CHAPTER 6: R IS FOR RETIREMENT AND AGING: WHEN YOU STOP LEARNING, YOUR BRAIN STARTS DYING

We don’t stop playing because we grow old.
We grow old because we stop playing.

GEORGE BERNARD SHAW

BETTY

Betty was 94 when she first came to see me. I had seen three generations of people in her family for attention deficit hyperactivity disorder (ADHD): her son, grandson, and great-granddaughter. When I asked her why she wanted to be evaluated, she said that she wanted to be able to finish reading the paper in the morning, something she had never been able to do. When Betty came back for her first follow-up visit after a month on our program, she told me she had read her first book! It was a joyous appointment. Several months later, she wondered aloud how her life would have been different if she had addressed her attention and impulse-control issues earlier in her life, yet she was grateful her children, grandchildren, and great-grandchildren would not have to suffer as she had.

Too often, elderly (let’s say those over 70) people are dismissed with brain health/mental health issues —such as ADD/ADHD, depression, anxiety or memory issues —because they are older; but research has found that no matter what your age, your brain can be better if you put it in a healing environment. Brain imaging work at the Amen Clinics has also clearly shown the gravity of age. As your skin starts to sag and wrinkle and show other signs of aging, the same type of process occurs in the brain. Following are three typical scans at 35, 55, and 85.

Typical Aging Brain SPECT Scans

TYPICAL AGING BRAIN SPECT SCANS

35 years old

55 years old

85 years old

Yet your brain doesn’t have to deteriorate with age if you remain diligent about your health for as long as you want to have a clear and happy mind! Here is a scan of my grandmother Margaret when she was a 92-year-old, and she was cognitively sharp until the day she died at age 98. One of her secrets of brain health was that she knitted her whole adult life, which is an exercise that works out the cerebellum.

Grandmother

Scan at 92

In a study the Amen Clinics and others published in the Journal of Alzheimer’s Disease in 2018 on 62,454 SPECT scans, we presented the overall pattern of brain aging and factors that accelerated it.[205] For example, we showed that children have very active brains that tend to settle down in activity around their mid-20s. From the mid-20s, brain activity then tends to stay relatively stable until the 60s, when it begins to decline, often due to poor vascular health and the other BRIGHT MINDS risk factors. But this doesn’t have to happen —there’s nothing inevitable about it. We have scanned many elderly patients and found really healthy scans, mostly because they were serious about taking care of themselves. Look at a typical aging pattern for the posterior cingulate gyrus, an area critical to memory and mood, in the graph below.

Activity in the Aging Posterior Cingulate Gyrus

ACTIVITY IN THE AGING POSTERIOR CINGULATE GYRUS

(One of the first areas that dies in Alzheimer’s disease)

These were the factors that accelerated aging the most in our study in order of importance: schizophrenia, marijuana abuse, bipolar disorder, and ADD/ADHD, along with alcohol abuse, and smoking. Other studies show that high iron levels in your blood[206] and red meat consumption[207] are also associated with premature aging.

The world’s population is on average becoming older, and age is the biggest risk factor for Alzheimer’s disease and other forms of dementia.[208] According to the World Health Organization, between 2015 and 2050 the percentage of people over 60 years will nearly double, from 12 percent to 22 percent.[209] This is really challenging for individuals as well as governments because as many as 10 percent of all people 65 years of age and older have serious memory problems, and up to 50 percent of all people 85 and older will be diagnosed with dementia. That means that if you are fortunate enough to live to 85, you have a one in two chance of losing your mind. Plus, the really bad news is that our research and the scientific findings of others have shown that Alzheimer’s disease and other forms of dementia actually start in the brain decades before people have any symptoms. For too many people, the golden years are anything but golden. The older you get, the more serious you need to be about the health of your brain.

Other brain health/mental health issues also worsen with age. The older you get, the more likely you are to struggle with your memory, social isolation, hearing problems, and overall cognitive function. As the brain deteriorates with age, it leads to a greater risk of mood problems, anxiety, irritability, temper flare-ups, and irrational behavior. Combine the lowered brain activity with detrimental changes to the four circles —biological, psychological, social, and spiritual —and it can accelerate brain health/mental health issues. Let’s look at how the four circles can contribute to brain health/mental health issues in the aging brain:

• Biological: If you’re racked by pain and stiffness (especially if you played football in high school like yours truly), it can make you feel cranky and depressed. (Try fish oil, s-adenosyl methionine [SAMe], and curcumins as I do to help pain.) If you have a medical condition, such as cancer, it can sap the joy from your life. If you have failing eyesight (Where did I put my glasses?), you may have a hard time enjoying your favorite hobbies, like reading or knitting. If you’re experiencing hearing issues (“What?” is the most common word I seem to say), you may begin feeling disconnected from your loved ones. As you’ll learn in chapter 18, what you put into your body (i.e., food) also matters. For example, consuming charred meats —think about those burgers or steaks on the grill at summer barbecues —creates toxic chemicals called glycotoxins that have been linked to memory problems and other cognitive problems.[210]

• Psychological: You may become increasingly worried about being either financially or physically dependent on others. You may find that your thoughts are more focused on what’s wrong with you than on what’s right.

• Social: The death of parents, siblings, or friends can increase a sense of loneliness, which can have a major impact on your mental well-being. Unfortunately, one-third of seniors between the ages of 50 and 80 say they feel a lack of companionship, and 25 percent of them feel socially isolated, according to a 2018 University of Michigan poll.[211]

• Spiritual: Retiring from work may leave you feeling as if you have no purpose in life. When you lack passion, purpose, social contribution, faith, or a connection to God or something greater than yourself, you are at a higher risk for developing brain health/mental health issues. Depression is more common after retirement, especially when retirees don’t find a new source of purpose. In fact, following an initial boost in health, retirement increases your risk of clinical depression by 40 percent while raising your chances of being diagnosed with a physical illness by 60 percent.[212]

I saw some of these changes happening to one of my uncles. As he aged, his behavior became downright embarrassing whenever we went to dinner together. He had always been a bit impulsive, but later in life he was rude to servers and often made inappropriate comments. I could see his brain deteriorating before my eyes. Also, when depression strikes in the elderly, it may well be one of the first signs of dementia. Ultimately, when you stop learning, your brain starts dying.

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When you stop learning, your brain starts dying.

 

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YOU DON’T HAVE TO BE OLDER TO HAVE THESE ISSUES

Anyone who is in a job that does not require ongoing learning is at a higher risk of memory problems and brain health/mental health issues. Numerous studies show that people who struggled in school, who learned to hate learning, or who dropped out of school early also have a higher incidence of cognitive problems and mental health challenges.

If you want to create a mental illness, never fully support children with ADD/ADHD or learning disabilities. Every day of their lives that they feel they are failing or that someone is disappointed in them ratchets up chronic stress, which shrinks the hippocampus, a critically important brain structure involved in memory, mood, and learning. My nieces were at great risk for this because of their home situation before their mother got help for her brain. Likewise, if you want to create a mental illness, start your children in school too early. Research shows that younger children in school are more likely to be diagnosed with ADD/ADHD and treated with stimulant medication.[213]

Research also shows that purpose and social contribution across the lifespan have a surprising pattern: They tend to peak when people are young (late adolescence/young adulthood), then begin to wane during middle age and decline sharply through late adulthood.[214] When purpose is absent or low, it increases the risk of mental illnesses, particularly depression, and decreases self-acceptance.[215]

Likewise, you are more likely to develop a mental illness if you have an “old mind-set,” where you find yourself saying things such as:

• I’m too old for that.
• I don’t have the energy for that.
• I just want to be left alone.
• I’m going to die soon, so why bother changing my habits?
• This is how I’ve done things for years, so why should I change now?
• I can’t give up . . . candy, muffins, wine, chips . . . you name it. I’d rather deal with anxiety or get Alzheimer’s disease.

Retirement/Aging Risk Factors
(and the Four Circles They Represent)

1. 1. Increasing age, especially over 65.

1. 2. Having a job that does not require new learning.

1. 3. Loneliness or social isolation. Humans are social animals: Social connectivity is hardwired into our brains, and when we are lonely and/or disconnected from others, it can have negative consequences for us cognitively, emotionally, and physically.[216] More than one in eight people report having no close friends.[217] The loneliest among us experience cognitive decline 20 percent faster than people who are connected to others, and loneliness has been associated with depression, social anxiety, addictions, even hoarding.[218] Loneliness peaks at several periods in life: during the late 20s, mid-50s, and late 80s.[219] Loneliness does not mean being alone or not having friends. It is subjective distress, meaning the discrepancy between the social relationships you have and the ones you want. The physical damage associated with being lonely was found to be equivalent to 15 cigarettes a day.

1. 4. Retired without new learning endeavors or passion or purpose.

1. 5. Too much or too little iron (blood test) —ferritin measures iron stores in the blood. Get yours checked. Levels between 50 and 100 nanograms/mL are ideal. Levels below 50 ng/mL can cause problems, such as anxiety, fatigue, restless legs, and ADD/ADHD. A 2015 study among psychiatric patients found that more than 25 percent of them were also suffering from anemia, with the condition being most common in people with psychotic disorders, anxiety, obsessive-compulsive disorder (OCD), and bipolar disorder.[220] High levels (over 250 ng/mL) are associated with iron overload and increase the risk of inflammation, heart disease and neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease.[221]

1. 6. Decline of neurotransmitters (brain chemicals), such as serotonin, dopamine, gamma-aminobutyric acid (GABA), and acetylcholine. As we age, we lose brain cells that produce these important chemicals that help our neurons communicate effectively. Low serotonin activity increases risk of depression;[222] low dopamine increases risk of Parkinson’s disease and loss of motivation and pleasure;[223] low GABA increases the risk of anxiety;[224] and low acetylcholine can affect learning and memory.[225]

Take a look at how the evil and benevolent rulers would ensure that aging and retirement helped or perpetuated mental illness.

RETIREMENT/AGING

THE EVIL RULER WOULD . . .

1. 1. Recommend everyone retire early, stop learning new things, and watch all the television they want, especially the news that focuses on violence, natural disasters, and partisan politics that breeds anger and stress.
2. 2. Let people watch as many scary movies as they want or play violent video games, both of which wear out the pleasure centers.
3. 3. Encourage people to spend their days in meaningless activities in isolation and demand that people spend hours on social media every day, which increases the risk of depression and obesity.
4. 4. Start children in school too young.

THE BENEVOLENT RULER WOULD . . .

1. 1. Encourage lifelong learning, purpose, and knitting.
2. 2. Discourage children from starting school too young.
3. 3. Promote cross-training in the workplace.
4. 4. Limit television, social media, and scary movies to keep the pleasure centers healthy.
5. 5. Encourage regular blood donation for those who have high iron blood levels.
6. 6. Educate people about the benefits of intermittent fasting.
7. 7. Provide treatment for ADD/ADHD and learning disabilities, so people would enjoy learning.
8. 8. Mandate brain health education at schools and businesses, which would highlight the positive effects of lifelong learning.

Despite the dire news about aging and your brain, you don’t have to give in to decline. Yes, you will age, but you can slow the process while keeping your brain sharp, focused, and clear. Imagine entering the latter part of your life with just as much mental capacity and energy as you have now, if not more. It’s possible.

PRESCRIPTIONS FOR REDUCING YOUR RETIREMENT/AGING RISK FACTORS
(AND THE FOUR CIRCLES THEY REPRESENT)

1. 1. Care! The older you get, the more serious you need to be. I turned 65 this year, and I’m planning to have one of the healthiest brains when I reach my 90s. I often ask myself, “Do you want an old brain or a young one?” to stay motivated when I don’t feel like working out or eating well. I recently saw a world-famous boxing champ who was struggling with his memory. After looking at his brain, I used the metaphor that he was in the “fight of his life.” He was going to have to break up with Colonel Sanders, one of his great loves, if he was going to keep his memory healthy. He told me he would train diligently because “you ain’t got nothing without your memory.”

1. 2. Avoid anything that accelerates aging —such as no new learning, being in a job that does not require ongoing learning, high iron levels, smoking anything, alcohol or marijuana abuse, standard American diet, loneliness, and a lack of purpose.

1. 3. Know your why for being healthy. Do you believe you need to be healthy because God has a calling for you? Is it independence? I love my four children, but honestly, I never want to have to live with them. I never want to be a burden, and I do not want them telling me what to eat or what to wear or worrying about taking my driver’s license from me. If that is true for you, then you need to be serious about your health.

1. 4. Exercise your brain with new learning. Engage in lifelong learning to keep your brain strong. Take a cue from actress Dame Judi Dench, who continues to act even though she is now in her eighties. She told the Telegraph in 2015 that retired is the rudest word in the dictionary. “I don’t think age matters at all. What matters is your determination not to give up and not to stop learning new things.”[226]

   The best mental exercises involve acquiring new knowledge and doing things you haven’t done before. Even if your daily activities are complex, such as teaching coding, interpreting brain scans, or engineering a new bridge, they won’t challenge your brain as much as new learning. Whenever the brain repeats an activity over and over, it uses less and less energy each time to accomplish it. New learning, such as a new hobby or game, establishes new connections, which maintains and improves other brain areas that you use less often.

   The parts of your brain that you use will grow, and the parts of your brain that you do not use will atrophy, or shrink. This provides guidance on how to exercise the brain. If you were to only play Scrabble or do the Sunday crossword puzzle, you wouldn’t get the full benefits you want. That’s like going to work out and only doing right bicep curls and then leaving. See the graphic below for more ideas.

Brain Health Workouts by Region

BRAIN HEALTH WORKOUTS BY REGION

1. 5. Balance your iron levels. Causes of too much iron include regular alcohol consumption, cooking in iron pans, foods fortified with iron, well water high in iron, or vitamin or mineral supplements with extra iron. Some people are genetically predisposed to absorb too much iron from food. Donating blood can help you lower iron levels. Green tea, rosemary[227], and curcumin may also help.[228]

   If you are low in iron, supplement with iron but never take iron in combination with other vitamins because it can make them toxic, and always take the iron supplement a couple of hours away from other supplements.

1. 6. Fast intermittently. Fasting helps your brain stay healthy because it cleans out the buildup of toxic proteins that damage neurons, reducing inflammation and slowing down aging. A simple way to do a nightly 12- to 16-hour fast is to eat dinner at 7 p.m., for example, and not eat again until 7 a.m. (or 11 a.m. for a longer fast). Even longer fasts of 24 hours can also be helpful.

1. 7. Get connected. To reduce the risk of loneliness and isolation, invest time with your family, church, or other groups. Sign up for a class or meet new people, anything to stay connected and build relationships. Research shows that caring for others increases your life expectancy.[229] Grandparents who care for their grandchildren, for example, live longer, on average, than grandparents who do not. In one study, older people who volunteered over two years actually increased the size of their hippocampus (involved in mood and memory).[230]

1. 8. Take nutraceuticals that are most useful to slow aging.
   • N-acetylcysteine (NAC). NAC has shown promising results in people with bipolar disorder, schizophrenia, OCD, and addictions.[231] It can also decrease inflammation[232] and may help delay brain atrophy in Alzheimer’s disease.[233]

     Dose suggestion: The typical adult dose is 600–2,400 mg a day; more than 1,800 mg/day can upset your stomach. I usually start patients at 600 mg twice a day.

   • Huperzine A. This remarkable compound, studied in China for nearly 20 years, improves the cognitive impairment that is often seen in people with depression[234] or schizophrenia,[235] as well as with several types of dementia.[236] It can have adverse side effects such as gastrointestinal issues, headaches, dizziness, and increased urination, as well as side effects with certain medications. Caution: Huperzine A should only be used with a doctor’s supervision.

     Dose suggestion: The typical adult dose is 50–100 micrograms (mcg) twice a day.

   • Saffron. Recent clinical trials have found that it helps for depression,[237] bipolar disorder, and anxiety. As a potent antioxidant[238] and nerve protector,[239] saffron enhances memory,[240] protects the hippocampus, boosts blood flow[241] and acetylcholine,[242] and fights toxic buildup of the proteins thought to cause dementia.[243]

     Dose suggestion: The typical dose of saffron in trial is 30 mg a day of standardized concentrates. The dose of the patented preparation of saffron called Satiereal is 176.5 mg a day, and its potency is comparable to that of 30 mg per day of other saffron concentrates.

   • Sage. In the 17th century, herbalist Nicholas Culpeper wrote that the herb sage could “heal” the memory while “warming and quickening the senses.” Centuries later, research shows the brain-enhancing effects of sage extracts[244] including potential relief from depression.[245]

     Dose suggestion: The typical dose is 300–600 mg of dried sage leaf in capsules or essential oil in doses of 25–50 microliters (mcL). Caution: Those who have high blood pressure or seizure disorders should only use it under the direction of their physicians.

   • Phosphatidylserine (PS). Clinical trials show that PS improves attention, learning, memory and verbal skills in aging people with cognitive decline, and it is the best documented nutraceutical for memory. Even people with Alzheimer’s have been found to benefit from taking PS. PS may also be effective in controlling stress, as it has been found to reduce cortisol levels,[246] and may reduce symptoms of ADD/ADHD in children.[247] You can get PS from egg yolks, muscle meats, and organ meats.

     Dose suggestion: The typical adult dose is 100–300 mg a day.

BRIGHT MINDS: RETIREMENT/AGING

STEPS TO CREATE MENTAL ILLNESS . . . AND MAKE MY NIECES, ALIZÉ AND AMELIE, SUFFER

1. 1. Don’t care about your aging brain.
2. 2. Engage in habits that accelerate brain aging.
   • Don’t treat ADD/ADHD or learning disabilities so children learn to hate learning.
   • Have a job that requires no new learning.
   • Retire early without a new hobby, passion, or purpose in life.
   • Don’t think about why you want to have a healthy brain.
   • Live alone and isolate yourself from friends and family.
   • Don’t check your iron level or treat abnormal levels.
   • Focus on all your aches and pains and other reasons why your life isn’t as good as it used to be.
   • Adopt an “old mind-set.”
   • Watch a lot of TV, especially news that focuses on violence, natural disasters, and partisan politics that breeds anger.
   • Spend hours on social media, which increases the risk of depression and obesity.
3. 3. Avoid the strategies that slow the brain aging process.

STEPS TO END MENTAL ILLNESS . . . AND KEEP MY NIECES, ALIZÉ AND AMELIE, HEALTHY

1. 1. Care about your brain at all ages.
2. 2. Avoid anything that prematurely ages your brain.
3. 3. Engage regularly in healthy habits that slow the aging process.
   • Focus on learning new things to keep your mind active, and engage in a variety of exercises that work different brain regions.
   • Cross-train at work to learn new skills.
   • At retirement age, continue working or volunteering, or find a new passion.
   • Know why you want to keep your brain healthy as you age.
   • Consider intermittent fasting to help clear the brain of toxic proteins that damage neurons.
   • Stay connected to family and friends, and engage in church or other group activities to form bonds with others.
   • Check your iron level and treat it if it is abnormal.
   • Maintain a youthful outlook on life.
   • Avoid watching too much distressing TV news.
   • Limit the amount of time you spend on social media.
   • Get treatment for ADD/ADHD or other learning disabilities so you will enjoy learning.
   • Consider nutraceuticals to optimize your brain health.

Pick One BRIGHT MINDS Retirement/Aging Tiny Habit to Start Today

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1. I’ll limit charred meats.
2. I’ll ask my doctor to check my ferritin (iron) levels.
3. If my iron is too high, I’ll donate blood.
4. I’ll try a daily fast for 12–16 hours.
5. In my diet, I’ll include potent antioxidants such as blueberries, other berries, green tea, and cloves.
6. To obtain the basic nutrients my brain needs to generate energy and use it to power its functions, I’ll take a multiple vitamin-mineral supplement and concentrated fish oil.
7. I’ll add acetylcholine-rich foods, such as shrimp.
8. I’ll stay connected to others and volunteer to avoid loneliness and isolation.
9. I’ll start or continue music training.[248]
10. Today, I’ll start a daily habit of new learning.

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[205] Daniel G. Amen et al., “Patterns of Regional Cerebral Blood Flow as a Function of Age throughout the Lifespan,” Journal of Alzheimer’s Disease 65, no. 4 (2018): 1087–92.

[206] D. J. Hare et al., “Is Early-Life Iron Exposure Critical in Neurodegeneration?” Nature Reviews Neurology 11, no. 9 (September 2015): 536–44.

[207] R. McClelland et al., “Accelerated Ageing and Renal Dysfunction Links Lower Socioeconomic Status and Dietary Phosphate Intake,” Aging 8, no. 5 (May 2016): 1135–49.

[208] L. E. Hebert et al., “Change in Risk of Alzheimer Disease Over Time,” Neurology 75, no. 9 (August 31, 2010): 786–91.

[209] “Mental Health of Older Adults,” World Health Organization, December 12, 2017, www.who.int/news-room/fact-sheets/detail/mental-health-of-older-adults.

[210] W. Cai et al., “Oral Glycotoxins Are a Modifiable Cause of Dementia and the Metabolic Syndrome in Mice and Humans,” Proceedings of the National Academy of Sciences of the United States of America 111, no. 13 (April 1, 2014): 4940–45.

[211] “National Poll on Healthy Aging,” University of Michigan (March 2019), ihpi.umich.edu/sites/default/files/2019-03/NPHA_Loneliness-Report_FINAL-022619.pdf.

[212] Gabriel H. Sahlgren, “Work Longer, Live Healthier,” IEA discussion paper no. 46 (May 2013), http://iea.org.uk/sites/default/files/publications/files/Work%20Longer,%20Live_Healthier.pdf.

[213] Kapil Sayal et al., “Relative Age within the School Year and Diagnosis of Attention-Deficit Hyperactivity Disorder: A Nationwide Population-Based Study,” Lancet Psychiatry 4, no. 11 (November 1, 2017): 868–75.

[214] Corey L. M. Keyes, “Authentic Purpose: The Spiritual Infrastructure of Life,” Journal of Management, Spirituality & Religion 8, no. 4 (November 2011): 281–97.

[215] P. A. Boyle, et al., “Effect of Purpose in Life on Risk of Incident Alzheimer Disease and Mild Cognitive Impairment in Community-Dwelling Older Persons,” Archives of General Psychiatry 67, no. 3 (March 2010): 304–10.

[216] T. J. Holwerda et al., “Feelings of Loneliness, but Not Social Isolation, Predict Dementia Onset: Results from the Amsterdam Study of the Elderly (AMSTEL),” Journal of Neurology, Neurosurgery, and Psychiatry 85, no. 2 (February 2014): 135–42.

[217] “Loneliness on the RISE: One in Eight People Have No Close Friends to Turn To,” Express, March 1, 2017, http://www.express.co.uk/news/uk/773002/One-in-eight-people-faced-with-loneliness.

[218] Kira Asatryan, “4 Disorders That May Thrive on Loneliness,” Psychology Today, July 23, 2015, https://www.psychologytoday.com/us/blog/the-art-closeness/201507/4-disorders-may-thrive-loneliness.

[219] E. E. Lee et al., “High Prevalence and Adverse Health Effects of Loneliness in Community-Dwelling Adults across the Lifespan: Role of Wisdom as a Protective Factor,” International Psychogeriatrics (published online December 18, 2018): 1–16.

[220] S. Korkmaz et al., “Frequency of Anemia in Chronic Psychiatry Patients,” Neuropsychiatric Disease and Treatment 11 (October 22, 2015): 2737–41.

[221] Joseph Mercola, “Iron: This Life-Saving Mineral Found to Actually Increase Senility in Many,” Mercola, July 19, 2012, http://articles.mercola.com/sites/articles/archive/2012/07/19/excess-iron-leads-to-alzheimers.aspx#_edn1.

D. J. Hare et al., “Is Early-Life Iron Exposure Critical in Neurodegeneration?”

A. C. Leskovjan et al., “Increased Brain Iron Coincides with Early Plaque Formation in a Mouse Model of Alzheimer’s Disease,” Neuroimage 55, no. 1 (March 1, 2011): 32–38.

[222] C. C. Meltzer et al., “Serotonin in Aging, Late-Life Depression, and Alzheimer’s Disease: The Emerging Role of Functional Imaging,” Neuropsychopharmacology 18, no. 6 (June 1998): 407–30.

[223] S. E. Hemby et al., “Neuron-Specific Age-Related Decreases in Dopamine Receptor Subtype mRNAs,” Journal of Comparative Neurology 456, no. 2 (February 3, 2003): 176–83.

Jean-Claude Dreher et al., “Age-Related Changes in Midbrain Dopaminergic Regulation of the Human Reward System,” Proceedings of the National Academy of Sciences of the United States of America 105, no. 39 (September 30, 2008): 15,106–11.

[224] Thomas McNeill and Michael Jakowec, “Neurotransmitters: GABA and Glutamate,” Medicine Encyclopedia (2019), http://medicine.jrank.org/pages/1225/Neurotransmitters-GABA-glutamate.html.

[225] J. L. Muir, “Acetylcholine, Aging, and Alzheimer’s Disease,” Pharmacology, Biochemistry, and Behavior 56, no. 4 (April 1997): 687–96.

[226] John Hiscock, “Judi Dench Interview: ‘Retirement Is a Rude Word,’” Telegraph, February 21, 2015, https://www.telegraph.co.uk/culture/film/film-news/11420407/Judi-Dench-interview-second-exotic-marigold-hotel.html.

[227] S. Samman et al., “Green Tea or Rosemary Extract Added to Foods Reduces Nonheme-Iron Absorption,” American Journal of Clinical Nutrition 73, no. 3 (March 2001): 607–12.

[228] Y. Jiao et al., “Iron Chelation in the Biological Activity of Curcumin,” Free Radical Biology and Medicine 40, no. 7 (April 1, 2006): 1152–60.

[229] Sonja Hilbrand et al., “Caregiving within and beyond the Family Is Associated with Lower Mortality for the Caregiver: A Prospective Study,” Evolution and Human Behavior 38, no. 3 (May 2017): 397–403.

[230] M. C. Carlson et al., “Impact of the Baltimore Experience Corps Trial on Cortical and Hippocampal Volumes,” Alzheimer’s and Dementia 11, no. 11 (November 2015): 1340–48.

[231] O. Dean et al., “N-acetylcysteine in Psychiatry: Current Therapeutic Evidence and Potential Mechanisms of Action,” Journal of Psychiatry and Neuroscience 36, no. 2 (March 2011): 78–86.

[232] Ibid.

[233] J. C. Adair et al., “Controlled Trial of N-acetylcysteine for Patients with Probable Alzheimer’s Disease,” Neurology 57, no. 8 (October 23, 2001): 1515–17.

W. R. Shankle et al., “CerefolinNAC Therapy of Hyperhomocysteinemia Delays Cortical and White Matter Atrophy in Alzheimer’s Disease and Cerebrovascular Disease,” Journal of Alzheimer’s Disease 54, no. 3 (October 4, 2016): 1073–84.

[234] Wei Zheng et al., “Huperzine A for Treatment of Cognitive Impairment in Major Depressive Disorder: A Systematic Review of Randomized Controlled Trials,” Shanghai Archives of Psychiatry 28, no. 2 (April 25, 2016): 64–71.

[235] Wei Zheng et al., “Adjunctive Huperzine A for Cognitive Deficits in Schizophrenia: A Systematic Review and Meta-Analysis,” Human Psychopharmacology 31, no. 4 (July 2016): 286–95.

[236] B. S. Wang et al., “Efficacy and Safety of Natural Acetylcholinesterase Inhibitor Huperzine A in the Treatment of Alzheimer’s Disease: An Updated Meta-Analysis,” Journal of Neural Transmission 116, no. 4 (April 2009): 457–65.

[237] H. A. Hausenblas et al., “Saffron (Crocus sativus L.) and Major Depressive Disorder: A Meta-Analysis of Randomized Clinical Trials,” Journal of Integrative Medicine 11, no. 6 (November 2013): 377–83.

[238] M. A. Papandreou et al., “Inhibitory Activity on Amyloid-Beta Aggregation and Antioxidant Properties of Crocus sativus Stigmas Extract and Its Crocin Constituents,” Journal of Agricultural and Food Chemistry 54, no. 23 (November 15, 2006): 8762–68.

[239] Shinji Soeda et al., “Neuroprotective Activities of Saffron and Crocin” in The Benefits of Natural Products for Neurogenerative Diseases: Advances in Neurobiology, vol. 12, eds. M. Mohamed Essa, Akbar Mohammed, and Gilles Guillemin (New York: Springer, 2016), 275–92.

[240] M. Tsolaki et al., “Efficacy and Safety of Crocus sativus L. in Patients with Mild Cognitive Impairment: One Year Single-Blind Randomized, with Parallel Groups, Clinical Trial,” Journal of Alzheimer’s Disease 54, no. 1 (July 2016): 129–33.

S. Akhondzadeh et al., “A 22-Week, Multicenter, Randomized, Double-Blind Controlled Trial of Crocus sativus in the Treatment of Mild-to-Moderate Alzheimer’s Disease,” Psychopharmacology 207, no. 4 (January 2010): 637–43.

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