Untangling Alzheimer’s

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Alzheimers

Breakthroughs in understanding dementia are leading to new healthcare approaches. Nutrition, lifestyle, and sleep may be the keys to prevention.

Some days, Greg O’Brien doesn’t recognize his wife. Other days, he mistakes his family or his friends. He has not yet woken up in the morning and failed to recognize himself in the mirror. But he knows that day is coming.

O’Brien is losing his mind, one day at a time, to Alzheimer’s disease.

“It’s like having a slice of your brain cut away every day,” he says. “Alzheimer’s is death in slow motion.”

O’Brien, a nationally recognized writer and journalist, was diagnosed in 2009 with early-onset Alzheimer’s at age 59. He’s one of 5.4 million Americans with Alzheimer’s. Every 3.2 seconds, someone around the globe is newly diagnosed with Alzheimer’s or one of various forms of dementia, prompting the World Health Organization to label dementia “a public health priority” in 2012. In the United States, Alzheimer’s is the sixth-leading cause of death; one in three elderly people dies with dementia.

The cultural and economic burdens of Alzheimer’s are immense. Caring for dementia patients in the United States alone cost an estimated $236 billion in 2016. While one in nine Americans over 65 has Alzheimer’s, one in three people is affected by it, either dealing with the illness themselves or caring for suffering family members. Beyond the hospitals, nursing homes, and special facilities that provide care for Alzheimer’s patients, 15 million Americans — often spouses or other family members — provide unpaid care.

Perhaps most alarmingly, the graying of baby boomers could nearly triple the number of Americans with Alzheimer’s by 2050.

In the past, little was known about how Alzheimer’s affects our minds, so little was done to mitigate it. Funding for research lagged far behind the support provided for cancer and AIDS studies because the disease was deemed incurable. This is starting to change, led in part by former president Barack Obama, who dedicated a record $350 million to Alzheimer’s research at the National Institutes of Health in 2016.

Our understanding of the workings of Alzheimer’s has expanded exponentially in just the past two decades. New findings focus on the importance of lifestyle (including how we eat and exercise, inflammation reduction, and adequate sleep) in combating the neurodegeneration associated with the disorder. Research even suggests that the genesis of Alzheimer’s may be traced to our gut’s microbiome.

For the first time, there is hope that we may be able to prevent the disease.

For his part, O’Brien, now 67, is chronicling how Alzheimer’s is affecting his life and his family as a way of raising public awareness of the illness.

In 2014 he published a memoir, On Pluto: Inside the Mind of Alzheimer’s, detailing his daily battle to preserve his mind. The book is not a misery memoir. Instead, he tells his story as a means of providing others with “a blueprint of how to fight” the onset of dementia.

O’Brien talks frankly about his daily coping strategies: He sends himself constant email reminders of everyday tasks on his smartphone — sometimes up to 50 a day. He labels his mouthwash to differentiate it from a bottle of isopropyl alcohol so he doesn’t mistake the two as he did one morning. He runs three miles on a treadmill daily in an effort to keep his mind charged by the restorative powers of exercise. And he surrounds himself with photos of his family, including one of his mother, who died from Alzheimer’s, as well as framed clippings of favorite articles he’s written — all in an attempt to refresh and retain those memories.

“There’s only so many things I can do now, but the one thing I’m going to do until I can’t anymore is be a reporter,” O’Brien says. “By documenting Alzheimer’s, I’m getting even with it. It’s my way of living with the disease, not dying from it.”

Uncovering Alzheimer’s

Dementia is not simply misplacing your keys, being unable to recall a word, or having other so-called senior moments. The National Institute on Aging broadly defines it as a brain disorder affecting communication and performance of daily activities. Alzheimer’s is the most prevalent form of dementia in the world today, accounting for 50 to 70 percent of dementia cases. (Other forms include Parkinson’s, Huntington’s, Creutzfeldt-Jakob disease, and Lewy-body dementia.) Alzheimer’s specifically affects parts of the brain that control thought, memory, and language.

The disease was identified in 1901 by Alois Alzheimer, a German psychiatrist and neuropathologist. He first noted the form of presenile dementia in the case of a 51-year-old woman named Auguste Deter, writing, “She sits on the bed with a helpless expression. What is your name? Auguste. . . . Your husband? Ah, my husband. She looks as if she didn’t understand the question.”

When Deter died in 1906, Alzheimer autopsied her brain. What he discovered was startling: Shrunken and shriveled, it was mottled with miniscule particles clinging to it like barnacles. The cortex was emaciated. No one had ever seen a brain like this before.

Alzheimer described his findings that same year to a meeting of German alienists, doctors who specialized in treating mental ill-nesses. The abnormalities in Deter’s brain included amyloid beta-protein plaque, a substance that can trigger neurodegeneration by strangling brain nerve cells. The plaque causes tangles within the nerves; the tangles are made of another protein called tau.  These two pathologies begin in and radiate out from the hippocampus and other brain regions involved with cognition and memory.

In the early 20th century, doctors and researchers assumed that aging was the primary factor in the development of dementia. And for decades, the understanding of Alzheimer’s disease was limited to this theory of aging.

Alzheimer’s Breakthroughs

As recently as the 1980s, when Alison Goate, PhD, was doing her doctoral work at the University of Oxford, medical school curricula devoted little attention to Alzheimer’s because of the persistent belief that it could not be prevented, slowed, or cured.

Since then, the understanding of dementia has grown dramatically — and exponentially in the last 10 years. Part of the dramatic growth in our understanding of dementia since then is due to a breakthrough discovery made by Goate, now a professor of neuroscience and director of the Ronald M. Loeb Center for Alzheimer’s Disease at the Icahn School of Medicine at Mount Sinai in New York City.

In 1991 Goate and her colleagues discovered a particular gene mutation in three successive generations of a family in which several members of each generation developed dementia. When she saw the gene variation for the first time, Goate says, she thought, “I am the first person to see a cause of Alzheimer’s disease. . . . It was a eureka moment . . . but it was also spooky and scary.”

This advance led to more genetic findings, as well as a more prosaic development that dramatically influenced dementia research: the use of transgenic mouse models for laboratory studies, which broke open the doors of Alzheimer’s research.

Researchers have since uncovered two other genes that can carry rare mutations that lead to Alzheimer’s and a fourth gene that carries several common variations — known as single nucleotide polymorphisms, or SNPs — that may predispose a person to Alzheimer’s. (For more on SNPs, see “Making Sense of SNPs“.)

These are the mutations Goate and other researchers have identified:

Amyloid precursor protein (APP): Goate and her colleagues located the inherited APP gene mutation on chromosome 21. It strongly correlates with an early-onset form of Alzheimer’s known as Mendelian. It is inherited as a result of a single mutant copy of the gene. While only about 1 percent of the population carries this mutation, it is “highly penetrant,” she explains: 95 to 100 percent of people with it develop Alzheimer’s.

Presenilins (PSEN1 and PSEN2): Mutations in these two genes may also lead to early-onset Mendelian Alzheimer’s. These mutations are rare but powerful: Less than 1 percent of people have them, but 95 to 100 percent of those develop the illness. Mutations in PSEN1 account for 80 percent of early-onset familial Alzheimer’s, explains Goate.

Apolipoprotein E4 (Apo E4): Those with this gene variation have brains that are less efficient at clearing amyloid beta, leading to plaque formation. About 15 percent of people carry this variation, which can increase your risk of Alzheimer’s by threefold, according to Goate. This is the mutation running in Greg O’Brien’s family.

Other SNPs: There are some 30 other gene variations that researchers working with the genome-wide association studies (GWAS) have recently discovered. These typically carry lower risk: A person with one of these variations has no more than a 10 percent greater risk of developing Alzheimer’s than someone without it, Goate says.

The Inflammation Factor

Your inheritance of certain genes may increase your risk of Alzheimer’s, but DNA does not determine your destiny. In a relatively new research field known as epigenetics, researchers are studying the external factors that turn genes on — or leave them dormant. A key factor in determining your genes’ activation is your lifestyle.

In 2014, Harvard neurology professor Rudolph Tanzi, PhD, one of the world’s leading Alzheimer’s researchers and coauthor with Deepak Chopra, MD, FACP, of Super Genes and the New York Times bestseller Super Brain, synthesized Alzheimer’s in a petri dish using “mini brains” created from human stem cells. This breakthrough and subsequent research led to the identification of a third brain pathology that is central to Alzheimer’s disease: inflammation. Neuroinflammation occurs in response to the plaques and tangles, and it rapidly accelerates the onset of dementia.

Along with the discovery of neuroinflammation’s effects came a related finding: Researchers have since autopsied people who died in their 80s and who, despite their brains being full of plaques and tangles, had no cognitive issues. Tanzi believes they exhibited no symptoms of dementia because there was no inflammation.

“Plaques and tangles start the cell death, like starting brushfires. Those brushfires spread, but if you don’t have neuroinflammation, you don’t get the full-blown forest fire,” he explains.

“A key to staving off Alzheimer’s is fighting neuroinflammation in order to keep your brain resilient.”

This profound finding offers the first real hope that the disease might be conquered — or at least held at bay.

The Brain–Gut Connection

The new understanding of Alzheimer’s as an inflammatory disease has been revolutionary in comprehending its pathologies — and in developing new strategies to fight it. The next step forward, according to David Perlmutter, MD, an associate professor at the University of Miami Miller School of Medicine and author of the New York Times bestseller Grain Brain, is to uncover the source of that deadly inflammation in the body.

Inflammation is a basic immune-system response that rushes to your body’s aid when you’re injured. Skin your knee, and your body’s inflammatory response directs white blood cells to the scrape to battle any invading bacteria while also mending damaged tissue.

Inflammation can become chronic, however, and aging is one of the biggest risk factors for chronic inflammation. As we age, our immune systems become less well-regulated for a variety of reasons.

Still, aging doesn’t cause inflammation on its own.

“Ultimately, inflammation and the chemicals it produces, such as cytokines, lead to cellular destruction,” explains Perlmutter. “It’s the corner-stone of coronary artery disease, diabetes, cancer, and Alzheimer’s.” (For more on inflammation, go to “Fighting Inflammation“.)

We need to find the origin of that inflammation, he says. “And all arrows are pointing to changes in the microbiome — the hundred trillion microbes in our gut.”

Several factors can harm the helpful bacteria in our microbiome, Perlmutter explains: drugs like antibiotics, proton pump inhibitors, even aspirin and ibuprofen; chlorinated water and environmental toxins; and what we eat, especially processed foods, sugar, gluten, and diets with too little fiber and too few healthy fats.

Damaging the microbiome can lead to leaky-gut syndrome, a condition that occurs when food particles or other toxins break through the one-cell-thick gut lining and run rampant in our bodies. The immune system tries to fight off these foreign objects, resulting in chronic inflammation. (For more on this, see “How to Heal a Leaky Gut“.)

One key inflammatory chemical from the gut that penetrates the lining is lipopolysaccharide, or LPS. “We see huge elevations of this marker, LPS, showing gut permeability in people with Lou Gehrig’s disease, autism, major depressive disorders, and Alzheimer’s disease — all of which have been classically thought of as being disorders of the brain,” says Perlmutter.

The Future of Alzheimer’s

Alzheimer’s — like obesity, type 2 diabetes, and cardiovascular disease — has become a worldwide epidemic. As we live longer and the global population becomes disproportionately older, the prognosis is dire. The number of new dementia cases worldwide estimated for 2015 increased 30 percent over 2010 estimates, according to Alzheimer’s Disease International. And the global population with dementia is expected to nearly double every 20 years, reaching 74.7 million in 2030.

“Everything we’re doing to try to reduce the risk of Alzheimer’s could be undone by the large number of people who are now developing what are often age-related diseases at younger ages,” Goate says.

“We have teenagers with type 2 diabetes, which was almost unheard of a couple of decades ago. What does that mean for dementia and Alzheimer’s disease in 20 to 30 years among this group of individuals if they live a lifetime with type 2 diabetes starting in their teens and 20s? That’s of great concern to the health community.”

Still, Goate and many researchers are optimistic about the progress they and others have made in understanding the disease. Five Alzheimer’s drugs have been approved by the FDA, and others are in testing; all of them work to slow or block the progress of the illness, not cure it. But many experts believe the greatest advances have been made in understanding what can be done for prevention.

“We now know that there is a very long asymptomatic period of the disease,” Goate says. “There’s a window of opportunity for treating the disease that is huge. If we have early detection and we can pick up these changes 15 or 20 years before someone actually begins to show any clinical symptoms, then we should be able to prevent it from occurring.”

4 Ways to Fight Alzheimer’s Now

“Living a fit and healthy lifestyle is your best protection against getting Alzheimer’s,” says Alison Goate, PhD, a professor of neuroscience and director of the Ronald M. Loeb Center for Alzheimer’s Disease at the Icahn School of Medicine at Mount Sinai in New York City. Aging is the most important risk factor, so your lifestyle choices are key to protecting yourself. What you eat and how you live and exercise can all help you fight neuroinflammation and keep your brain healthy over time. Experts offer the following four essential ways to fight dementia.

1. Eat Well

Keeping your microbiome healthy with quality whole foods is critical. Eating too much sugar, too many simple carbohydrates, and too little fiber and healthy fat will harm your gut bacteria. “Your microbiome, via the gut–brain axis, is in constant communication with your brain and regulates neuroinflammation,” explains Rudolph Tanzi, PhD, one of the world’s leading Alzheimer’s researchers.

Fermented foods like sauerkraut, pickles, kombucha, and yogurt with probiotic bacteria, as well as prebiotic fibers, are essential because they feed good gut bacteria, says David Perlmutter, MD, an associate professor at the University of Miami Miller School of Medicine.

“When a woman is pregnant, we say, ‘You have to be careful because you’re eating for two.’ But actually, each and every one of us is eating for the hundred trillion bacteria in our guts,” he explains. “Everything you eat either nurtures or damages your microbiome, so you really want to focus on avoiding things that are going to damage the microbiome.”

Perlmutter also recommends choosing organic and non-GMO foods whenever possible because pesticides, herbicides, and other toxins can harm that bacterial habitat.

“In 2015 the World Health Organization characterized glyphosate, the active ingredient in Roundup, as being a probable human carcinogen. That’s powerful language for the most pervasive herbicide used on the planet,” he says. “Clearly, one of the ways that glyphosate may induce cancer is because of the changes it causes in the human microbiome.”

To reinforce the need to eat well, Tanzi reports that people with cardiovascular risk factors like type 2 diabetes, hypertension, and obesity also have increased risk of Alzheimer’s.

“Being very aggressive about managing your microbiome is important, and that means staying away from greasy fried foods, fast foods, and processed foods while consuming probiotics like live-culture yogurt and kefir,” he says. “If you take care of your microbiome, it’ll take care of you — and that’s all the way up to your brain.”

2. Get Your Z’s

Your brain produces less amyloid beta-protein when you’re in deep, slow-wave sleep, according to David Holtzman, MD, professor and chairman of the Department of Neurology at Washington University School of Medicine in St. Louis. “All the things that decrease amyloid accumulation probably decrease the chances that tau will accumulate and spread,” he says.

During deep sleep, your brain also cleans out amyloid produced during the day, as well as other “brain debris” that could be at the root of the brain’s inflammatory process, explains Jeffrey Iliff, PhD, assistant professor in the Department of Anesthesiology and Perioperative Medicine at Oregon Health & Science University.

As people age, their ability to reach deep sleep falters, Iliff says. In addition, those with Alzheimer’s often find it difficult to sleep. This creates what could be a vicious cycle.

“As people get older, the rate of clearance of amyloid beta is lost, so it’s actually not that more amyloid beta is made in the brains of old people with Alzheimer’s disease; it’s the clearance that seems to be defective,” Iliff explains.

“We don’t yet know that worsening sleep causes Alzheimer’s disease — we can’t say that. Does worsening sleep promote amyloid deposition, or does amyloid deposition promote worsening sleep? The two seem to be linked in some way, and we’ll know more about that in the coming years,” he says.

Iliff and his colleagues are now delving into this question by developing new MRI-based approaches to see this process at work in the sleeping human brain for the first time.

In the meantime, Tanzi advises getting seven to eight hours of sleep religiously, especially if you’re over 40. “If you don’t, you’re not giving your brain enough of a chance to clean itself,” he says.

3. Move Your Body

Exercise does several things that combat Alzheimer’s, explains Tanzi. First, as you exercise, you create enzymes in the brain that attack and chew up amyloid. Second, exercise increases neurogenesis, the process by which your brain makes new nerve cells in the hippocampus, the area affected by Alzheimer’s. Finally, as the results of a new study by Tanzi’s research team show, exercise actually reduces neuroinflammation.

His recommendation? “The very simple prescription of 8,000 to 10,000 steps per day is a good goal. You don’t have to go crazy; just keep moving.”

4. Exercise Your Mind

Help keep your brain sharp by learning new things and staying socially active. There are several reasons for this, and although they are theoretical, studies are under way by Holtzman and others.

The cognitive-reserve hypothesis holds that the more you learn, the more neuronal connections you have in your brain. These serve as a sort of brain trust as you age and compensate for the loss of other cells, so you can afford to lose more neurons before you show clinical symptoms of Alzheimer’s, explains Goate. Brain games like Sudoku and bridge, intellectual conversations, and learning a musical instrument or foreign language can all help build those vital neurons.

“When you’re ready to retire, think about not just financial reserves but also synaptic reserves,” advises Tanzi. “Save up your synapses by learning new things. Keep moving emotionally and intellectually. Don’t be stagnant.”

He also recommends you keep moving spiritually with meditation. Tanzi and his colleagues recently published a study about the positive effects of meditation on gene activity. “Meditation shows a positive effect on inflammatory genes and even on the biomarkers for amyloid in the brain,” he says.

is an Experience Life deputy editor.

Illustration by David Cutler

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