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Alzheimer’s Study Finds Diet, Lifestyle Changes Yield Improvements

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By Alvin Powell | Harvard Staff Writer | Harvard Gazette

New intensive regimen upends prior results, but researchers say larger, longer trials needed

Tantalizing new research suggests intensive diet and lifestyle changes may not only forestall cognitive decline related to Alzheimer’s disease but possibly bring some improvement to those in early stages.

The small, limited study varied from earlier findings, which concluded a healthy lifestyle could lower risk but showed little promise in reversing damage. That result had co-authors on the paper, published in June in the journal Alzheimer’s Research & Therapy, tempering excitement with caution.

“To get significant results on these cognitive tests in just 20 weeks, in just 50 patients, only altering lifestyle, to be very honest was just shocking to me, but shocking because it says maybe this matters,” said senior author Rudolph TanziHarvard Medical School’s Joseph P. and Rose F. Kennedy Professor of Child Neurology and Mental Retardation, and co-director of the MassGeneral Institute for Neurodegenerative Disease. “But I’m the first to say that it’s a small study. It was only 20 weeks, so let’s not jump to any conclusions. But boy, what a great start.”

Steven Arnold, professor of neurology at HMS, Massachusetts General Hospital’s E. Gerald Corrigan Chair in Alzheimer’s Therapeutic Science, and an author on the paper, said the findings showed promising results but cautioned against “overinterpreting” them and advised against making wholesale diet and lifestyle changes based on this study alone.

“I think this is a well-done study. It needs to be bigger. It needs to be longer,” Arnold said. “I want people to be intrigued and enthused by its findings, but not overinterpret them because more data is needed.”

The trial took an everything-but-the-kitchen-sink approach to treating Alzheimer’s disease, pulling together an array of interventions that individually have been seen to lower risk. In addition to their comprehensiveness, researchers said the interventions were also intensive. That is a possible reason, they suggested, their results varied from earlier studies that employed more moderate interventions.

The study’s 51 subjects, whose average age was 73.5, were in the initial stages of Alzheimer’s disease. and all had been diagnosed with mild cognitive impairment or early dementia. Twenty-six were randomly assigned to the intervention group and 25 to the control group.

Interventions

Lifestyle followed by study participants in the intervention group

Diet

All meals plus snacks for subjects and their spouses were delivered to their homes.

The vegan regimen, which was not calorie-restricted, was augmented by supplements believed to support cognition, including omega 3 fatty acids, curcumin, a multivitamin, vitamins C and B12, magnesium L-threonate, coenzyme Q, a probiotic, and lion’s mane.

Exercise

Participants did 30 minutes of aerobic exercise daily and strength training three times a week.

For stress reduction, subjects meditated, did yoga poses, stretching, and breathing exercises in a daily hour led by a stress management specialist.

Socialization

Subjects participated in an hourlong support group three times a week led by a mental health professional.

Over 20 weeks, those in the intervention group were asked to eat a strict vegan diet, with all meals plus snacks for subjects and their spouses delivered to their homes. The regimen, which was not calorie-restricted, was augmented by supplements believed to support cognition, including omega 3 fatty acids, curcumin, a multivitamin, vitamins C and B12, magnesium L-threonate, coenzyme Q, a probiotic, and lion’s mane.

Those interventions were coupled with 30 minutes of aerobic exercise daily and strength training three times a week. For stress reduction, subjects meditated, did yoga poses, stretching, and breathing exercises in a daily hour led by a stress management specialist.

To boost social support, subjects and spouses participated in an hourlong support group three times a week led by a mental health professional. In all, subjects received 12 hours per week of professional support — delivered via Zoom — for the lifestyle interventions.

“In my heart of hearts, I think there is something real here.”

–Steven Arnold

“In my heart of hearts, I think there is something real here,” said Arnold, who is also MGH’s head of translational neurology and managing director of its Interdisciplinary Brain Center. “If you do significantly change the metabolic, inflammatory, vascular milieu of the body and the brain, that is good for our brain function. And this diet, exercise, stress reduction/socialization intervention may work as well or better than some of the drugs we use for Alzheimer’s disease.”

To establish a baseline and gauge progress, participants took four standard tests used to measure cognitive performance in FDA drug trials. The results varied by test but generally showed the intervention group improved or stayed the same while the control group stayed the same or worsened. On the Clinical Global Impression of Change, for example, 10 — more than 40 percent — improved after 20 weeks, seven were unchanged, seven worsened slightly, and none worsened moderately. Among the controls, by comparison, none improved, eight were unchanged, and 17 worsened slightly or moderately. Two other tests showed that the intervention group improved on average, while the control group worsened. The fourth test showed both groups doing worse, with the control group worsening significantly more.

Researchers, who hailed from institutions in the U.S., U.K., Finland, and Sweden, also examined participants’ blood and microbiomes. One biomarker, called pTau 181, showed little change between the controls and the intervention group, but researchers found improvements in another marker, which measures the ratio of two forms of the amyloid beta protein, which forms plaques in the brain that are hallmarks of Alzheimer’s disease.

Researchers found improvements in another marker, which measures the ratio of two forms of the amyloid beta protein, which forms plaques in the brain that are hallmarks of Alzheimer’s disease.

Measures associated with cardiac and metabolic health like cholesterol, A1c, hemoglobin, and others also improved. The intervention group’s microbiome shifted, with populations of beneficial bacteria increasing and those thought to be associated with Alzheimer’s disease decreasing. In addition, there was a dose-response effect in both biomarkers and cognitive tests, with the degree of change positively associated with adherence to the lifestyle interventions.

The work received financial support from more than two dozen private foundations and charitable funds and comes at a moment of optimism about Alzheimer’s disease. After years of failed drug trials that had researchers questioning whether they really understood the disease, a drug called lecanemab gained FDA approval last year after a study of 1,800 people over 18 months showed it to be the first treatment to slow progression in those in early stages of the disease.

Tanzi and Arnold acknowledged their study’s relatively small sample size was a shortcoming but said the its design as a randomized controlled trial, considered a scientific gold standard, was a strength. The trial was designed to be multimodal, but the fact that so many different lifestyle factors were at play made it difficult to tease out the effect of each, said Tanzi, who is also the director of MGH’s Genetics and Aging Research Unit and its Henry and Allison McCance Center for Brain Health.

The next step, he and Arnold said, would be a larger study to see whether the results are replicated. Arnold said that among questions such a trial would answer is whether subjects would stick with such an intensive intervention over the long term.

Conduct of the trial was significantly affected by the pandemic. Enrollment, which occurred between 2018 and 2022, was still underway when COVID-19 hit in early 2020, curtailing enrollment, which originally had targeted 100 participants. The need for distancing forced researchers to shift sessions to online, which may have altered the effect of the social support sessions. It did, however, allow expansion of the study population from a single site in San Francisco to others around the country, including Massachusetts General Hospital.

“This should be looked at as a pilot study, but the pilot data are significant and strongly suggest that lifestyle intervention was effective,” Tanzi said.

This story is reprinted with permission from The Harvard Gazette.

***

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World Suicide Prevention Day 2024: Changing the Narrative For Men and Their Families

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September 10, 2024 was World Suicide Prevention Day. According to the World Health Organization,

“Every year 726,000 people take their own life and there are many more people who make suicide attempts.”

When I was five years old my mid-life father took an overdose of sleeping pills after he had become increasingly depressed because he couldn’t support his family doing the work he loved. Fortunately, he survived, but our lives were never the same. I grew up wondering what happened to my father, when it would happen to me, and what I could do to prevent it happening to other families.

Although females, as well as males, can die by suicide, males at every age are at higher risk than are females. Yet rarely is suicide discussed as a health issue for boys and men.

World Suicide Prevention Day (WSPD) was established in 2003 by the International Association for Suicide Prevention in conjunction with the World Health Organization (WHO). On September 10th each year they focus attention on the issues, reduce stigma and raise awareness among organizations, governments, and the public, giving a singular message that suicides are preventable.

The triennial theme for World Suicide Prevention Day for 2024-2026 is “Changing the Narrative on Suicide” with the call to action “Start the Conversation”. This theme aims to raise awareness about the importance of reducing stigma and encouraging open conversations to prevent suicides. Changing the narrative on suicide is about transforming how we perceive this complex issue and shifting from a culture of silence and stigma to one of openness, understanding, and support.

The call to action encourages everyone to start the conversation on suicide and suicide prevention. Every conversation, no matter how small, contributes to a supportive and understanding society. By initiating these vital conversations, we can break down barriers, raise awareness, and create better cultures of support.

I have been writing a series of articles—”Homecoming: An Evolutionary Approach for Healing Depression and Preventing Suicide.” In Part 1, I shared statistics from the National Institute of Mental Health, comparing the suicide rates for males and females at various ages:

Even during our youth where suicide rates are relatively low, males are still more likely to die by suicide than are females. It is also clear to me as my wife and I move into our 80s, that males and females face many challenges as we age, but it is older males who more often end their lives by suicide with rates 8 to 17 times higher rates than for females.   

In Part 2, I discussed the evolutionary roots of male/female differences and quoted Dr. Roy Baumeister,  one of the world’s leading social scientists. Understanding his work can better help us understand a lot about why men are the way they are and specifically why men are the risk-taking gender.

In his groundbreaking book, Is There Anything Good About Men? How Cultures Flourish By Exploiting Men, he says,

“If evolutionary theory is right about anything, it’s right about reproduction. Nature will most favor traits that lead to success at reproducing. But for thousands of years, men and women have faced vastly different odds and problems in reproducing. On this basic task, women faced good odds of success, whereas men were born to face looming failure.”

Men not only take greater risks than women, but also are less resilient and more prone to feelings of failure when they don’t feel they can offer something of value to those they love.

In Part 3, I show that suicide is the most prevalent form of violence and is the cause of more death than either war or homicide. We don’t often think of suicide as a form of violence or depression as an underlying cause of violence, but they are intimately related. The World Health Organization (WHO) produced an in-depth analysis of violence and published the information under the title, “The World Report on Violence and Health.” The report is the result of 3 years of work, during which WHO drew on the knowledge of more than 160 experts from more than 70 countries.

            The report detailed estimated global-related deaths as follows:

These numbers vary in different years and rates of violent deaths also vary according by country and within each country with different groups. But clearly violence from suicide accounts for nearly as many deaths as war-related violence and homicides combined. All forms of violence are tragic and many have come to believe that violence is simply a part of human nature. But this is not true.

Violence of all kinds can be understood and prevented.

“Violence thrives in the absence of democracy, respect for human rights and good governance,”

said Nelson Mandela. We often talk about how a ‘culture of violence’ can take root. This is indeed true—as a South African who has lived through apartheid and is living through its aftermath, I have seen and experience it. No country, no city, no community is immune. But neither are we powerless against it.”

As we approach another presidential election in the United States, most everyone is aware of the threat to democracy we are facing and the conflicts that divide our country.

In Part 4, I offered guidance for all those who are ready to see the truth about the times in which we live and how we can live, love, and work, for good in the world.

For most of my professional life I believed that treating depression and preventing suicide involved helping individuals, couples, and families. A new perspective opened for me in 1993 at a men’s leadership conference in Indianapolis, Indiana. I’ve written a number of articles about my experience over the years, including my most recent, “Transformations: The End of the U.S. and the World as We Know It and The Truth About Our Collective Future.”

I said that an old kind of masculinity was on the way out. My colleague Riane Eisler describes two competing systems that humans have been engaging with that she calls the dominator system and the partnership system. Throughout the world emotionally wounded men who ascend to power have chosen a dominator approach to asserting power.

            The old dominator systems were ruled by frightened men who came to believe that the only way to survive was to rule by force. Historian Ruth Ben-Ghiat describes these men in her book, Strongmen: Mussolini to the Present. She says,

“For ours is the age of authoritarian rulers: self-proclaimed saviors of the nation who evade accountability while robbing their people of truth, treasure, and the protections of democracy.”

            Among the seventeen protagonists in her book she includes: Adolph Hitler, Saddam Hussein, Benito Mussolini, Vladamir Putin, and Donald J. Trump. Pulitzer-Prize winning journalist Anne Applebaum describes the way modern-day autocrats support each other in her book, Autocracy Inc.: The Dictators Who Want to Run the World.

“Nowadays, autocracies are underpinned by sophisticated networks composed across multiple regimes…The autocrats are rewriting the rules of world trade and governance as their propagandists pound home the same messages about the weakness of democracy and the evil of America.”

            At MenAlive I have been supporting men and their families to embrace the partnership system and have recently created a way for organizations and individuals to belief in these ideas and practices to stay connected. You can learn more at our website, MoonshotforMankind.org and get news you can use on our substack, substack.com/@moonshotformankind.

            If you’d like to read more articles on men’s mental, emotional, and relational health, you can subscribe for free at https://menalive.com/email-newsletter/.

Every suicide is a tragedy that affects families, communities and entire countries and has long-lasting effects on the people left behind.

Suicide does not just occur in high-income countries but is a global phenomenon in all regions of the world. In fact, close to three quarters (73%) of global suicides occurred in low- and middle-income countries in 2021.



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Considering the 75 Hard Challenge? Read This First

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Sticking to new habits isn’t easy, especially when they mean giving up old ones that make you feel good—at least temporarily—like binging talking dog videos or inhaling a burger on the way home from work. But there comes a time when making a change in the name of your health and happiness is more attractive than another night spent plastered to your couch. That’s where a program like the 75 Hard Challenge comes in. It’s not a weight-loss app, although followers do tend to shed some pounds. Instead, it’s a “mental toughness” protocol that helps instill new habits in fewer than three months. That’s not to say it’s without flaws.

This challenge is not easy to stick to. People often believe the more intense something is, the better the results. But this is a mistake if you aren’t careful. It’s important to learn about any new routine that overhauls your diet, exercise, and entire life and really evaluate if the pros and cons make it worthwhile. Learn all about 75 Hard, including 75 Hard Challenge rules and what you might stand to gain—or lose—if you try it.

What Is the 75 Hard Challenge?

The 75 Hard Challenge is primarily a mental toughness program with physical and behavioral habits created by entrepreneur and author Andy Frisella in 2019. In short, the challenge aims to build discipline and resilience—physically and mentally—by adopting a set of daily rules that you complete without fail for 75 days straight. Frisella sells a book about the challenge, but you can also learn about it from his podcast and all over the internet.

75 Hard rules dictate you drink one gallon of water daily and cut out alcohol and cheat meals including soda. 

Jarren Vink

75 Hard Challenge Rules

There are five 75 Hard rules to follow during the 75 Hard Challenge. Here’s where it gets particularly tough: If you skip any of the items on the 75 Hard checklist on any given day, you need to start over from day one as a practice in forging mental toughness and self-control.

1. Follow a Diet

During the entire challenge, you should stick to a specific meal plan without cheat meals or alcohol. There’s no 75 Hard diet, per se. You get to choose. If you’re hoping to drop body fat, we recommend the best diets for weight loss. But if you’re just trying to adhere to a lifelong habit of healthy eating, stick to the best diets recommended by experts. Something like the Mediterranean Diet is more sustainable for life than, say, the keto or Paleo diet. Get more tips below.

2. Two Daily Workouts

Every day, you have to complete two 45-minute workouts with one being outdoors. Unfortunately, you can’t count activities like mowing the lawn, yard work, or leisure sports into the 75 Hard workout plan like golf, because they’re considered “daily chores” or “routines.” Typically, we don’t recommend two-a-days, especially if you’re not a professional athlete. To ensure you don’t overtrain, keep one akin to an active recovery, like steady-state cycling or yoga. If it starts to diminish your physical and mental well-being, stop.

3. Drink a Gallon of Water

Drink one gallon of water every day. This doesn’t include any other fluid intake, just clear H2O. Hydrating is obviously important. Drinking a gallon is likely unnecessary, but it won’t necessarily hurt you. If it helps up your intake, great. 

4. Read Nonfiction

Part of the mental fortitude aspect of the challenge is reading 10 pages of a nonfiction book each day. Unfortunately, audiobooks don’t count, nor do magazines or sports pages. Sorry—there’s a reason this is called the hard 75 challenge.

5. Take a Daily Progress Picture

Take a photo of your body to track your progress each day. This could be a mirror selfie or one you loop your partner or roommate into taking for you. Just be sure to keep the lighting, location, time of day, and clothing items similar for each shot. For some, this is helpful over time to see incremental progress, however a daily log can be detrimental to others’ self-esteem if their body image isn’t positive. 

Mediterranean Diet

Sam Kaplan

75 Hard Diet

Diet just might be the worst four-letter word in the English language. The good news is that you can choose your own diet structure for the 75 Hard Challenge.

Choose a Diet Plan

While you can pick your ideal diet, it has to be one that fosters positive physical change. Whether you’re losing fat, gaining muscle, building strength, boosting your intake of a specific micro or macronutrient (like protein), or improving overall diet quality for skin health, just pick something you think you can stick to for the entire 75 days without falling off the wagon.

Here are some of the best structured diets to consider:

  • Mediterranean diet
  • DASH diet
  • MIND diet
  • Mayo Clinic diet
  • Flexitarian
  • WeightWatchers diet
  • Volumetrics diet
  • Dr. Weil’s Anti-Inflammatory diet
  • TLC diet
  • Vegan diet

No Cheat Meals

Can you go 75 days without a hot slice of pizza or a burger? If you want to complete the 75 Hard Challenge, you’ll have to give up all of your normal cheat meals for the duration. That’s right—zero cheat meals (what would Dwayne “The Rock” Johnson say?). Instead, make some healthier swaps that are still tasty but easier on the waistline.

No Alcohol

There’s a strict no-booze rule for the 75 Hard Challenge, so plan accordingly. If you know you’ll be in a high-pressure social situation like a bachelor party or Super Bowl gathering, and you don’t have the willpower of steel, you might want to forego the plan until you know you can stick to it. Might we suggest nonalcoholic drinks like NA spirits, wine, and beer.

Running

Patrick Giardino/Getty Images

75 Hard Workout Plan

If you aren’t currently very physically active or have a difficult time sticking to a consistent routine, this may be a wallop: For the 75 Hard Challenge, you have to do two 45-minute workouts each day, and one of them has to be in the great outdoors. Luckily, the types of workouts you can do are pretty flexible so long as they are physically challenging and aren’t part of your regular daily routine. Here are some examples:

Cardio Workouts

Cardio should be part of your workout routine during 75 Hard, but you don’t have to go hell-for-leather every day. Many of the best cardio workouts can double up as your outdoor workout session.

  • Running or jogging
  • Cycling
  • Swimming
  • Power walking
  • Rowing
  • Hiking
  • Jump rope
  • Martial arts

Related: The Best Workout Apps for Beginners

Resistance Training

Resistance training is a must for any serious training plan, so pick a style you enjoy or one you’re excited to try and stick to it for 75 days. Be sure to plan out your sessions in advance, increase the challenge as you go, and track your progress.

  • Strength training
  • Hypertrophy training
  • Bodyweight exercises (like pushups, pullups, and squats)
  • Powerlifting

Recovery and Flexibility Training

Including some low-key workouts into your routine is the ultimate overtraining prevention strategy. The less fit you are, the more of these sessions you should include—maybe four to five per week counting toward the 45-minute sessions. Scale down from there if you are more fit or as you progress throughout the challenge.

  • Yoga
  • Pilates
  • Mobility work
  • Walking
  • Stretching

High-Intensity Interval Training (HIIT)

If you plan to include HIIT training, do it sparingly. Too much high-intensity work will burn you out in no time. It’s not possible to do true HIIT training for a full 45 minutes, so if you’re going to add this modality to your routine, stick to 10 to 15 minutes at the end of a cardio session or after resistance training two to three times a week.

Pro tip: Skip high-intensity training altogether if your diet plan includes cutting calories. It’s a recipe for burnout.

  • Circuit training
  • Tabata workouts
  • Sprints

Battle Ropes

Justin Steele

75 Hard Pros

There’s a lot going for the 75 day Hard Challenge. Here are some of the main pros.

Builds Habits

We all know that consistency is king when it comes to results, and that’s the main tenant of 75 Hard: to build and maintain a consistent routine that includes five daily tasks every day without fail. Habits are automatic behaviors triggered by specific cues and learned through repetition, strengthening every time you complete the behavior—think brushing your teeth every night before bed or locking up when you leave the house, according to 2021 research published in Social Psychology.

Good habits help you keep up desirable behaviors over time since you’ll start to automatically perform them without having to rely on conscious motivation—something that’s notoriously fickle, according to the study.

Tracks Progress

Tracking your progress is the best way to see how far you’ve come and it’s also a great way to get a motivational buzz when you start seeing a difference in how you look, feel, and act. Progress tracking with a photo is one of the Hard 75 rules, so it’s built into the routine.

Gets You Active

Obviously, physical activity is a huge part of the challenge and a behavior many people struggle to maintain. If you’re doing 75 Hard, you’ll definitely get your daily movement in through the two 45-minute workouts each day.

Includes Time in Nature

While you don’t explicitly have to go on a nature walk, even cityscape fresh air and sunlight are better than nothing. Since the challenge requires you to complete one 45-minute workout outdoors each day, you’ll get benefits from sunlight exposure (which improves sleep), stress relief, and a brain boost.

Related: The Best Workout Routine Ever, According to Science

75 Hard Cons

Aside from giving up your favorite tasty snacks and foregoing a beer during the game, the 75 Hard Challenge has other practical issues.

Not for Everyone

Although 75 Hard has consistency built in, if you don’t include your own context cues for each habit you want to keep once the challenge is over, you likely won’t stick to it. In other words, if you don’t incorporate the habits into your everyday routine in a way that you’ll stick to once the challenge ends, you’ll probably revert to the same old habits—good or bad—that you were doing before. This is the exact reason why most people regain all the weight they lose during diets.

Easy to Overdo It

Without any actual professional nutritional or fitness guidance (Frisella is not a health expert), you can easily go overboard trying to meet the steep expectations of the challenge. You might not pair the ideal diet with your exercise program—such as a muscle-building calorie surplus with your hypertrophy training—unless you know what you’re doing.

You can accidentally choose habits that do more harm than good if you attempt high-intensity training alongside a low-carb diet or push past your body’s signals for rest in order to get in that second 45-minute workout.

Very Strict

Rigidity is the entire point of the 75 Hard Challenge. In fact, Frisella says in an interview with Megyn Kelly, “The whole point of the program is to put yourself in the most inconvenient, non-compromising situation that you possibly can,” with no room for substitutions.

He goes on to say that giving yourself a break or a “mental day” is a no-go because “letting yourself off the hook is the reason you are where you are in this state of unhappiness and unfulfillment.” If you get sick, sore, or have an emergency—too bad—you’ve failed.

Can Lower Confidence

Battering yourself into submission is not always the best for your mental health and certainly won’t work for everyone. Plus, not everyone who wants to improve their health is unhappy or unfulfilled.

In reality, positive thinking can boost self-confidence by helping you see challenges as temporary and conquerable. Overcoming setbacks and still working toward your health goals is a fast track to becoming more resilient and increases internal motivation and confidence. And for the record, internal motivation is stronger than the kind you’ll get from any challenge.

Related: The Best Workout Routine Ever, According to Science

Final Verdict: What Do Experts Say About the 75 Hard Challenge?

As a personal trainer and nutrition coach, I believe that most people, even those with advanced fitness levels, shouldn’t attempt two workouts every single day. Combining cardio and strength training can interfere with recovery and overall results and is a recipe for burnout. Physically, mentally, and socially, two-a-day workouts can be draining and unsustainable and put you at risk of overtraining, which requires lengthy recovery.

If you’re set on following the two-workouts rule, make sure one is recovery-based—light yoga, walking, or stretching. Organized activities like jiu-jitsu or gym classes can count as one workout, with walking or something gentle for the second. For strength training, limit it to three to five days a week and always pair with recovery exercises.

I don’t recommend avoiding rest days, as even lighter workouts can be mentally exhausting and, on a practical level, can get in the way of other areas of your life, like relationships, work, and family responsibilities. Missing a session and starting over can feel defeating, which I’d never want for my clients. If you miss a workout you had intended to complete, it’s better to reassess and adjust instead of stressing over rigid plans.

In my opinion, the idea that “mental toughness” comes from strict workout rules is absurd. True consistency comes from internal motivation, doing what you enjoy for reasons that matter to you. Building skills in activities you love—whether yoga, strength training, running, or a new sport—will make you proud and boost your confidence in the long term.

Real toughness also means listening to your body. Sometimes, backing off is harder than following a rigid plan. Focus on consistency and finding joy in what you do rather than chasing the next challenge.

Why You Should Trust Us

I’m a certified personal trainer, strength and conditioning specialist, and nutrition coach, among other fancy titles—but my passion is communicating the countless benefits of being active and striving toward a healthier mind and body through attainable action. I use a hefty dose of science to guide the advice I give, along with the real-world experience I’ve gained over the last 15 years. 



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Blood Test Can Warn Women of Risk Decades Before Heart Attack, Stroke

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By BWH Communications | Harvard Gazette

Three biomarkers in blood can better predict the risk of major cardiovascular events in women decades earlier than previous tests, giving them more time to address their risk with lifestyle changes and therapeutics, according to research from Brigham and Women’s Hospital, a Harvard affiliate.

In a landmark study of 27,939 initially healthy American women, the researchers used a single measure of low-density lipoprotein cholesterol (LDL-C), or “bad cholesterol”; high-sensitivity C-reactive protein (hsCRP), a marker of vascular inflammation; and lipoprotein(a), a genetically determined lipid fraction, to predict risk over a 30-year follow-up period.

The findings were presented at the European Society of Cardiology Congress in London and published simultaneously in the New England Journal of Medicine.

Waiting until women are in their 60s and 70s to initiate heart attack and stroke prevention is a prescription for failure.

–Julie Buring, principal investigator of the Women’s Health Study

A wake-up call for women

Heart disease is the leading cause of death for women in the U.S., with 44 percent living with some form of heart disease. In 2021, it was responsible for the deaths of 310,661 women — or about 1 in every 5 female deaths — yet only about half of U.S. women recognize that heart disease is their No. 1 killer, according to the American Heart Association and the Centers for Disease Control and Prevention.

To assess each marker as well as the combined effect of elevated levels of two or all three, the research team divided participants into five quintiles, ranging from those with the highest to the lowest levels of the markers. Researchers found that, compared to women with the lowest levels of individual markers:

  • Women with the highest levels of hsCRP had a 70 percent greater risk of a major cardiovascular event;
  • Women with the highest levels of LDL-C had a 36 percent greater risk;
  • Women with the highest levels of Lp(a) had a 33 percent greater risk.

While hsCRP was the strongest of the three biomarkers, all were very important. More markers meant greater risk; women who had elevated levels of all three markers were 2.6 times likelier to have a major adverse cardiovascular event. This association was even stronger for stroke — women with the most elevated levels were 3.7 times likelier to have a stroke over the next 30 years.

“These data should be a wake-up call for women,” said co-author Julie Buring, principal investigator of the Women’s Health Study and an epidemiologist in the Brigham’s Division of Preventive Medicine. “Waiting until women are in their 60s and 70s to initiate heart attack and stroke prevention is a prescription for failure.”

At the time the participants were enrolled in the cohort, their mean age was 54.7 years; 25 percent had hypertension, 12 percent were current smokers, 2.5 percent had diabetes, and 14.4 percent had a parental history of myocardial infarction before 65 years of age. Nearly all were white, with good access to healthcare and medical information.

Reducing risk

Each of the three risk factors is modifiable with a combination of lifestyle changes and drug therapy. Multiple randomized trials have demonstrated that lowering cholesterol and lowering inflammation both significantly reduce risks of heart attack and stroke. Further, several new drugs that markedly reduce Lp(a) as well as second-generation anti-inflammatory agents are being tested to see if they too can lower rates of clinical events.

The new data strongly support earlier and more aggressive use of targeted preventive interventions, particularly among women for whom cardiovascular disease remains underdiagnosed and undertreated.

“Doctors cannot treat what they don’t measure,” said lead author Paul Ridker, director of the Center for Cardiovascular Disease Prevention at BWH. “To provide the best care for our patients, we need universal screening for inflammation, cholesterol, and lipoprotein(a), and we need it now.

“While we still need to focus on lifestyle essentials like diet, exercise, and smoking cessation, the future of prevention is clearly going to include combination therapies that target inflammation and Lp(a) in addition to cholesterol,” he added.

The research team analyzed data from the Women’s Health Study, funded by the U.S. National Institutes of Health through research grants to preventive cardiology investigators in the Division of Preventive Medicine at the Brigham. The trial began in 1993 and has followed female health professionals aged 45 years and older ever since. Participants had their hsCRP, LDL-C, and Lp(a) levels tested in a blood sample obtained when they enrolled in the study. The primary endpoint was a first major adverse cardiovascular event — heart attack, coronary revascularization, stroke, or death from cardiovascular causes.

Disclosures: Ridker has received research grant support to the Brigham and Women’s Hospital and/or served as a consultant to entities developing preventive strategies and treatments that target inflammation, cholesterol, and lipoprotein(a), including Novo Nordisk, Novartis, Pfizer, Agepha, and Kowa. Full disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Supported by grants (HL043851, HL080467, and HL099355) from the National Heart, Lung, and Blood Institute and grants (CA047988 and CA182913) from the National Cancer Institute, National Institutes of Health.

This story is reprinted with permission from The Harvard Gazette.

***

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