Pill Pushing©

The Best of Pill Pushing - Do dementia drugs really help? - (6/6/2019)

By Dr. Ron Gasbarro

Society at the time

The year was 1996. The 68th Academy Awards honored Nicholas Cage as Best Actor (Leaving Las Vegas), and Susan Sarandon as Best Actress (Dead Man Walking); Best Picture was Braveheart, directed by Mel Gibson who received the Oscar for Best Director. Alanis Morrisette cleaned up at the Grammy’s that year, winning 4 top awards for her album Jagged Little Pill, including Album of the Year and Best Rock Album. Frasier won the Emmy for Best Comedy Show for the third time, eventually grabbing a total of 5 awards in that category. 


In 1996, Amber Hagerman, a 9-year-old American child victim and namesake for the AMBER Alert system, is murdered in Arlington, Texas. Six-year-old JonBenét Ramsey is murdered in the basement of her parents' home in Boulder, Colorado; had she lived she would be 27 years old today. 


Embroiled in the Whitewater scandal, US First Lady Hillary Clinton testified before a grand jury. The British government announced that Bovine spongiform encephalopathy (aka Mad Cow Disease) has been likely transmitted to people. Suspected "Unabomber" Theodore Kaczynski is arrested at his Montana cabin.


In the fight for gay rights, the case Romer v. Evans: The Supreme Court of the United States ruled against a law that prevents any city, town or county in the state of Colorado from taking any legislative, executive, or judicial action to protect the rights of homosexuals. The Nintendo 64 video game system is released in Japan. Dolly the sheep, the first mammal to be successfully cloned from an adult cell, is born at the Roslin Institute in Midlothian, Scotland. Their Royal Highnesses, the Prince and Princess of Wales, are formally divorced at the High Court of Justice in London. 


In 1996, the first drug indicated to treat mild, moderate and severe dementia of the Alzheimer’s type is introduced to the market: Aricept® (donepezil).



The good, the bad, and the ugly


Who was Alzheimer?

Dr. Aloysius "Alois" Alzheimer (June 14, 1864 – December 19, 1915) was a German psychiatrist and neuropathologist. Alzheimer is credited with identifying the first published case of "pre-senile dementia", later identified as Alzheimer's disease (AD).


In 1901, a 51-year-old woman, Auguste D, was admitted to the state asylum in Frankfurt [Berrios, 1990]. She was suffering from cognitive and language deficits, auditory hallucinations, delusions, paranoia and aggressive behavior, and was studied by Alzheimer, who worked at the hospital. Alzheimer moved to the Munich medical school in 1903 to work with Emil Kraepelin one of the foremost German psychiatrists of that era. When Auguste D died in April 1906, her brain was sent to Dr. Alzheimer for examination. In November of that year, Alzheimer presented Auguste's case at a psychiatry meeting, and he published his talk in 1907.




A growing and expensive health problem

An estimated 5.4 million Americans have AD [Figure 1] [Alzheimer’s Assoc.; 2016]. By mid-century, the number of people living with AD in the United States is projected to grow to 13.8 million, fueled in large part by the aging baby boom generation. Today, someone in the country develops AD every 66 seconds.  By 2050, one new case of Alzheimer's is expected to develop every 33 seconds, resulting in nearly 1 million new cases per year. In 2013, official death certificates recorded 84,767 deaths from AD, making it the sixth-leading cause of death in the US and the fifth leading cause of death in Americans age =65 years. Between 2000 and 2013, deaths resulting from stroke, heart disease, and prostate cancer decreased 23%, 14%, and 11%, respectively, whereas deaths from Alzheimer's disease increased 71%. The actual number of deaths to which AD contributes is likely much larger than the number of deaths from AD recorded on death certificates. 


In 2016, an estimated 700,000 Americans age >65 years will die from AD, and many of them will die because of the complications caused by AD. In 2015, more than 15 million family members and other unpaid caregivers provided an estimated 18.1 billion hours of care to people with Alzheimer's and other dementias, a contribution valued at more than $221 billion. Average per-person Medicare payments for services to beneficiaries age >65 years with AD and other dementias are more than 2.5-fold as great as payments for all beneficiaries without these conditions, and Medicaid payments are 19 times as great. Total payments in 2016 for health care, long-term care, and hospice services for people age >65 years with dementia are estimated to be $236 billion. The costs of AD care may place a substantial financial burden on families, who often have to take money out of their retirement savings, cut back on buying food, and reduce their own trips to the doctor. In addition, many family members incorrectly believe that Medicare pays for nursing home care and other types of long-term care. Such findings highlight the need for solutions to prevent dementia-related costs from jeopardizing the health and financial security of the families of people with AD and other dementias.




The drug(s) in question

AD is an irreversible and progressive neurodegenerative disorder [Lee, 2015]. AD is the most common cause of dementia worldwide, and its incidence is increasing in line with population aging. The primary feature of AD is a progressive cognitive decline, and severe AD is characterized by reduced communication skills and mobility. However, successful treatment with pharmacotherapy can greatly improve the quality of life. 


Donepezil is an acetylcholinesterase inhibitor (Figure 2) approved for use across the full spectrum of mild, moderate, and severe AD. Donepezil has been available at doses of 5 or 10 mg once daily for more than a decade and, more recently, a single high once-daily sustained-release 23-mg dose has been approved for treatment of patients with moderate to severe AD. The rationale for the higher dose formulation was the expected increase in acetylcholinesterase inhibition given the dose-response relationship of donepezil, with the benefits of the higher dose being most apparent in patients with more advanced AD. Donepezil 5 and 10 mg/day have been well studied in mild-to-moderate AD, and a clinical trial has confirmed the benefits of donepezil 23 mg/day in patients with moderate to severe AD, particularly for language and visuospatial ability.



To understand how Alzheimer's medications work, you first need to understand the communication network in the brain. The picture below depicts nerve cells, or neurons, in the brain. Neurons are the chief cells destroyed by AD.





How AD drugs work [Alz.org; 2017]

In the brain, neurons connect and communicate at synapses, where tiny bursts of chemicals called neurotransmitters carry information from one cell to another. Alzheimer's disrupts this process, and eventually destroys synapses and kills neurons, damaging the brain's communication network.

Current FDA-approved AD drugs support this communication process through two different mechanisms:

1) Cholinesterase inhibitors work by slowing down the process that breaks down a key neurotransmitter. Donepezil, galantamine, and rivastigmine are cholinesterase inhibitors.

2) Memantine is an NMDA (N-methyl-D-aspartate) receptor antagonist, which works by regulating the activity of glutamate, an important neurotransmitter in the brain involved in learning and memory. Attachment of glutamate to cell surface "docking sites" called NMDA receptors permits calcium to enter the cell. This process is important for cell signaling, as well as learning and memory. In AD, however, excess glutamate can be released from damaged cells, leading to chronic overexposure to calcium, which can speed up cell damage. Memantine helps prevent this destructive chain of events by partially blocking the NMDA receptors.


The effectiveness of cholinesterase inhibitors and memantine varies across the population.


Table: AD drugs and their characteristics [alz.org; 2017] (* indicates that a generic is availablle)





Aricept® (donepezil); 1996

Prevents the breakdown of acetylcholine in the brain; all stages of AD

·                     Tablet*: Initial dose of 5 mg once a day

·                     May increase dose to 10 mg/day after 4-6 weeks if well tolerated, then to 23 mg/day after at least 3 months

·                     Orally disintegrating tablet*: Same dosage as above

·                     23-mg dose available as brand-name tablet only

Nausea, vomiting, diarrhea, muscle cramps, fatigue, weight loss

Exelon® (rivastigmine); 2000

Prevents the breakdown of acetylcholine and butyrylcholine (a brain chemical similar to acetylcholine) in the brain; all stages of AD

·                     Capsule*: Initial dose of 3 mg/day (1.5 mg twice a day)

·                     May increase dose to 6 mg/day (3 mg twice a day), 9 mg (4.5 mg twice a day), and 12 mg/day (6 mg twice a day) at minimum 2-week intervals if well tolerated

·                     Patch: Initial dose of 4.6 mg once a day; may increase dose to 9.5 mg once a day and 13.3 mg once a day at minimum 4-week intervals if well tolerated

·                     Oral solution: Same dosage as capsule

Nausea, vomiting, diarrhea, weight loss, decreased appetite, muscle weakness

Namenda® (memantine); 2003

Blocks the toxic effects associated with excess glutamate and regulates glutamate activation; moderate to severe AD

·                     Tablet*: Initial dose of 5 mg once a day

·                     May increase dose to 10 mg/day (5 mg twice a day), 15 mg/day (5 mg and 10 mg as separate doses), and 20 mg/day (10 mg twice a day) at minimum 1-week intervals if well tolerated

·                     Oral solution*: Same dosage as above

·                     Extended-release capsule: Initial dose of 7 mg once a day; may increase dose to 14 mg/day, 21 mg/day, and 28 mg/day at minimum 1-week intervals if well tolerated

Dizziness, headache, diarrhea, constipation, confusion

Namzaric® (memantine extended-release and donepezil); 2014

Blocks the toxic effects associated with excess glutamate and prevents the breakdown of acetylcholine in the brain; severe AD

·                     Capsule: 28 mg memantine extended-release + 10 mg donepezil once a day

·                     14 mg memantine extended-release + 10 mg donepezil once a day (for patients with severe renal impairment)

Headache, nausea, vomiting, diarrhea, dizziness, decreased appetite

Razadyne® (galantamine); 2001

Prevents the breakdown of acetylcholine and stimulates nicotinic receptors to release more acetylcholine in the brain; mild to moderate AD

·                     Tablet*: Initial dose of 8 mg/day (4 mg twice a day)

·                     May increase dose to 16 mg/day (8 mg twice a day) and 24 mg/day (12 mg twice a day) at minimum 4-week intervals if well tolerated

·                     Oral solution*: Same dosage as above

·                     Extended-release capsule*: Same dosage as above but taken once a day

Nausea, vomiting, diarrhea, weight loss, decreased appetite



How AD has impacted society

Because AD is common, many notable people have developed it. Well-known examples are President Ronald Reagan and Irish writer Iris Murdoch, both of whom were the subjects of scientific articles examining how their cognitive capacities deteriorated with the disease. Other cases include the retired footballer Ferenc Puskás, former Prime Ministers Harold Wilson (United Kingdom) and Adolfo Suárez (Spain), Indian politician George Fernandes, actress Rita Hayworth, actor Charlton Heston, actor-director Robert Loggia, actor-writer Gene Wilder, the author Harnett Kane, Nobel laureate Charles K. Kao, novelist Terry Pratchett, director Jacques Rivette, and politician and activist Sargent Shriver.


AD has been portrayed in films such as: Iris (2001), based on John Bayley's memoir of his wife Iris Murdoch; The Notebook (2004), based on Nicholas Sparks' 1996 novel of the same name; A Moment to Remember (2004);Thanmathra (2005); Memories of Tomorrow (Ashita no Kioku) (2006), based on Hiroshi Ogiwara's novel of the same name; Away from Her (2006), based on Alice Munro's short story "The Bear Came over the Mountain"; Still Alice (2014), about a Harvard professor who has early onset AD, based on Lisa Genova's 2007 novel of the same name and featuring Julianne Moore in the title role, who later won the Oscar for Best Actress. Documentaries on AD include Malcolm and Barbara: A Love Story (1999) and Malcolm and Barbara: Love's Farewell (2007), both featuring Malcolm Pointon. 



The economics of it all 

The costs of health care and long-term care for individuals with AD and other dementias are substantial. Dementia is one of the costliest conditions to society. Total payments in 2017 for all individuals with Alzheimer's or other dementias are estimated at $259 billion. Medicare and Medicaid are expected to cover $175 billion, or 67%, of the total health care and long-term care payments for people with AD and other dementias. Out-of-pocket spending is expected to be $56 billion.



Health care costs increase with the presence of dementia.

People with AD or other dementias have twice as many hospital stays per year as other older people.

Medicare beneficiaries with AD or other dementias are more likely than those without dementia to have other chronic conditions.

People with AD or other dementias make up a large proportion of all elderly people who receive adult day services and nursing home care.


Total per-person health care and long-term care payments in 2016 for Medicare beneficiaries with AD or other dementias were over 3 times as great as payments for other Medicare beneficiaries. Average per-person out-of-pocket costs for AD and other dementias are almost 5 times higher than average per-person payments for seniors without these conditions. Total annual payments for health care, long-term care and hospice care for people with AD or other dementias are projected to increase from $259 billion in 2017 to more than $1.1 trillion in 2050. This dramatic rise includes more than 4-fold increases both in government spending under Medicare and Medicaid and in out-of-pocket spending.



Where the drugs and the disease are today

Clearly, more drugs are needed to more effectively treat AD. According to the Alzheimer’s Association, the arc of scientific progress is now requiring a change in how AD is diagnosed. Both the National Institute on Aging – Alzheimer's Association (NIA-AA) 2011 workgroup and the International Work Group (IWG) have proposed guidelines that use detectable measures of biological changes in the brain, commonly known as biological markers, or biomarkers, as part of the diagnosis.


The development and validation of AD biomarkers — including those detectable in the blood or cerebral spinal fluid, or through neuroimaging — is a top research priority. Biomarkers have the potential to markedly change how AD is diagnosed and, as a result, how the number of people with this disease is counted and subsequently treated.


As research advances a biomarker-based method for diagnosis and treatment at the earliest stages of AD, we envision a future in which AD is placed in the same category as other chronic diseases, such as cardiovascular disease or diabetes, which can be readily identified with biomarkers and treated before irrevocable disability occurs.



Is the incidence of Alzheimer disease decreasing?

According to a paper published by the Alzheimer Disease Research Center at the University of Southern California, several recent studies support the idea that the incidence of dementia and AD has been decreasing over at least the past 25 years, and at a remarkable rate. In cohort studies, key observations were a decreased mortality by 35-37%, increased longevity, increased education, and increased statin use are associated with lower dementia incidence [Qiu, 2013; Schrijvers, 2012]. In one study, the decrease was about 25% over 10 years [Schrijvers, 2012]. An earlier US study suggested a 3% annual decline in dementia incidence over 10 years around the early 1990s in Rochester, Minnesota [Rocca, 2011]. These observations – if supported by other studies – somewhat temper the dire predictions for a boomer-fueled, Alzheimer’s “Silver Tsunami” as some charities call the projected increase in dementia.



It is probably not too speculative to consider that any decrease in the age-specific incidence of dementia in cohorts separated by only about 10 years may result from environmental and public health interventions that were implemented just within the last 40 years. Both the Flynn effect [Flynn, 2009] and Fries’ prediction of optimal longevity and compression of morbidity [Fries, 1980] may be in action. At least in Western countries, people may be getting smarter and healthier, surviving better, and pushing morbidity back toward the end of life such that they get cardiovascular disease and dementia later and die sooner afterward.


Baby-boomers may have been weaned on bacon, eggs, toast, butter, frosted flakes, and Marlboros; but beginning in the 1970s they have had some profoundly improved public health options: better food information and choices; gyms as destinations for purposeful exercise; smoking awareness and restrictions; cardiovascular medications and statins, and arguably better air quality. Any one or several of these options combined with genetics, better education, and luck could have helped to lower the chances of cardiovascular disease or dementia. Looking forward there may be continuing benefits from mandatory restrictions in trans fats, sweetened drinks, and no cigarettes until age 21.


The decrease in dementia as well as in cardiovascular deaths, interestingly, may be occurring in the presence of greater obesity and diabetes. Some factors may outweigh others and the trends may not last. As these are observational studies over short periods and not experiments, little can be proven, and both suspected and unknown biases may be at play. However, the idea that public health interventions may not only work but also have marked effects, that we might grow our way out of a dementia “tsunami” and substantially reduce risk is intriguing and wholly consistent with the range of hypotheses about AD. Thus, the boomers – even at their advanced age – can look forward to a longer life with less heart disease and dementia. 




Ron Gasbarro, PharmD, is a registered pharmacist, medical writer, and principal at Rx-Press.com. Read more at www.rx-press.com.



Alzheimer's Association. 2016 Alzheimer's disease facts and figures. Alzheimers Dement. 2016;12:459-509.


Flynn JR. What Is Intelligence: Beyond the Flynn Effect. Cambridge: Cambridge University Press; 2009:1-2.


Fries JF. Aging, natural death, and the compression of morbidity. New Eng J Med. 1980;303:130-5.


Lee JH, Jeong SK, Kim BC, Park KW, Dash A. Donepezil across the spectrum of Alzheimer's disease: dose optimization and clinical relevance. Acta Neurol Scand. 2015;131:259-67.


Qiu C, von Strauss E, Bäckman L, Winblad B, Fratiglioni L. Twenty-year changes in dementia occurrence suggest decreasing incidence in central Stockholm, Sweden. Neurology 2013; 80:1888-94.


Rocca WA, Petersen RC, Knopman DS, et al. Trends in the incidence and prevalence of Alzheimer’s disease, dementia, and cognitive impairment in the United States. Alzheimers Dement. 2011;7:80-93.


Schrijvers EMC, Verhaaren BFJ, Koudstaal PJ, Hofman A, Ikram MA, Breteler MMB. Is dementia incidence declining? Neurology. 2012;78:1456-63.


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