function and oxidative capacity.²⁴

More recent research has replicated the effect of exercise on mitochondria in other organs, notably the brain. The brain utilizes 20% of the body’s total oxygen and depends on mitochondria for 90% of its ATP production.²⁰ Radak et al reported that endurance exercise increases VO₂max and is associated with mitochondrial biogenesis partly through sirtuins (SIRT-3), a mitochondrial protein. SIRT-3 is responsible for oxidative phosphorylation, oxidation of fatty acids, and synthesis of ketone bodies. Endurance exercise increases SIRT-3 levels in the hippocampus, skeletal muscle, liver, and heart.²⁵

Effects of Exercise on Brain Structure and Cerebral Blood Flow

 General cerebral atrophy is a well-known occurrence with aging, and hallmarks of this include volume loss, cortical thinning, enlarged ventricles, and brain folding changes. Global volume changes begin at age 35 with a total brain volume loss yearly of 0.2%, which escalates to 0.5% annually after age 60.²⁶ The hippocampus and prefrontal cortex appear more vulnerable to aging; the hippocampus and prefrontal cortex atrophy by 1% to 2% for every year after age 55.³ Cortical thinning occurs at a rate of 0.004 mm/year and is associated with memory decline. Ventricular enlargement occurs from the accumulation of cerebrospinal fluid in the ventricles, which causes compression of brain parenchyma. Specifically, the lateral and third ventricles are associated with impaired attention, visual memory, and speed.²⁶ A study comparing middle-aged adults with healthy older individuals noted that sulci were, on average, 17.3% wider in elderly patients (aged 66-90 years).²⁶ Of note, the most significant difference between the middle age and elderly adults was in the depth of the left superior frontal sulcus.²⁶ A larger longitudinal study with 132 participants followed over a 7 year period found the largest rate of increase in fold opening in the superior frontal sulcus (0.131 mm/year). Like other neurodegenerative diseases, AD accelerates and intensifies structural changes that occur with aging.²⁶  

Vascular changes that occur with age include arterial stiffness, reduced capillary density, and increased blood-brain barrier permeability.²⁶ Decreased cerebral blood flow is associated with increased dementia risk, and is noted prior to structural brain changes in AD. Reduced cerebral blood flow has been predictive of progression to AD from healthy controls and individuals with mild cognitive impairment.²⁷

Exercise is correlated with increased hippocampal volume, hippocampal neuroplasticity²⁸, increased gray matter volume²⁸, white matter integrity³,^, and cortical thickness.²⁴ A 1-year study of 120 participants aged 55 to 80 found that moderate-intensity aerobic training showed a 2% increase in anterior hippocampal volume.²⁹ Conversely, a study by Pani et al showed increased hippocampal atrophy in high-intensity interval training groups, and that brain structure was best preserved in those following the national guidelines of 30 minutes of physical activity per day. This study also noted that those with higher VO₂max at inclusion had better-preserved brain structure.³⁰ A study of 29 participants with mild cognitive impairment by Eisenstein et al correlated increased VO₂max with reduced hippocampal volume. However, there was a decreased correlation between hippocampal volume and memory performance compared with low VO₂max.⁴ Alfini et al determined that cessation of exercise for 10 days reduced hippocampal blood flow.⁷  

Regular exercise and a higher VO₂max in mid-life seem to have the most robust evidence for ameliorating cognitive changes that occur with age. A study by Kurl et al followed over 2000 men over 20 years and found that one standard-deviation increase in VO₂max (3.5 mL/kg/min) correlated with a 20% decrease in dementia.²⁹ Men with a VO₂max less than 23.7 mL/kg/min (low cardiac fitness) had a 1.92-fold risk of developing dementia compared with those with a VO₂max greater than 36.5 mL/kg/min at baseline testing.²⁹ Horder et al followed 1462 women and reported a 9.5-year delay in dementia onset in more fit women in midlife.³⁰

While these studies looked at how various exercise regimes influence VO₂max, brain structure, and cognition, the most beneficial exercise program seems to be moderate-intensity cardiovascular exercise, performed consistently 5 to 6 days a week, and starting by mid-life. VO₂max improves with repeated sessions of physical activity of at least 30 minutes that elevates the heart rate, such as brisk walking, jogging, biking or hiking. Although some studies indicate cognitive gains with single bouts of exercise, longer term studies highlight the importance of cardiorespiratory fitness starting in mid-life. Higher V0₂max at age 50 correlates with delaying dementia onset by a decade.³⁰ Midlife cardiovascular risk factors (including BMI ≥30, smoking, hypertension, diabetes, hypercholesterolemia) are associated with elevated dementia risk later in life.¹² Since exercise is known to improve cardiovascular risk factors, it seems likely that it should also reduce dementia risk. More research is needed in this area and to evaluate the effects of other forms of exercise, such as weight training or yoga, on cognitive decline.

Conclusion   

AD is typically an age-related disease occurring later in life, with an increased risk associated with cardiovascular disease, diabetes, and obesity. As people continue to live longer, and the age of the world’s population increases, dementia is also increasing. 

Inflammation is a known by-product of aging and exercise reduces inflammation. While reports of the impact of exercise on memory are conflicting, most show at least modest improvement in one or more aspects of cognition. Studies have shown that as little as a single exercise session can cause changes in the body. 

Measurement of cardiorespiratory fitness utilizing VO₂max is a way to standardize studies of physical fitness. Limitations include self-reported exercise and a minimal number of participants. As more studies are done, specific recommendations for VO₂max levels will help individuals quantify their fitness goals to maximize their cognitive health. 

Cynthia Sieto, MSPAS, DMSc, graduated with her MSPAS from DeSales University in 2001 and her DMSc from Rocky Mountain University in 2023. She has specialized in psychiatry for 20 years and is currently employed by St. Luke’s University Health Network in Allentown, PA. To maximize her cardiorespiratory fitness, she completed the 2023 NYC marathon.