A Former AD Care Partner’s Perspective on Leqembi

 

Social workers facilitating support groups for Alzheimer’s disease (AD) care partners or for people in early stages of AD should expect many questions in the coming months and years about some of the newer AD medications that are receiving, or about to receive, FDA approval. How should social workers respond to these questions that may be asked by AD patients and care partners? Aside from the obvious response that such questions should be directed to the patients’ doctors, here’s the view of one former AD care partner. On July 6, 2023, the FDA gave full approval for Japanese drugmaker Eisai and its American partner Biogen to market its latest medication, lecanemab (to be known as Leqembi) for those with mild AD. Announcing the approval, Teresa Buracchio, acting director of the Office of Neuroscience in the FDA's Center for Drug Evaluation and Research, says, “Today’s action is the first verification that a drug targeting the underlying disease process of Alzheimer’s disease has shown clinical benefit in this devastating disease. This confirmatory study verified that it is a safe and effective treatment for patients with Alzheimer’s disease.”1 That same day, The New York Times noted that the FDA acknowledged that Leqembi clinical trial results indicated that those taking the new medication showed a significant difference on an 18-point scale measuring cognitive functioning and memory, and that Leqembi “slowed memory and cognitive decline by about five months for those receiving the medication as opposed to those receiving the placebo.”2 However, as a doctor noted in that same article, “The benefits of slowing are subtle. You’re not going to experience the perception of changes in your cognition or function in the same amount of time.”2 In that same New York Times article, the author noted that Leqembi will carry a” black-box warning” about possible side effects such as brain swelling and bleeding, with a notation that “additional caution should be exercised” when considering whether to give blood thinners to Leqembi patients. Elsewhere in that same article it’s noted that “Concerns about safety have been stoked by reports of deaths of three clinical trial participants who experienced brain swelling and brain bleeding, two of whom were being treated with blood thinners. Eisai has said it’s unclear if Leqembi contributed to their deaths because the patients had complex medical issues.” According to an NBC news release online on Leqembi that same day, “About 12.6 % of patients who got Leqembi in the trial developed brain swelling, compared with 1.7% of those in the placebo group. About 17% of the Leqembi group experienced brain bleeds, compared with 9% in the placebo group.”3 I don’t think my late wife would have considered taking such a medication. Why? Three reasons: First, just the procedure for having to get dressed and get into the car to go to and from a doctor’s office for IV injections every two weeks for a year would have been a very stressful experience. And there would be additional doctor visits for various brain and blood scans while receiving the medication. In addition, my wife always felt pain with injections and bled readily, with her skin turning all pretty colors whenever receiving a needle for any reason, possibly due to all the heavy-duty heart medications she was taking each day as well as 325 mg of daily aspirin. A second reason would be the side effects. AD is serious enough as it is—a death sentence with no cure and the 100% certitude of worsening conditions. Gaining a few additional months of time to continue leading a more “normal” life before cognitive and memory issues worsen even more would be wonderful, but much too heavy a price if those side effects occurred. Dealing with AD and heart disease was enough of a double whammy for my wife. Possibly compounding that with brain swelling, bleeding, headaches, and other effects of this medication would have made her situation even worse. The final reason is the “real world effectiveness” of this new medication. Study participants taking the medication showed a gain of less than one half of one point on testing—a statistically significant outcome, perhaps, but I question how much of a clinical difference that really would have made in my wife’s life or in mine. By the time my wife was in early stages of AD, our lives had already changed dramatically. A few more months of slower decline would have been welcome but would probably not have changed much about our daily lives. Especially when one considers that the trade-off to perhaps gaining a few months of slower decline might have led to losing the quality of life we still had. Slowing decline doesn’t mean ending it, and we may not have even noticed that slowing. The added stress of two more doctor visits each month, the pain and after-effects of IV needles, and possible additional pain or hospitalization due to severe side effects of this new medication would have easily lessened whatever quality of life we still had. Would I have loved my wife to have declined at a slower rate for a few more months in those early stages? Of course. Would I have loved to have taken more trips with her? Absolutely. But worrying about the possibility of her having a serious brain hemorrhage or other serious side effect while traveling away from home would have worried me too much to have taken that chance. In fact, I would have been worried every single day, whether at home or not, had she been taking this new medication. I haven’t even mentioned another real-world effect of this new medication—the demands placed upon the AD patient’s care partner. Even in early stages, some AD patients may need assistance in dressing and with mobility and may angrily object to going out in bad weather or going out at a certain time of day. Helping people with AD can strain even the best of relationships. In addition, many care partners are still working when their loved ones are in early stages, and time demands of taking loved ones to two office visits each month for IV injections, along with additional visits for brain scans and other required testing to remain in this program, could be an additional burden. And, of course, there’s the financial burden this would be for many people with AD and their care partners. Even with expected 80% reimbursement by Medicare, out-of-pocket costs would still be high for both the medication and the additional office visits and scans. “Patients with traditional Medicare will pay 20% of the bill for Leqembi, according to the federal Centers for Medicare and Medicaid Services. That means these patients could see an annual bill of more than $5,000.”4 As a former 24/7 AD spouse caregiver, I am often skeptical of reports of “statistically significant” test results because I find that, too often, such results do not translate into meaningful observable differences in the real world. There is a big difference between “statistically significant” and “clinically different.” I often think of “statistically significant” AD test results in this way. Suppose one has 2,000 equally healthy and robust house plants, each producing 100 healthy leaves, with each plant expected to live for one full year before losing all of its healthy leaves. Then, suppose a clinical trial is conducted to determine if something added to the water might produce healthier plants. During the clinical trial to test whether or not a chemical added to “enrich” the water is better than just plain water for these plants, 1,000 plants receive only regular water and 1,000 plants receive only “enriched” water for an entire year. Then suppose that after one year, the plants receiving regular water have 99 dead leaves, while the plants receiving enriched water “only” have 98 dead leaves. If the authors of that hypothetical study then concluded that the difference in dead leaves is statistically significant by some sort of testing metric, results would still be totally meaningless to me. The plant with “only” 98 dead leaves would not look appreciably healthier to me than the plant with 99 dead leaves. Statistically significant differences? Maybe. Clinically significant differences? Not to me. The bottom line, to me, is one would have two dead plants. I am hoping for the day when a new AD medication will prove clinically effective in the real world, which to me would lead to many, many months or years before symptoms develop, worsen, or disappear with no serious potential side effects. I don’t see that happening with Leqembi. I won’t get too excited about Leqembi or other new medications with similar “statistically significant” results that also carry great risks of dangerous side effects. Not just yet. I have been disappointed too many times. I have seen too many dead plants. Social workers must always be careful not to involve themselves in discussions about advantages and/or disadvantages of any medications, referring all such questions to medical personnel. As someone who has facilitated support groups for AD care partners in the past, I was often asked medical questions by participants in my group. So social workers must accept that they may be asked by some care partners, if not by people with AD, questions such as “I know you cannot give me medical advice, but as someone I trust, what would you do if it were your mother/father/sister/brother/spouse? At least you will now have this former AD care partner’s perspective! — Allan S. Vann is a retired public school principal and former Alzheimer’s disease (AD) spouse care partner. To date he’s had more than 100 articles about AD published in peer reviewed medical journals, caregiver magazines, on AD organizational websites, and in major newspapers. Although his wife died of AD in 2016, he remains an active AD advocate for change, continues writing for publication, and continues to serve on advisory panels to help educate professionals working with AD patients and their care partners.   References 1. FDA converts novel Alzheimer’s disease treatment to traditional approval. U.S. Food & Drug Administration website. https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval. Published July 6, 2023. 2. Belluck P. New federal decisions make Alzheimer’s drug Leqembi widely accessible. The New York Times. July 6, 2023. https://www.nytimes.com/2023/07/06/health/alzheimers-leqembi-medicare.html 3. Lovelace B Jr. FDA grants full approval to new Alzheimer's drug meant to slow disease. NBC News website. https://www.nbcnews.com/health/health-news/leqembi-alzheimers-drug-fda-approval-eisai-biogen-rcna92377. Updated July 6, 2023 4. Kimball S. Medicare will pay for Alzheimer’s drug Leqembi. What patients and doctors should know. CNBC website. https://www.cnbc.com/2023/07/08/leqembi-and-medicare-what-patients-and-doctors-should-know.html. Published July 8, 2023.     Published as a Web Exclusive for Social Work Today, online only,  on 5/8/24 at https://www.socialworktoday.com/archive/exc_050724.shtml

 

Personal Blog #35 … Biogen is Ending Sale of Aduhelm … 2/1/24

Yesterday, 1/31/24, Biogen announced that it will stop selling Aduhelm, its Alzheimer’s disease (AD) medication, by the end of this year.  When initial approval was given by the Food and Drug Administration (FDA) to market this medication in 2021, FDA required Biogen to conduct additional studies to prove the efficacy of this new drug.  Biogen announced yesterday that it is ending its study needed to obtain full approval from the FDA. 

Readers may remember reading my Personal Blog #23, posted on this site on 6/11/21 … “Letter to Acting FDA Commissioner re Aduhelm.”  In the first paragraph of that PB #23 column, I wrote: “On 6/7/21, the FDA approved the drug Aduhelm, Biogen’s aducanumab medication, an intravenous infusion to be administered monthly for people with Alzheimer’s disease.  Despite not one member of the FDA’s Advisory panel voting to approve this med, FDA approved its use anyway.  FDA determined that since Aduhelm helped clear some amyloid protein from the brain, it may be “expected to help slow dementia.”  However, Biogen’s own data do not support such a claim, and readers can read my Personal Blogs #11 and #12 to learn more about results of clinical trials with this drug.” 

I also wrote the following: “For many patients and caregivers, the high costs of AD medications present an economic hardship. Money spent on (ineffective) AD medications is money that might otherwise be spent on day care programs, companions, home health aides, or other services that would actually improve the quality of their lives.”

“I witnessed AD spouse caregivers having to spend life savings on AD meds.  Some had to sell their homes when placing spouses in assisted living or to cover costs of home health care aides.  Now even more will have to do so because of money needlessly spent on this latest bottle of hope you have approved.  Based upon data I have seen ... a difference of 0.39 on an 18 point scale of cognitive and functional ability ... I can understand why not one member of your 11 member Advisory panel of experts that evaluated the data for FDA voted for approval.”

“I am SO sorry that FDA has approved yet another costly "bottle of hope" that will now financially ruin the lives of more AD spouse survivors with virtually zero benefit to their loved ones.  This is just not fair to people with AD, and not fair to their eventually surviving spouses.”

I also shared an email correspondence I had with Dr. Janet Woodcock, then acting FDA Commissioner.  In one email I had written, “My gripe is that there is no clear evidence that this med will actually slow cognitive decline in a meaningful way.  Unless and until Biogen can produce clear evidence that their medication does slow cognitive decline to a significant extent, it remains only an expensive bottle of hope.”

I also quoted one of several members of the FDA Advisory panel who resigned from the panel in protest, Dr. Aaron Kesselheim, a professor of medicine at Harvard Medical School.  Kesselheim said that FDA’s decision on Biogen “was probably the worst drug approval decision in recent U.S. history … based on the debatable premise that the drug’s effect on brain amyloid was likely to help patients with Alzheimer’s disease.”

In the last paragraph of PB#23, I noted my final comment to acting FDA Commissioner Woodcock re Aduhelm: “I want so much to see a new medication that will truly slow down the progression of the disease to allow a longer period of quality of life.  I want so much to see development of a new medication that will successfully treat if not cure AD.  (But) When an Advisory FDA panel has 11 experts and not even one of those experts votes to approve this medication, one has to wonder how something like this could happen.”

According to yesterday’s report by The Associated Press (AP), about 2,500 people worldwide are currently taking Aduhelm.  The AP report further stated, “Initially priced at $56,000 a year, analysts predicted it would quickly become a blockbuster that would generate billions for Biogen.  Medicare raised the premiums it charges for its coverage partially because of an expected influx of Aduhelm claims.  But doctors were hesitant to prescribe the IV drug, given weak evidence that it meaningfully improved Alzheimer’s patients lives.”

Although it comes as no surprise to me, I am deeply saddened to see yet another much hyped potential AD medication be declared a failure.  I have expressed my concerns about 2 other new AD meds targeting amyloid proteins (plaques) in the brain in Personal Blogs #28, #31 and #32.  These columns expressed my strong views on Lecanemab (now marketed as Leqembi), and Donanemab, a med that the FDA is expected to consider for approval within the next month or two. 

Given Biogen’s failure with Aduhelm, I can only reiterate what I wrote in last month’s PB #34.  Until science discovers exactly what causes AD … and as of today there is no definitive proof that AD is caused by the build-up of amyloid proteins in the brain … it will be extremely difficult if not impossible to develop a medication that can prevent AD or treat AD effectively.

 

 

 

 

Personal Blog #34 … Will 2024 Be the Year We Finally Discover the Cause(s) of Alzheimer’s Disease? … 1/14/24

I didn’t know much about Alzheimer’s back in 2007, but that was the year when I started searching the Internet for reasons to explain why, in my opinion, my wife was exhibiting worrisome behaviors.  Nobody else seemed to be noticing those behaviors, but I was seeing them more and more.  I continued worrying, I continued educating myself, and by early 2008 I was convinced that my wife was already dealing either with Mild Cognitive Impairment (MCI) or the early stages of Alzheimer’s disease (AD). 

Although my wife saw no reason to do so, I was able to convince her to see a neurologist after we returned from a particular trip in 2007.  During that trip, my wife exhibited many worrisome behaviors.  She was forgetting simple things (like our hotel room number or the names of our children and grandchildren), losing and misplacing things (leaving her sweater, coat, camera, and pocketbook in hotel rooms and restaurants) and was frequently disoriented when visiting sites in cities. 

My wife and I had recently entered our 60s and, like many friends our age, we were already starting to have those occasional “senior moments” when we’d forget something we knew well.  But my wife getting us lost on a regular basis was a major worrisome behavior.  I always got lost because I have no sense of direction, but I had always relied upon my wife’s “built-in GPS system” that, until that trip, had always guided us correctly wherever we were.  On that 2007 trip, however, even I knew she was repeatedly leading us in the wrong direction, we were frequently lost, and I, the one with no sense of direction, had to somehow lead us back to the correct location.

Throughout the rest of that year and in 2008, my wife’s doctors … first just our internist, and then the neurologist … saw no signs of MCI or AD.  They were both treating her first for stress, then for anxiety, and then for depression.  Throughout that time, I could not get my wife to agree to see another doctor for a second opinion, and each time I’d bring up that suggestion she would scream at me saying it was unnecessary.  Towards the end of 2008 and into early 2009, the neurologist suggested that my wife also be seen weekly by a clinical psychologist to help her with “coping mechanisms.”

At home I was regularly seeing new worrisome behaviors emerge, but none of my wife’s doctors observed these behaviors and all of her cognitive testing (MMSE tests, mostly) and brain scans seemed to be normal.  Despite what the doctors told me, I was now totally convinced that my wife was in the early stages of AD based upon all of my online reading from highly reputable governmental sites (such as NIA, NIH, and CDC), hospital sites (such as Mayo Clinic, Johns Hopkins, and Cleveland Clinic) and organizational sites (such as the Alzheimer’s Association, Fisher’s Center for Alzheimer’s Research Foundation, and UsAgainstAlzheimer’s).

In early 2009, feeling very frustrated that my wife was not properly diagnosed and was not being treated properly, I confronted the clinical psychologist.  I asked that if it were his wife being treated for more than a year for stress, anxiety, depression… and was actually getting worse … would he take his wife for a 2^nd opinion?  The psychologist said he had just spoken that morning with my wife’s neurologist.  I cut him off in mid-sentence, saying I had no faith in that neurologist.  I again repeated, would he take his wife for a 2^nd opinion?  The psychologist, now red-faced, said yes.  I turned to my wife and asked, “Now can I take you for a 2^nd opinion?”  She said “yes.”

Within a month my wife was seen by a geriatric psychiatrist affiliated with an Alzheimer’s Disease Research Center.  After just two lengthy visits and many hours of bloodwork, interviews, cognitive testing (not just the MMSE, but many tests), and new brain scans … and lengthy interviews of me to determine behaviors I was witnessing …  my wife was diagnosed with early onset AD.  Within a month my wife was taking Aricept, enrolled in a promising clinical trial, and my frustrations eased considerably because I now felt (in retrospect, naively so) that my wife was finally being treated effectively.

It has now been 15 years since my wife’s diagnosis in 2009.  What have we learned about the cause or causes of AD in those 15 years?  Sadly, the short answer is … not all that much.

Fifteen years ago I learned about amyloid-beta proteins (plaques) and tau proteins (tangles) and noted that most AD research money flowed into projects intended to definitively determine how one of both of those proteins were the cause(s) of AD.  Unfortunately, here we are in 2024 and we still haven’t conclusively determined if that is true, and at this stage many researchers are wondering if the presence of amyloid proteins may the results of AD rather than the cause.

Based upon a 2022 study at the University of Cincinnati, the chief neurologist and his research colleagues “hypothesized that plaques are simply a consequence of the levels of soluble amyloid-beta in the brain decreasing. The paradox is that so many of us accrue plaques in our brains as we age, and yet so few of us with plaques go on to develop dementia.” ¹

The latest statement from CDC, the Centers for Disease Control and Prevention, states the following: “Scientists do not yet fully understand what causes Alzheimer’s disease. There likely is not a single cause but rather several factors that can affect each person differently.” ² 

CDC does note some risk factors for AD  and several of those are listed on the CDC site.  Unfortunately, people have no control over the number one risk factor … age.  As we have long known, “Age is the best known risk factor for Alzheimer’s disease.”   All other risk factors noted by CDC are either ones we cannot control (e.g., family history) or statements with caveats such as, “a healthy life style may (my emphasis added) play a role in developing AD.” 2

The NIA, National Institute of Aging, notes the following on its site: “In recent years, scientists have made tremendous progress in better understanding Alzheimer’s and the momentum continues to grow. Still, scientists don’t yet fully understand what causes Alzheimer’s disease in most people.” ³  The NIA site suggests something similar to what is on the CDC site.  In its section, “What causes AD,” The NIA page has the following statement: “The causes probably (my emphasis added) include a combination of age-related changes in the brain, along with genetic, environmental, and lifestyle factors. ³

Similar non-emphatic statements can be found on just about any reputable site.  According to the Mayo Clinic, “The exact causes of Alzheimer's disease aren't fully understood … Scientists believe (my emphasis added) that for most people, Alzheimer's disease is caused by a combination of genetic, lifestyle and environmental factors that affect the brain over time.” ⁴

Organization websites, such at that of the Alzheimer’s Association, say something similar: “Researchers believe there isn't a single cause of Alzheimer's disease. It likely (my emphasis added) develops from multiple factors, such as genetics, lifestyle and environment. Scientists have identified factors that increase the risk of Alzheimer’s. While some risk factors — age, family history and heredity — can't be changed, emerging evidence suggests there may (my emphasis added) be other factors we can influence.” ⁵

So, whereas we have made some progress in learning about AD in these past 15 years, we still haven’t learned what causes AD.  It is extremely difficult to effectively prevent or treat a disease when we do not know the cause(s).  We are basically proceeding with common-sense advice that seems rational … that a healthy life style of eating nutritious foods, regularly exercising, avoiding brain injuries, etc. may (my emphasis added) prevent some (my emphasis added) people from developing AD.  But, as of today, we do not know that for sure.

It is too late for my wife, who died in 2016, and millions of others who have passed away directly because of AD or with AD as a major contributing factor.  Although continually listed among the top 10 causes of death in this country, the number of people dying with or because of AD is considered significantly greater than what is reported on death certificates.  According to the Alzheimer’s Association, “Death certificates for individuals with Alzheimer’s often list acute conditions such as pneumonia as the primary cause of death rather than Alzheimer’s … even though Alzheimer’s disease may well have caused the acute condition listed on the death certificate.” ⁶

When I received the death certificate from the nursing home after my wife’s death, I was shocked to note that AD was not mentioned as either the direct cause or as a contributing cause. ⁷   When I asked the nursing home doctor why, his response was that he couldn’t prove that AD was the cause.  When I asked why he didn’t even include AD as a contributing cause, he said he couldn’t prove that either. 

Therefore, 2016 CDC mortality statistics for deaths due to AD in the U.S. did not include my wife’s death.  On page 6 of its 2016 report on mortality rates, CDC listed AD as the 6^th leading cause of death in this country in 2016. ⁸   On page 62 of that same CDC report, the following statement appears: “Quality of mortality data is largely dependent on proper and thorough completion of death certificates by certifiers. Accuracy and completeness of information entered on death certificates can vary by state from year to year.” ⁸   One can only wonder how many thousands of deaths in this country due in whole or part to AD each year have not been reported accurately on death certificates.

I hope our government continues to increase funding for AD research in hopes of finding an effective means of prevention or cure.  In 2009, the NIH allocated $457 million for AD research. 9   I am very pleased to note that estimated NIH funding for AD research proposed for 2024 is approximately $3.5 billion. 10   Hopefully, increased federal spending will result in promising research and discovery.

Discovering a definitive way to prevent AD is the goal, but I’d be very happy if we can just learn how to more effectively treat this disease.  Recent medications approved by the FDA to help those with AD do not excite me.  In fact, if my wife were still alive, I doubt whether she or I would have wanted her to take any of these new medications. ¹¹   

But even if AD remains a death sentence with no cure, treatment that can enable people with AD to maintain and enjoy a high quality for life for 10, 15, or 20 years after diagnosis would be a wonderful advance. 

Maybe 2024 will be the year when this happens.

1.  Tedeschi, Tim. UC study: Decreased proteins, not amyloid plaques, tied to Alzheimer’s disease.  Accessed on January 14, 2024.  https://www.uc.edu/news/articles/2022/09/decreased-proteins-not-amyloid-plaques-tied-to-alzheimers.html

2.  Alzheimer’s Disease and Healthy Aging.  Centers for Disease Control and Prevention.  Accessed on January 14, 2024.  https://www.cdc.gov/aging/alzheimers-diseasedementia/aboutalzheimers.html#:~:text=Scientists%20do%20not%20yet%20fully,risk%20factor%20for%20Alzheimer's%20disease.

3.  What causes Alzheimer’s disease?  Accessed on January 14, 2024.    https://www.nia.nih.gov/health/alzheimers-and-dementia/alzheimers-disease-fact-sheet 

4.  Alzheimer’s disease.  Mayo Clinic.  Accessed on January 14, 2024.  https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/symptoms-causes/syc-20350447

5.  Causes and Risks for Alzheimer’s disease.  Alzheimer’s Association.  Accessed on January 14, 2024.  https://www.alz.org/alzheimers-dementia/what-is-alzheimers/causes-and-risk-factors

6. 2023 Alzheimer’s Disease Facts and Figures.  Alzheimer’s Association.  Accessed on January 14, 2024, p. 35.  https://www.alz.org/media/documents/alzheimers-facts-and-figures.pdf

7.  Vann, Allan S.  Reporting Deaths of Patients with Alzheimer’s.  Journal of the American Geriatrics Society.  December, 2016. 64:12, pp. 2419-2420.

8. Deaths: final data for 2016, July 26, 2018.  Centers for Disease Control and Prevention.  Accessed on January 14, 2024.  https://stacks.cdc.gov/view/cdc/57989

9.  Research Priority Setting, and Funding Allocations across Selected Diseases and Conditions.  National Institutes of Health.  Accessed on January 14, 2024.   https://www.gao.gov/assets/gao-14-246.pdf

10.  Estimates of Funding for Various Research, Condition, and Disease Categories (RCDC).  NIH RePORT.  Accessed on January 14, 2024.  https://report.nih.gov/funding/categorical-spending#/

11.  Vann, AS. ”Reflections of An Alzheimer’s Spouse.”  Personal Blog columns # 28, 31, and 32 discuss recent medications approved by the FDA within the past 2 years.  https://allansvann.blogspot.com/

Personal Blog # 33 … Concerns About AD? Be Sure to See the Right Doctor! ... 10/10/23

 

Personal Blog # 33 … Concerns About AD?  Be Sure to See the Right Doctor!

A friend of mine recently told me about the problems she went through trying to obtain an accurate diagnosis for the causes of increasingly worsening gastrointestinal issues her daughter was facing.  Despite being seen and treated by her primary care doctor, an internist, a gastroenterologist, and numerous MDs in hospital ERs, her issues continued to worsen.  Why?  It turned out that for many years she was repeatedly misdiagnosed and given medications that were not helpful.  Conditions such as anemia, appendicitis, nervous stomach, stress, hemorrhoids, and ulcerative colitis are just some of the misdiagnoses given to people who actually have Crohn’s.

At a certain point, my friend’s daughter was seen by a gastroenterologist with experience diagnosing and treating patients with Crohn’s disease.  Once properly diagnosed and treated for Crohn’s disease, there was immediate improvement in her condition and ability to function more normally.

According to the Mayo Clinic website, “Crohn's disease is a type of inflammatory bowel disease (IBD). It causes swelling of the tissues (inflammation) in your digestive tract, which can lead to abdominal pain, severe diarrhea, fatigue, weight loss and malnutrition.  Inflammation caused by Crohn's disease can involve different areas of the digestive tract in different people, most commonly the small intestine. This inflammation often spreads into the deeper layers of the bowel.  Crohn's disease can be both painful and debilitating, and sometimes may lead to life-threatening complications. There's no known cure for Crohn's disease, but therapies can greatly reduce its signs and symptoms and even bring about long-term remission and healing of inflammation. With treatment, many people with Crohn's disease are able to function well.  (https://www.mayoclinic.org/diseases-conditions/crohns-disease/symptoms-causes/syc-20353304)

Doctors misdiagnosing various diseases is nothing new, and my friend’s daughter was fortunate to finally be with a doctor who correctly diagnosed and treated her condition.  However, there are steps one can take to help minimize chances of misdiagnoses.  By reading about some of the mistakes I made with my wife, some readers may be able to avoid similar mistakes with their loved ones when there are concerns about AD.

Readers of my articles and blog columns already know that my wife, who died in 2016 due to AD, had been misdiagnosed for several years.  When I first began to notice behavioral changes in my wife and grew increasingly concerned that those changes might be signs of AD, we discussed these changes with our primary care doctor.  That doctor administered an MMSE … Mini-Mental State Evaluation … a very common test used by doctors to screen for possible AD.  My wife aced the test with a perfect score.  Unfortunately, I didn’t know that the MMSE was never intended to be used to screen for possible AD because, among other reasons, it does not test higher order thinking skills.  Our doctor gave my wife a prescription to reduce stress and anxiety.

My mistake was thinking that all was well based upon that MMSE score.  Even though our family physician said he was not an expert in AD, he could not detect any problems that, in his opinion, would warrant any additional testing. 

Months later, and observing new and worsening behaviors that I now thought could possibly be signs of AD, we met with the most highly respected neurologist in my geographic area, chair of the neurology department at a large and well-respected hospital.  I was also quickly educating myself about AD by visiting various internet sites such as those of the NIH, Mayo Clinic, Johns Hopkins, and the Alzheimer’s Association.

I was maintaining weekly logs noting new or worsening behaviors that I felt were clear signs of Mild Cognitive Impairment (MCI), if not early signs of Alzheimer’s disease (AD).  During the next 12-18 months, at every visit with every doctor I shared my latest logs, but doctors dismissed my logs without comment … often not even bothering to take time to skim or read what I had written.  The neurologist treating my wife for stress, for anxiety, and depression then also had her meet weekly with a clinical psychologist. 

My mistake was thinking that any neurologist or clinical psychologist would be easily able to diagnose AD.  My wife’s neurologist, a specialist in other brain disorders, was not an expert in AD.  My wife’s psychologist was a specialist in treating anxiety disorders, not AD.  Signs of AD that were obvious to me were misinterpreted by them and her diagnosis remained stress, then anxiety, and then depression … not AD.  I shared what the neurologist and clinical psychologist were saying about my wife with our primary care doctor, telling him that what I was observing seemed to clearly indicate early stages of AD.  Our doctor said that, based upon the behaviors I was observing, it was possible that my wife was in early stages of AD … but he deferred to the opinion of the neurologist who had much more experience with brain issues.

My mistake was not being strong enough to challenge my wife who continued to resist going for a second opinion.  We “fought” over it, but invariably she’d adamantly argue that she didn’t need to see another doctor and I couldn’t force her to do so.  I backed down each time, but I should never have backed down.  My wife said that since our family doctor, the neurologist, and the clinical psychologist all agreed that her problems were due to stress, anxiety, and/or depression … not MCI  and certainly not AD … there was no need to get another opinion. 

I was only able to bring my wife for a second opinion after I decided to confront the psychologist in my wife’s presence after a particular session.  I asked if his wife was being treated for stress, anxiety, and/or depression … and if his wife not only was not improving but was actually getting worse … would he take his wife for a second opinion?  When he said, red-faced, that yes, he would do so, I turned to my wife and asked, “Now will you let me take you for a second opinion?”

I was not going to repeat my mistakes of the past.  I had already gathered information on three doctors whose entire practices were focused on diagnosing and treating people with AD.  Two were geriatric psychiatrists affiliated with an Alzheimer’s Disease Research Center (ADRC) and one was a neurologist at another major hospital.  I showed the information on all three doctors to my wife and she chose one of the two geriatric psychiatrists.  We made an appointment and when the doctor learned that I had been keeping weekly logs of her behaviors, he asked me to email copies of those logs prior to our visit.  We then had several email exchanges about those behaviors, and even before our first visit I felt that we were now finally seeing the right doctor! 

My wife’s initial 3+ hour evaluation included the MMSE but also many, many more tests. After just thirty minutes spent evaluating my wife, the geriatric psychiatrist said that my wife was definitely not suffering from stress, anxiety or depression.  He wanted her taken off all of those medications, saying that ”something is going on in her brain’s frontal lobe.”  One month after all of her testing was completed … extensive cognitive testing, blood work, brain scans, physical exams, etc. … I received a call from the ADRC that, after a team meeting discussing all of her test results, my wife was diagnosed with probable early onset AD.

What is my advice to people with concerns about possible signs of AD in their loved ones?  Don’t visit just any doctor.  See  only a doctor experienced in diagnosing and treating people with AD.  Not all brain doctors … not even specialists such as neurologists and geriatric psychiatrists … have enough experience with AD to diagnose it properly.  Make sure you see a doctor who can do this.

And one more thing, something that is very sad to note.  Not all ADRCs will even take the time to make an initial diagnosis for people with concerns about possible AD symptoms!  I only recently learned about a friend who felt that he may be experiencing early signs of AD.  He made an appointment to see a specialist at his local ADRC, but they refused to see him once they learned that he did not yet have “sufficient” testing by other doctors first … brain scans, blood work, etc.

I emailed the following question to the person in charge of ADRCs at the National Institutes of Health: “Can my friend simply go to an ADRC for a complete evaluation, or must he first undergo imaging and blood work and other tests by his internist or neurologist.  So far he is acing the MMSE given to him by his internist but yet he recognizes he is still having cognitive problems.  Can he just get a consult at his local ADRC?  Following is the response I received:

“Thank you for contacting the federal government’s National Institute on Aging (NIA), part of the National Institutes of Health (NIH) at the U.S. Department of Health and Human Services. NIA was established to improve the health and well-being of older adults through research. The institute conducts and supports basic, clinical, and social and behavioral research on aging and the special problems and needs of older adults and is the lead federal agency for Alzheimer’s disease and related dementias research.   We appreciate your interest in the services provided by the Alzheimer’s Disease Research Centers.  While NIA provides funding to these Centers, we are not involved in their daily operations. Therefore, you will need to contact each Center you are interested in to inquire about their protocols for diagnosis and testing.”

That response is very unfortunate.  An ADRC has precisely those experts who should be available to meet with people who have the earliest AD concerns.  Months of delay before seeing such experts will undoubtedly lead to increased mental anguish.  In addition, the need to undergo additional expensive testing is a critical issue if one does not have outstanding health insurance.  Conducting initial AD diagnoses are too important … they should be included in all ADRC mission statements and protocols for diagnosis and testing.

One more thing.  If you do go to a doctor who administers the MMSE and makes a decision solely based upon those test results, please go to another doctor … asap!  There are many evaluative instruments better than the MMSE to help in diagnosing MCI or AD.  No doctor should still be using the MMSE, a test created in 1975, as a sole test to diagnose probable AD.  A score of 24 or less on the MMSE is considered indicative of possible cognitive impairment.  As I noted, my wife continually got a score of 30 in her earliest years of undiagnosed AD.  But even two years after being diagnosed with AD at the ADRC, my wife was still scoring 25 or higher on the MMSE!  Enough said.

Personal Blog #32 … New AD Medication, Leqembi (Lecanemab), Receives FDA Approval and Coverage Under Medicare … 7/6/23

 

The U.S. Food and Drug administration (FDA) gave full approval today for Japanese drugmaker Eisai, and its American partner, Biogen, to market its latest medication, lecanemab (to be known as Leqembi) for those with mild Alzheimer’s disease (AD).  According to Teresa Buracchio, acting director of the Office of Neuroscience in the FDA's Center for Drug Evaluation and Research, “Today's action is the first verification that a drug targeting the underlying disease process of Alzheimer's disease has shown clinical benefit in this devastating disease." 

Six months ago the FDA gave conditional approval for this new medication, but there was much debate in the medical community about the effectiveness demonstrated by its data.  Medicare said it would not pay for routine use of Leqembi until the FDA gave its full approval.  Today the FDA has given its full approval.  The FDA acknowledged that after an 18-month clinical trial with 1800 participants, results showed that those taking the new medication showed a significant difference on an 18-point scale measuring cognitive functioning and memory.  According to FDA, this study showed that Leqembi “slowed memory and cognitive decline by about 5 months for those receiving the medication as opposed to those receiving the placebo.”

A doctor quoted this afternoon in a USA Today article said, “This drug is not a cure. It doesn't stop people from getting worse, but it does measurably slow the progression of the disease. That might mean someone could have an extra six months to a year of being able to drive."  A doctor quoted this afternoon in The New York Times stated, “The risks are very vivid.  Within the first few months, you may have small bleeds or swelling in your brain, which may or may not be symptomatic and if not detected in time can cause disability.”

The FDA indicated that Leqembi will carry a” black-box warning” about possible side effects such as brain swelling and bleeding. The warning does not mention patients who are taking blood thinners, but Leqembi’s label says that “additional caution should be exercised” when considering whether to give blood thinners to Leqembi patients.  As also noted in The New York Times article, “Concerns about safety have been stoked by reports of deaths of three clinical trial participants who experienced brain swelling and brain bleeding, two of whom were being treated with blood thinners. Eisai has said it is unclear if Leqembi contributed to their deaths because the patients had complex medical issues.“

 

In my Personal Blog #28, I noted that ”17% of the patients taking this medication suffered cerebral micro and macro hemorrhages and superficial siderosis compared to 8.7% in the placebo group.”  I also shared my feelings in PB #28 about medications yielding “statistical differences,” noting that although statistically significant those differences might not result in “real world” differences.

This new IV medication is priced at about $26,500 for a year’s supply of injections that are to be given every 2 weeks and Medicare will now cover about 80% of its costs.  This still leaves patients with 20% of the cost, plus other related expenses for doctor visits, required scans, etc.  Personally, I’d prefer that Medicare spend its money more wisely than subsidizing patients taking this new medication.  And I think patients can better spend their money on support groups, saving for the future when home health aides or assisted living or nursing home facilities may be needed, or for other present expenses or future costs.

So what is my take on this FDA approval of Leqembi?  Whereas I am truly pleased that we now have a medication that has shown it may be able to slow cognitive decline and memory loss by up to 5 months in an 18-month period of real time, I don’t think my late wife would have considered taking such a medication.  Why?  Three reasons:

First, getting IV injections every 2 weeks for a year would have been a very stressful experience.  Just getting ready to go and driving to and from the doctor’s office to receive IV injections twice a month would have been stressful.  In addition, my wife always felt pain with injections, bled easily, and her skin turned all pretty colors whenever receiving a needle for any reason … possibly due to all the heavy-duty heart medications she took each day, including 325 mg of daily aspirin.  Even had my wife  started this medication, I don’t think she would have continued for too long. Those IV needles would have been painful as well as stressful.

A second reason is the side effects.  AD is serious enough as it is, a death sentence with no cure and the 100% certitude of worsening conditions.  Gaining a few additional months of time to continue leading a more “normal” life before cognitive and memory issues worsen even more would be wonderful … but what a heavy price if those side effects occurred.  Dealing with AD and heart disease was enough of a double whammy for my wife.  Possibly compounding that with brain swelling, bleeding, headaches, etc. due to this medication could have made her situation even worse than it already was

The final reason is the real world “effectiveness” of this new medication.  Study participants taking the medication showed a gain of less than one half of one point on testing … a statistically significant outcome, perhaps, but I question how much of a clinical difference that difference would have really made in my wife’s life or in mine.  As that doctor quoted in The New York Times noted with respect to the slowing of decline with Leqembi, “The benefits of slowing are subtle. You’re not going to experience the perception of changes in your cognition or function in the same amount of time.”  As I noted in PB #28, not all studies demonstrating results showing “statistical differences” in testing translate into meaningful and/or observable differences in the real world.

By the time my wife was in early stages of AD, our lives had already changed dramatically.  A few more months of slower decline would have been welcome, but would probably not have changed much about our daily lives.  Especially when one considers that the trade-off to perhaps gaining a few months of slower decline might have led to losing the quality of life we still had.  Slowing decline doesn’t mean ending it and we may not have even noticed that slowing.  The added stress of two more doctor visits each month, the pain and after-effects of IV needles, and possible additional pain or hospitalization due to severe side effects of this new medication could have easily lessened whatever quality of life we still had.

So what is my bottom line reaction to this FDA approval of Leqembi?  It is this:  Would I have loved my wife to have declined at a slower rate for a few more months in those early stages?  Of course.  Would I have loved to have taken more trips with her? Absolutely.  But worrying about the possibility of her having a serious brain hemorrhage or other serious side-effect while traveling away from home would have worried me too much to have taken that chance. In fact, I would have been worried every single day, whether at home or not, had she been taking this new medication.

I haven’t even mentioned another real word effect of this new medication … the demands place upon the care partner of having to bring the AD patient to and from doctor appointments.  Even in early stages, AD patients may need assistance in dressing, mobility, may object to going out in bad weather or going out at a certain time of day, etc.   In addition, many care partners of AD patients are still working when their loved ones are in early stages, and time demands of taking loved ones to two visits each month for IV injections could be an additional burden for them as well.

So whereas I am truly pleased to welcome a new medication to try to help those with AD, I would not have found Leqembi worth the risk. 

Personal Blog #31 … Donanemab, a Proposed New AD Medication … 5/8/23

 

I debated whether or not to even write this blog offering my opinion about donanemab.  Last week there was yet another big pharma announcement of clinical trial data for a new medication as an effective treatment for those in early stages of Alzheimer’s disease (AD) … donanemab.  No one wants more than I do to learn about new effective treatments for those in any stage of AD.  However, I have been disappointed too many times by big pharma companies releasing announcements of positive clinical trial results without simultaneous disclosure of all supporting data and peer review commentary.  Early announcements of rosy results have too often overplayed the positive effects of new medications and too often downplayed serious negative side effects.  I fear that donanemab is just the latest AD medication that a big pharma company has touted as having promising results that are “statistically” significant but not really “clinically” significant, and with extremely dangerous side effects.  (Please see PB # 28, posted on 10/4/22, about my serious doubts about the “significant” published results and dangerous negative side effects of lecanemab (now sold under the brand name, Leqembi), last year’s new AD medication from Eisai and Biogen.  In that blog I also discuss how statistically significant differences in AD testing for new meds may be totally insignificant and meaningless with respect to functioning in the real world.)

According to an article published in Nature on May 4, “For the second time, an experimental drug has been shown to reduce the cognitive decline associated with Alzheimer’s disease. On May 3, pharmaceutical company Eli Lilly announced in a press release that its monoclonal antibody donanemab slowed mental decline by 35% for some participants in a 1,736-person trial — a rate comparable to that for competitor drug lecanemab.”  Lilly said it intends to seek FDA approval within the next month or two, will issue further results at a major AD conference in July, and seek publication of its data in a forthcoming peer reviewed journal.

Early reactions to this announcement have been mixed.  According to that same Nature article, “Researchers warn that until the full results are published, questions remain as to the drug’s clinical usefulness, as well as whether the modest benefit outweighs the risk of harmful side effects.  Some researchers who have reviewed the limited data released to date are doubtful of its effectiveness.”  Quoting Dr. Marsel Mesulam, a neurologist at Northwestern University, “The results that are described are extremely significant and impressive, but clinically their significance is doubtful.”

As reported in the May 3 NY Times article about donanemab, “24 percent of patients had the side effect of brain swelling and bleeding, and 6 percent had symptoms like dizziness, headache or fainting. Three patients in the Lilly trial died.  The company reported that two to three out of 10 patients taking donanemab progressed (to worsening stages of AD) over the next 18 months, compared to the expected three to four patients taking a placebo.” Lilly said that people with mild Alzheimer’s who received donanemab “showed 35% less clinical decline over 18 months than did those who received a placebo, and 40% less decline in their ability to perform daily tasks.”

According to the NY Times piece, Dr. Ronald Petersen, Mayo Clinic’s director of the Alzheimer’s Disease Research Center, said that “the donanemab results were modest but meaningful adding that  “patients and their families must be counseled about a dire side effect of donanemab - a risk of brain swelling that can result in death.”  Dr. Samuel Gandy, professor of Alzheimer’s disease research at Mount Sinai, noted that whereas the results for both lecanemab and donanemab were reported to be statistically meaningful, they have “only modest clinical benefit.” 

In an article about donanemab published in Science on May 3, the author wrote: “We cannot be sure that this drug will actually make a difference in the real-world care of patients with Alzheimer’s - not yet, anyway. This point is completely avoided in the Lilly press release, but it is nonetheless real and we will be hearing more about it from clinicians - well, if you listen closely above all the noise, that is.” Also noted is how the negative side effects in the donanemab trial were worse than those in the lecanemab trial.  For lecanemab, “the reported rates of ARIA-E and ARIA-H (measures of brain bleeds) were 13% and 17% of the trial participants, and the rates in this new donanemab trial were noticeably higher: 24% and 31%.”  That same article quoted a tweet from Dr. Robert Howard, a psychiatrist at University College London who has tested treatments for dementia.  Howard tweeted, “Looks as dangerous as lecanemab.”

I remain very skeptical while awaiting full data and peer review of results from Lilly’s new proposed medication, donanemab … and for the same reasons as noted in my PB #28 about lecanemab.  Here’s why: When my wife was diagnosed with early onset AD, we knew that most people, on average, progress through the stages of AD in about 8 years … some more quickly, some more slowly.  We thought that we could be reasonably confident of having at least 3 and maybe even 4 more really good years together before she would progress to moderate stages of AD.  And we did.  During those first few years after diagnosis, we traveled extensively both in this country and internationally.  We played our favorite word games like Scrabble and Boggle, continued to go bowling in our leagues, enjoyed going out by ourselves and with friends to see plays and movies, and enjoyed just sitting on a bench at the water’s edge on nice days. We had a very rewarding life together for those first three to four years after diagnosis.

Had a medication such as lecanemab or donanemab been available, would we have risked what turned out to be nearly four really good years together to take medication hoping my wife would be in the 35% of those who might gain an extra few good months, but all the while risking that she could be in the group of 24% who would suffer brain swelling or brain bleeds, stroke or death?  I think not. There is just too much downside risk, in my opinion … the high risk of negative side effects of this new medication simply outweigh any hope that there may be a slight reduction in the rate of decline for a few more months.  I await the published results and peer review of this new proposed medication later this summer or fall, but I am not very optimistic.