"There is clearly a large unmet need not only to improve our treatment of AD, but to provide treatment options for all the dementias."
FROM THE EDITOR
I remember the exact time I first heard of Alzheimer disease (AD) dementia. In 1982, the laboratory technician with whom I worked at the University of Massachusetts Amherst Department of Biochemistry and Molecular Biology asked me if I knew anything about it—she was applying for a job in a lab in Texas that researched AD; I did not. It was during my first 2 years of medical school that I became familiar with the devastating syndrome of dementia and began to learn about the wide-ranging diseases that cause it.
In the late 1990s, I worked for a geriatric psychiatry consultation group and worked at 8 long-term care facilities in the North Shore of Massachusetts. The No. 1 reason for consultations was agitated dementia. Drug development to aid in the treatment of dementia has been slow, which is not surprising given the challenges of treating a syndrome as heterogeneous as dementia and with so many diverse etiologies.
Dementia is a powerful, frightening, life-changing diagnosis that is followed by a trail of sadness, helplessness, grief, and loss. It is a syndrome that may affect many aspects of cognition (Table 1); it typically follows a neurodegenerative course with increased functional impairment and eventual total inability to care for oneself.
The order and initial severity of these different symptoms/impairments varies significantly across the different types of dementia.1
Recognizing the growing importance of dementia, this year alone Psychiatric Times has featured a cover story on AD as well as continuing medical education articles on Lewy body dementia and frontotemporal dementia. Yet these dementias are just the tip of the iceberg. This article will provide a brief overview of the many types of dementia (Table 21,2) and the history of our attempts to treat them pharmacologically.
Alzheimer Disease Dementia
AD is the most common type of dementia; it is estimated to be responsible for somewhere between 60% and 80% of all dementias in the United States. However, findings from large autopsy studies have demonstrated that more than 50% of individuals with established AD show evidence of a second or even third type of dementia, most commonly vascular or Lewy body disease. This phenomenon is referred to as a mixed dementia. Experts in the diagnosis and treatment of dementia can often differentiate the subtypes, especially as symptoms develop over years and decades.2
The National Institute on Aging-Alzheimer’s Association published a consensus biological definition for AD in 2018. They concluded3:
Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia.
Despite the wide-ranging subtypes of dementia with their unique etiologies and pathologies seen at autopsy, every drug that is currently approved by the FDA to treat some facet of dementia is only approved for the treatment of AD. There is one exception: rivastigmine, which the agency has approved for mild to moderate dementia associated with AD or Parkinson disease.
Given that AD is the most common type of dementia in the United States, this is not surprising. However, knowing that more than 50% of individuals with AD also have at least 1 other type of co-occurring dementia creates a complex disease state that should predictably create an unpredictable range of responses to these treatments.
Tacrine (Cognex) was our first FDA-approved treatment for AD; it became available in 1993. It provided much excitement, as its mechanism of action putatively directly reversed what was believed to be the cause of cognitive decline in AD—decreasing concentrations of acetylcholine in the brain. By its action as a cholinesterase inhibitor, acetylcholine concentrations would remain elevated in muscarinic neurons, which hopefully would improve cognition. Unfortunately, its benefits were modest at best and, with its risk of hepatotoxicity, it was withdrawn from the US market in 2012.
Next the FDA approved donepezil (Aricept) for the treatment of mild to moderate AD in 1996, after it demonstrated an improvement in cognition and patient function in this patient population. It is still widely used today and was subsequently approved for severe AD as well. Although the drug is beneficial, the improvement achieved is limited, and it does not modify the underlying disease process. Like tacrine, donepezil is a cholinesterase inhibitor, as are 2 subsequent AD drug approvals: rivastigmine (Exelon) in 1997 and galantamine (Reminyl) in 2001.
Galantamine’s manufacturer then developed an extended-release formulation, resulting in its renaming as Razadyne ER, which was FDA approved in 2004. Unique to rivastigmine is the additional approval for mild to moderate dementia associated with Parkinson disease.
Historically, galantamine tells an intriguing tale. It was originally derived from the bulbs of the wild daffodil (Narcissus pseudonarcissus), the common snowdrop (Galanthus nivalis), the summer snowflake (Leucojum aestivum), and the red spider lily (Lycoris radiata).
Its use was first mentioned in The Odyssey by Homer. The god Hermes gave Odysseus an herb called moly (believed to be the snowdrop) to protect Odysseus from the poisonous drugs used by the sorceress Circe. Circe’s drugs were reportedly extracted from jimsonweed, Datura stramonium, which is anticholinergic and causes memory loss and delirium. The cholinesterase inhibition by galantamine would have been the perfect antidote.
A new mechanism of action was added to our armamentarium with the FDA approval of memantine (Namenda) for patients with moderate to severe AD in 2003. Memantine antagonizes the NMDA-glutamate receptor with low to moderate affinity.
Glutamate is the primary excitatory neurotransmitter in the brain and plays a pivotal role in many important brain functions including learning and memory. It has been hypothesized that abnormally high levels of glutamate overexcite the NMDA-glutamate receptors in AD, resulting in neuronal cell dysfunction and death due to excessive calcium ion flow into the cell.
Memantine putatively interferes with this overexcitation from glutamate through its physical presence blocking some glutamate from accessing the NMDA receptors, especially at nonsynaptic locations on the neuron. The FDA approved a combination drug of memantine and donepezil in 2014 to allow for a single formulation of these drugs (Namzaric) with unrelated mechanisms of action.
A tremendous amount of research has occurred over the past 2 decades applying the technology of monoclonal antibodies to target 1 of the 2 main proteins associated with AD with the hope of intervening early on in the disease process and achieving a slowing of progression (and ideally providing a disease-modifying treatment).
Although not yet proved to be causal of AD, 2 proteins have become established biomarkers for AD and are quantifiable in samples of cerebral spinal fluid and with specific radioisotopes used in positron emission tomography (PET) scans specific to them: cerebral extraneuronal amyloid β plaques and cerebral intraneuronal tau deposits creating neurofibrillary tangles. A significant qualifier for the amyloid β plaque theory is that they begin accumulating in the brain 20 to 30 years before the onset of symptoms of dementia.4
Additionally, postmortem studies have demonstrated high brain concentrations of amyloid β plaques in individuals who demonstrated no cognitive decline prior to their death. These facts highlight the importance of the patient’s clinical presentation and a thorough medical and psychiatric evaluation before concluding that a person has AD and merits treatment because of the presence of amyloid β plaques.
The amyloid β plaques are extracellular and theoretically disrupt healthy neuronal function, eventually leading to memory loss, mild cognitive impairment AD, and ultimately AD, which progresses from mild to moderate to severe over a highly variable time period.
The 2 FDA-approved monoclonal antibodies are aducanumab (Aduhelm; approved in June 2021) and lecanemab (Leqembi; approved in January 2023), and both are specific to amyloid β plaque with no effect on the tau intracellular neurofibrillary tangles. These drugs are approved for patients with AD-associated mild cognitive impairment and mild AD, but not for moderate to severe AD.
The intracellular tau neurofibrillary tangles are also hypothesized to contribute to the development and progression of AD. Monoclonal antibodies that target these tau deposits are also being studied, although this is likely to be more challenging because of the need for the monoclonal antibodies to enter and leave the neurons to remove the tau protein deposits.
Both drugs are administered by intravenous infusion, with aducanumab administered every 4 weeks and lecanemab every 2 weeks. They share similar possible adverse events, including cerebral edema and cerebral microhemorrhages that are likely secondary to the removal of amyloid β, and amyloid-related imaging abnormalities.
Aducanumab’s approval was initially met with excitement, as it was the first novel treatment for AD since 2003. In addition to removing amyloid β in the early stages of AD, it was hoped to provide disease-modifying benefits by slowing the normal progression of cognitive impairment and other behavioral symptoms.
Shortly after aducanumab’s FDA approval, there was an aggressive pushback by neurology experts in AD who reviewed the clinical trial data and concluded that the risks of cerebral edema and microhemorrhages outweighed any equivocal benefit in disease modification. This resulted in the delay in the clinical use of aducanumab, which continues today.
Lecanemab received FDA approval with accompanying excitement as it demonstrated both a greater decrease in brain amyloid levels as well as “moderately less decline on clinical measures of cognition and function than placebo at 18 months but was associated with adverse events” in patients with early AD.5
Lecanemab was evaluated in a phase 3 trial with 1795 individuals aged 50 to 90 years with established mild cognitive impairment or mild dementia due to AD and demonstrated evidence of amyloid β on PET or cerebrospinal fluid testing. Researchers randomly assigned participants in an 18-month, multicenter, double-blind, placebo-controlled comparison of lecanemab (n = 898) or placebo (n = 897).
Treatment of Agitation in Dementia
As neurodegeneration of the brain progresses in dementias, the affected individual experiences increased cognitive impairment, engages in uncharacteristic dysfunctional behaviors, has greater difficulty suppressing unhealthy impulsive emotions and drives, is less able to recognize family and friends, and feels increasingly fearful and threatened in what once were familiar and comforting environments.
These changes can differ dramatically from person to person based on the type of dementia as well as on a range of predisposing factors. The clinical picture often becomes further complicated by the onset of paranoia, delusions, and hallucinations of all sensory types.
Not surprisingly, due to any of these changes in how they experience their world, many individuals with dementia begin to exhibit agitation that can manifest in a large range of behaviors, often creating a significant risk of injury to the individual or their caregivers (eg, family, friend, or professional care providers).
Up to and including the present time, there are no medications approved by the FDA to treat psychotic symptoms as a complication of dementia. In fact, all antipsychotic medications carry a boxed warning of an increased risk of death in patients with dementia whose psychotic symptoms are treated with antipsychotics as compared with placebo. This boxed warning was based on data from 17 studies assessing the benefits of 4 antipsychotics (risperidone, olanzapine, quetiapine, and aripiprazole) compared with placebo over a modal duration of 10 weeks in patients with psychosis complicating dementia.
The studies’ findings demonstrated a 1.7-fold increased risk of death in the patients receiving the antipsychotics compared with those patients receiving placebo. The most common causes of death were cardiovascular in nature (heart failure or sudden death) or due to an infection (most commonly pneumonia).
Out of necessity to manage the potential for injuries and other harmful consequences of these psychotic symptoms, clinicians in the United States commonly use antipsychotics off label despite the boxed warning of increased mortality by getting informed consent from either the patient (if competent) or more commonly the family, health care proxy, or legal guardian.
Over the years, many pharmacological agents from various classes have been evaluated in clinical trials in an attempt to gain FDA approval for use in this huge unmet area of patient care. For instance, Otsuka Pharmaceutical developed a clinical trial program in this area. However, instead of targeting psychotic symptoms as the primary outcome, they focused on the efficacy of brexpiprazole (Rexulti) in decreasing the episodes of agitated behaviors in individuals with AD regardless of the presence or absence of psychotic symptoms.
As a result, brexpiprazole became the first drug to be FDA approved for the treatment of “agitation associated with dementia due to Alzheimer’s disease” in May 2023.6 Brexpiprazole demonstrated a significant decrease in the number of agitation-related events in two phase 3 double-blind, placebo-controlled 12-week studies.
Brexpiprazole was titrated to a target dose of 2 mg daily at 15 days, and both 2 mg and 3 mg demonstrated effectiveness. Interestingly, the 1-mg dose did not separate from placebo, and the FDA product insert recommends not treating with doses lower than 2 mg, except during the initial titration. Also, it is important to note brexpiprazole is not approved to be taken as needed for acute agitation.
Over the past 30 years, starting with the FDA approval of tacrine in 1993 and through the most recent approvals of lecanemab and brexpiprazole in 2023, we have seen the clinical development of drugs with a range of mechanisms of action that primarily are approved for only 1 of the many types of dementia (AD).
Additionally, these drugs have attempted to target defined and well-researched pathophysiologies that are in some way contributory to the debilitating symptoms of AD.
The best interventions remain preventive behavioral lifestyle changes and are identical to all the preventive behavioral changes and health-promoting recommendations for slowing down the progression of cardiovascular disease.
One additional recommendation for AD is the continued learning of new information and cognitive problem solving, which may increase neuroplasticity and create a reservoir of neurons that can provide alternative pathways as amyloid β and tau accumulate, leaving a path of neuronal and brain degeneration in their wake.
There is clearly a large unmet need not only to improve our treatment of AD, but to provide treatment options for all the dementias. Thus far, 2023 has seen the addition of 2 novel FDA- approved agents to our armamentarium for the treatment of AD: lecanemab, which is approved to be used in mild cognitive impairment from AD and mild AD with demonstrated removal of amyloid β plaque and a quantifiable degree of disease modification, and brexpiprazole, which is approved to treat agitation, a common and dangerous complication of advancing AD.
We still have a long way to go. It has been and will remain a painstaking and discouraging endeavor, but one well worth aggressively pursuing.
Dr Miller is Medical Director, Brain Health, Exeter, New Hampshire; Editor in Chief, Psychiatric Times®; Staff Psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Exeter Hospital, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.
Disclosure: Dr Miller has indicated he is on the speaker’s bureau for Otsuka and Lundbeck.
1. Graff-Radford J, Lunde AM. Mayo Clinic on Alzheimer’s Disease and Other Dementias. 2nd ed. Mayo Clinic Press; 2020.
2. Alzheimer’s Association. 2020 Alzheimer’s disease facts and figures. Alzheimers Dement. 2020;16(3):391-460.
3. Jack CR Jr, Bennett DA, Blennow K, et al; Contributors. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562.
4. Jansen WJ, Ossenkoppele R, Knol DL, et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. 2015:313(19):1924-1938.
5. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9-21.
6. Rexulti. Prescribing information. Otsuka America Pharmaceutical/Lundberg; 2023. Accessed June 13, 2023. www.rexultihcp.com