The cholinesterase inhibitors like Aricept (i.e., donepezil) have been available for treatment of dementias such as Alzheimer’s disease for two decades. It is clear that long-term use of these medications slows the progression of Alzheimer’s disease (in those who tolerate them) and that discontinuing these medications after extended use produces a risk of more rapid decline even in those who are in middle and late stage dementia.

The standard of care for use of medications to treat Alzheimer’s related dementias recommends use of a cholinesterase inhibitor (donepezil, Exelon, and galantamine) starting in Mild Cognitive Impairment and early stage dementia. Namenda (i.e., memantine) has been available to treat middle and late stage (but not early stage) dementia for over a decade. A recent study (Cumulative, additive benefits of memantine and donepezil combination over component monotherapies in moderate to severe dementia: a pooled under the curve analysis (how’s that for a title?), Alzheimer’s Research and Therapy, 2015, 7, 28 PMID 25991927) indicates that adding memantine to donepezil improves outcome over either medication used alone.

The study combined results from 4 randomized clinical trials (RTCs) conducted over 6 months for a total study population of 1408 participants in middle to late stage Alzheimer’s disease (MMSE scores of 3-14 of a possible 30). There were 4 treatment conditions: placebo, memantine only, donepezil only, or combination of memantine and donepezil. Scores on standardized cognitive, functional, and behavioral scales were used to assess outcome.

The results indicated that:
 All participants who were treated with placebo declined on all outcome measures compared to either combined treatment or monotherapies (i.e., donepezil or memantine alone).
 Donepezil treatment alone was more effective than treatment with memantine alone.
 The combination of donepezil and memantine together was clearly the most effective treatment and “clinically significant.”
 The actions of the two medications were additive but not synergetic as has sometimes been stated by some.

These results make it clear that currently available medications for middle and late stage Alzheimer’s like dementias remain effective even into late stage disease. Furthermore, adding memantine to donepezil (and presumably other cholinesterase inhibitors) improves outcome over either treatment alone.

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It is increasingly clear that becoming demented as we age is more than just Alzheimer’s disease. There may be few if any “pure” cases of Alzheimer’s disease. It may be the added wear and tear from added medical burdens in conjunction with the pathology of Alzheimer’s that leads to dementia. We already test for factors such as B12 deficiency, thyroid deficiency, and acute infections as they may impact cognitive function and are treatable conditions.

However, we ignore many diseases that may take a toll on brain function and cognition. We are just coming to terms that such events as surgery, treatment of cancer, sleep apnea, and repeated head injuries have short and long term effects on cognition. The cumulative load is too much for biological and psychological compensation with time and aging. One often-ignored disease is lung disease such as COPD (chronic obstructive pulmonary disease) and asthma. Most with these diseases do not become demented but these conditions add to the risk and are often modifiable/treatable (Lung disease as a determinant of cognitive decline and dementia, James Dodd, 2015, Alzheimer’s Research and Therapy, 7, 32 PMID 25798202).

Lung disease increases cognitive impairment and brain pathology. We can add this to a list that includes smoking, cardiovascular disease, depression, physical inactivity, hypertension, diabetes, drugs, sleep disturbance, infections, and social isolation that puts us at risk for cognitive decline and are modifiable by life style and medical management starting at least in middle age. There is an independent association between lung function and cognitive performance.

The two main obstructive lung diseases are COPD and asthma. COPD is the most common lung disease. It is preventable and treatable. If left unchecked it is progressive and involves an inflammatory response to noxious particles or gasses most often secondary to tobacco smoke. Asthma is more frequent in children and young adults and is associated with inflammation and atrophy of lung tissue in response to allergy and hay fever rather than smoking. Treatment with inhaled bronchodilators and steroids improve both lung and cognitive function. Both conditions are often associated with cognitive impairment.

Although the focus of belief has been that hypoxia is the culprit, there is cognitive dysfunction in COPD without hypoxia. More likely the problem stems from cerebral small vessels disease, microbleeds in the brain, chronic inflammation, and oxidative stress. Smoking leads to decreased volume and density of frontal grey matter, risk of stroke, and cerebroatrophy. Finally, COPD has been linked to reduced hippocampal volume – a critical memory structure. In one study half of those with serious acute exacerbations of COPD had moderate to severe cognitive deficits that did not resolve after three months.

We can conclude that lung disease – especially COPD is a modifiable risk factor for cognitive decline and may contribute to the development of dementia. Lung disease independently from Alzheimer’s pathology is linked to memory/cognitive impairment but may or may not be associated with the rate of decline. Finally, the mechanisms for causing brain pathology are very complex.

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Lumosity, the “brain training company”, is booming. Everyone is looking for the magic, quick, easy way to fortify his or her brain in hopes of staving off dementia. However, know this. The brain is designed to elaborate itself from experience (in a very broad sense). The foundation of our being is learning and memory. That got us through growing up and it will get us through aging if we just do what comes naturally and you don’t have to pay a fee. That is, interact with the world about you.

There is so much marketing and appeal to science – that is often not founded in reality – that one can lose track of a very simple fact. The brain enriches itself by the mere act of engaging in the world. Here are some ideas from an article in the Business Insider (http://www.businessinsider.com/daily-habits-to-be-smarter-2015-5). The list is not and cannot be exhaustive but gives a range of possibilities. Doing these things may not actually make you smarter but they will enrich the connections in your brain.

1. Have an idea. I think its actually hard not to have an idea each day. It may not be the idea that changes the world but few ideas do.
2. Read a newspaper. Be sure not to skip ideas that challenge your beliefs.
3. Play devil’s advocate. Reading an editorial may help with this.
4. Read a book.
5. Watch an educational video or take a free online course.
6. Check with your favorite sources of knowledge. Yes, sports center counts.
7. Share what you have learned with others. We know and remember best that which we can and do explain to others.
8. Make a to do list including learning new things.
9. Track what you have accomplished from the to do list.
10. Create a “stop doing” list. For example, I get caught up in playing hearts and spider solitaire. I need to do it less often. Maybe I need to set a timer so I can get more interesting things done.
11. Keep a journal of what you have learned that you want to remember.
12. Talk to someone you find to be interesting.
13. Be with people who are smarter than you.
14. When you hear something interesting, follow up on it.
15. Learn new words to help you express yourself.
16. Get outside of your comfort zone. If you are really willing to confront a common fear, join toastmasters.
17. Travel and explore new places and cultures.
18. Set aside time to do nothing.
19. Engage in a hobby.
20. Exercise.

I am sure you can add to this list. The point is to paraphrase Carl Rogers, don’t just grow older bur rather continue to grow as you grow older.

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Has the diagnosis of Alzheimer’s disease outlived its usefulness? I have felt for some time that the diagnosis of Alzheimer’s disease has no clinical utility. First, one can have Alzheimer’s disease and never become forgetful. Second, one can have Alzheimer’s disease with memory loss but not become demented. Third, one can become demented and not have Alzheimer’s disease. Fourth, we do not know the cause of Alzheimer’s disease as evidenced by the massive failure of amyloid treatments to date. Fifth, there is no pure case of Alzheimer’s disease in the elderly. Finally, there is no specific treatment unique to Alzheimer’s disease.

The real life problem is not that someone has Alzheimer’s disease but rather the practical issue is whether one can be competent to handle the tasks of independent living: self-care, toileting, dressing, doing the checkbook, getting around, learn, being in relationships, etc. Some are more proficient at any of these tasks than others. But the clinical problem develops when one becomes disabled, unable to carry out independent activities in the real world. Dementia is a form of disability. Dementia is by definition irreversible. Dementia may come on suddenly from such things as head injuries or strokes. Dementia may develop over time from such things as Alzheimer’s disease, Lewy Body disease, or Huntington’s chorea.

Based on autopsy findings very few elderly that become demented have pure Alzheimer’s disease. For example, as we age, the brain is affected by strokes. Most of the strokes are “silent” that is without symptoms. There are small strokes that can be seen upon imaging techniques such as the MRI but we are not aware of events marking them. There are strokes so small that they cannot be seen via imaging like the MRI but can be seen under the microscope during autopsy. These silent strokes alone may double the rate of dementia. It may not be the pathology of Alzheimer’s disease alone that causes one to become demented but rather the added burden of a second pathology that overwhelms the ability to compensate.

So rather than use a term like Alzheimer’s disease wouldn’t we be better off just using labels like Mild Cognitive Impairment (still independent) and dementia (no longer independent)? If we made this change it would allow us to focus our attention on practical skills like doing a checkbook, driving, being able to express oneself, preparing meals, etc. This removes all of the connotations that a label like Alzheimer’s disease has. Rather we could then assess functional skills and develop treatments plans to address them.

We could also become more proactive. For example, we can address issues like cardiovascular disease to reduce (not prevent) the likelihood of ever becoming demented, even if we are unlucky enough to have the pathology that is Alzheimer’s disease. Aggressively treating such factors as blood pressure may reduce the odds of becoming demented by 50%. We can further protect ourselves by not smoking, limiting consumption of alcohol, managing diabetes, exercising, and eating a heart healthy diet.

It is time to redirect our thinking. The label “Alzheimer’s disease” limits our thinking and has outlived its usefulness. It reduces our options. It creates a hopelessness that may be unnecessary. Alzheimer’s disease is a label not an explanation for certain ways the brain becomes less competent with advancing age in some but not all.

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Despite the “therapeutic nihilism” that seems to dominate thinking about Alzheimer’s disease there are essential components that should be included in managing Alzheimer’s. Jeffrey Cummings details these components in the Annals of Clinical and Translational Neurology (A practical algorithm for managing Alzheimer’s disease: What, when, and why? 2015, 2, 307-323, PMID 25815358). An effective treatment plan should include:

Strategies for managing risk factors starting at least in middle age. Consider adopting a “Mediterranean style” diet; minimize consumption of alcohol; supplement with omega 3, B vitamins, and E (if already clinically diagnosed); exercise regularly; engage in intellectual interests; become educated about Alzheimer’s disease; participate at some level in music and art; get adequate sleep; manage stress, let a pet adopt you; include stimulating day programs appropriate for the various stages of memory loss for those already diagnosed; and use a calendar and external supports to stay engaged in life.

Once diagnosed, consider treatment with appropriate medications: cholinesterase inhibitors (Aricept/donepezil, Exelon, or galantamine). These medications slow/delay decline in many if tolerated. All three have similar efficacy and follow up is needed to assess and manage possible side effects. Begin assessing and monitoring cognition and ADLs 6 months after initiation of treatment. Consider adding Namenda in moderate to severe disease.

There may be potential for including a trial on therapeutic foods such as Axona, NAC, and Vayacog under clinical supervision. This seems more experimental to me at this point based on the data available.

Manage “comorbidities.” These include cardiovascular disease, thyroid function, sleep apnea (doubles the risk for Mild Cognitive Impairment and dementia over the course of 5 years), osteoporosis, cancer, glaucoma, depression, hypertension, diabetes, infections, incontinence, and rheumatoid conditions. These diseases increase the rate of cognitive decline and frailty.

Assess safety. Have an OT and PT assessment in the home. Remove firearms. Monitor and assess the appropriateness for driving.

Have legal directives in place. Make sure you have a durable power of attorney and living will in the context of your life planning. Develop a plan for assessing, protecting, and transfer of financial and medical decision making as the disease progresses.

Know the options for in-home and residential care should they be desired or needed. Discuss these issues early and openly. Have a plan that you hope to never need to use to protect against decision making during crisis.

Don’t forget to include family and caregivers in planning and treating Alzheimer’s disease. They are the foundation for success and practical management in everyday living. They need support, education, guidance to help the not only to be effective caregivers but also to be sure they do what is necessary to have a life beyond caregiving.

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There are two main pathways for cognition as we age: normal aging and cognitive decline (abnormal aging). It is important to understand that aging is not a disease, Alzheimer’s is. It seems clear that there are things we can do to protect and enhance cognition during normal aging. What is not clear is whether there are things that we can do to protect against abnormal aging.

Staying sharp cognitively is a goal for many seniors as evidenced by the popularity of “brain fitness” programs such as Lumosity. Lumosity alone has some 70 million members from 180 different counties. It’s marketing ads boast that it is “scientifically” developed. There is no clear evidence that mastering their 40 games makes any real world improvement in everyday cognitive functioning let alone protects against abnormal aging.

A recent report from the Institute of Medicine makes several cogent points. Clearly there is great variability in cognitive abilities in the aged. Many stay very sharp as they age. Two cognitive changes are associated with advancing age. First, as we age we process information more slowly than we did when we were younger. Second, as we age we multitask more poorly. Most of us actually do a good job of compensating for these changes in such skills as driving. For example, we slow down, leave more following distance, and limit night driving in unfamiliar places.

Even subtle changes in cognitive skills increase vulnerability for some. We may become more susceptible to scams so we become more suspicious. We may become less able to make complex financial decisions so we involve family and advisors. We may have difficulty in an increasingly complex technological society so we solicit guidance from our children and grandchildren. Long-term memory stays intact as evidenced by knowledge, skills, and routines despite decline in working memory. Hence we use more external memory supports.

The report makes several recommendations based on accepted evidence for helping maintain cognitive skills as we age. These suggestions include:

1. Stay physically active.
2. Control high blood pressure and diabetes. So goes the heart, so goes the brain.
3. Don’t smoke. Limit consumption of alcohol.
4. Some medications can be especially problematic for cognition as we age. These include antihistamines, sleep aids, anti-anxiety medications, older antidepressants, bladder medications, pain medications, and anti-seizure medications.
5. Stay socially and intellectually active.
6. Get enough sleep. Indeed, “power” naps can help memory and improve alertness.
7. Be wary of products that promise to improve cognition. This includes supplements as well as brain fitness games. The “MIND” diet has not been adequately tested.

Of course, these are the recommendations that we read about often and we have known for a long time. We can better manage cognitive changes that arise from normal aging. The suggestions for preventing abnormal aging remain elusive at his time.

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I finally got around to reading a book that one of my clients gave me a couple of years ago – My Stroke of Insight by Jill Bolte Taylor, 2006, Plume: New York, http://www.drjilltaylor.com. Dr. Taylor is a Neuroanatomist who had a stroke on December 10, 1996 when in her mid 30s. There are two types of stroke. One is caused by blockage (infarction) of blood vessels in the brain, the other caused by bleeding (hemorrhage). Hers was the latter caused by the rupturing of an abnormal blood vessel structure, ateriovenous malformation, which she didn’t realize she had until it bled. Her recovery took 8 years – don’t believe the 6 month rule. The stroke left her completely disabled – unable to walk, talk, read, write or recall much of her life.

Although the book is an excellent, approachable, personal, and philosophical treatise on stroke and recovery from the inside out by an accomplished neuroscientist, I was most moved by her succinct summary of how to approach the neurologically impaired whether victims of stroke, head injury, retardation, or dementia. These insights are summarized in detail in Appendix B of her book. What follows is my selective listing of some of her most important considerations that we all (especially professionals) need to keep in awareness when working with those with brain injuries.

1. “I am not stupid.”
2. “Come close, speak slowly, and enunciate clearly.”
3. “Be as patient with me the twentieth [or one hundredth] time you teach me something as you were the first.”
4. “Take your time.”
5. “Be aware of what your body language and facial expressions are communicating to me.”
6. “Make eye contact with me.”
7. “Please don’t raise your voice – I am not deaf. I’m wounded.”
8. “Honor the healing power of sleep.”
9. “Use age-[retained skill] appropriate … educational toys [objects] and books to … [engage] me”
10. “Teach me with monkey-see, monkey-do behavior.” Liberally use prompts, modeling, and gestures.
11. “Trust that I am trying – just not with your [or my past] skill level or on your schedule.”
12. “Ask me multiple- choice questions. Avoid yes/no questions.” Invite me to do things rather than asking “Do you want to ….”
13. “Do not assess my cognitive ability by how fast I can think [or respond].”
14. “Speak to me directly, not about me to others.”
15. “Break all actions down into smaller steps of action.”
16. “Look for obstacles that prevent me from succeeding on a task.”
17. “Celebrate all of my successes.”
18. “Focus on what I can do rather than bemoan what I cannot do.”
19. “Introduce me to my old life. Don’t assume that because I cannot play like I used to play that I won’t continue to enjoy music or an instrument, etc.”
20. “Love me for who I am today. Don’t hold me to being the person I was before. I have a different brain now.”

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“As the twig is bent, so is the tree inclined.” We have long believed that experience and stimulation in early life determines social and intellectual behavior. Indeed, Freud presented theories that personality is largely formed by the age of five. We have broadened our views since then but it is clear that the young brain is malleable, capable of neuroplasticity, based on experience, e.g., John Paul Scott, Early Experience And The Organization Of Behavior way back in 1968.

What about the effects of enrichment on the brain? Rosensweig, Bennet and Diamond performed their classic experiments with rats back in the early 70s. Animals were raised in either a standard, “impoverished,” environment or an “enriched” environment that provided objects to explore and interact with. The brains of enriched rats were thicker and denser than those of impoverished rats. Hence, circumstances in the environment determine brain complexity and we now have programs such as Head Start for the young.

But when it came to the old, the belief was quite different. Whereas early experience had a primacy the old brain was described as declining and not thought to be capable of neuroplasticity. “You can’t teach an old dog new tricks.” Fortunately, we are breaking out of this dogma but old stereotypes are hard to change. The most recent evidence comes from a European study that demonstrated that an enriched environment directly impacts the hippocampus. The hippocampus is a critical brain circuit regulating the formulation of new memories and regulation of emotions. As an aging man with a shrinking hippocampus, I need to take this to heart.

The study demonstrated that enriching the environment produced new innervation within the hippocampus as well as establishing distant connections to other brain regions. The effect persisted even after the enrichment was no longer present. Furthermore, exercise also increases hippocampal neurons. These effects probably don’t alter the course of dementia but they have important implications for the changes in cognition that go with aging.

Finally, naps are beneficial to the brain and learning. Volunteers learned word pairings. Half watched a DVD after learning, half took a nap. The group that took a nap recalled the pairings five times better than those who watched the DVD. In short, the nap reduced forgetting. Brain activity in the hippocampus was thought to explain this effect.

So you can teach an old dog new tricks. As we have known for some time, the best way to deal with the changes of aging are to stay stimulated by enriching activities (e.g., hobbies, reading, beautifying home and garden, getting out into nature, meeting people, engaging in art/music, and studying things of interest). Exercise regularly. And take a nap after learning. Your hippocampus will love it.

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We have known for quite some time that women are more likely to develop Alzheimer’s disease than men. The obvious inference is that women live longer than men, on average (the current average age of death for women is 81 and men 76). Given that age is the biggest risk factor for Alzheimer’s disease, women are more likely to live long enough to show symptoms than men.

But many studies have adjusted for age and it is clear that age is not the cause of this sex difference. Indeed, the risk for Alzheimer’s disease is twice that for women than men aged 70-79 but the same for those 80 and older. There is no clear explanation for this relationship.

Despite having a greater risk for Alzheimer’s disease, another interesting sex difference in memory is that healthy woman typically do better than healthy men on recalling lists of words as evidenced by the age norms for memory tests. A recent study from the Mayo Clinic adds an interesting complication (“Age, sex, and APOE4 effects on memory, brain structure and beta amyloid across the adult life span, 2015, JAMA Neurology, March 16, http://archneur.jamanetwork.com/article.aspx?articleid=2193880).

The study focused on 1246 (1209 aged 50 to 95, 37 aged 30-49) participants in a longitudinal study of aging and memory. All were cognitively “normal.” The variables assessed included, age, sex, APOE4 (the “risk gene” for Alzheimer’s disease), hippocampal volume (the short-term memory structure in the brain that is associated with memory loss), and amyloid (a current marker for Alzheimer’s disease based on PET scan results).

The findings:
1) Memory worsened between 30 and the 90s – as we all suspected.
2) Hippocampal volume reduced between 30 and 60s and reduced faster after the 60s – presumably the source of the memory inefficiency.
3) There was little amyloid until after age 70 – suggesting that the memory loss of aging was not related to Alzheimer’s disease.
4) The memory loss was greater for men than women after age 40.
5) Hippocampal volume was less in men than women especially beyond age 60.
6) There was no sex difference for amyloids – the findings do not appear to be related to the development of Alzheimer’s disease.
7) APOE status was unrelated to hippocampal volume, memory, or sex at any age.
8) After age 70 those with APOE4 displayed more amyloid than those with E2 or E3.
Obviously the relationship between dementia and sex is complicated. However, these results do fly in the face of the belief that memory loss in older adults is always a sign of Alzheimer’s disease. The best conclusion at this time is that the memory inefficiencies associated with normal aging are different from the memory loss associated with Alzheimer’s disease.

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I have been specialized in memory and memory disorders such as Alzheimer’s disease and related disorders for a quarter of a century. Interestingly, in all that time I have read very little about Dr. Alois Alzheimer (6/14/1864 – 12/19/1915). Engelhardt and de Mota Gomes wrote a recent article (“Alzheimer’s 100 anniversary of death and his contribution to a better understanding of senile dementia,” 2015, Arquivos De Neouro-Psiquiatria, 73, 159-162 PMID 25742587) in honor of the upcoming 100th anniversary of his death that helped me put Dr. Alzheimer in a broader context.

It’s important to understand that the concept of “senile dementia” dates back thousands of years. Both Aristotle and Plato held the belief that old age is linked to inevitable memory failure. The concept of mental stimulation as neuroprotective is also not new. Cicero believed that keeping mentally active prevented or delayed mental decline that he believed comes with age. Cullen defined senile dementia as “a decay in perception and memory” in the 18th century. Phillip Pinel, the great reformer of asylums, set the stage for not only more humane treatment but also increased empirical and pathological observation of those with mental disorders as the brain was increasingly viewed as cause of mental disorders. This has burgeoned into he current explosion of neuroscience and biological reductionism.

Aloysius Alzheimer was instrumental in transforming senile dementia into a brain disorder that is subject to scientific study. He was born in Marktbriet, Bavaria. He obtained his MD from Wurburg University in 1887. He was married with three children but widowed after 7 years. During his career he worked as what would now be known as a biological psychiatrist at hospitals in Frankfurt, Heidelberg, Munich, and Breslau. He had a long friendship and collaboration with Emil Kraepelin, the founder of modern scientific psychiatry, psychopharmacology, and psychiatric genetics.

Although his contribution to biological psychiatry was quit broad, his most famous case was Auguste Deter who was 51 in 1901. Her first symptom was jealousy toward her husband followed by memory decline, disorientation, aphasia, apraxia, agnosia, paraphrasing, and persecutory delusions. Alzheimer studied her for 5 months and later followed her until her death in 1906 at age 55. He was the first to describe “thick bundles of neurofibrils” now known at tangles along with “miliari foci of peculiar substance” now known as plaques based on post-mortem autopsy of her brain. He presented a paper at a Psychiatric Congress in 1906 and published his findings in 1907, which led Kraepelin to coin the name Alzheimer’s disease for this condition in his famous Textbook of Psychiatry in the 1910 edition.

Alzheimer died in 1915 of “renal and respiratory failure” at the age of 51.

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