Treatments Of Alzheimer’s Disease

Approach To The Patient

Guidelines on the treatment of Alzheimer disease are available from a number of organizations , including one developed by the American Academy of Family Physicians, in conjunction with the American College of Physicians.15 All guidelines emphasize the importance of educating patients and their families about the disease process and its expected course. Early referral to local support groups is recommended, and medicolegal issues such as driving and end-of-life planning should be addressed. Recommendations regarding pharmacologic treatment are described in Table 2,21â23 and a suggested algorithm for the treatment of Alzheimer disease is presented in Figure 1. The decision to treat with medication should be shared with the patient and caregivers, including a discussion of the modest clinical benefit, adverse effects, and cost. Physicians should consider discontinuing therapy in patients who continue to decline despite maximal therapy.16 The National Institute on Aging and the Alzheimer’s Association have released recommendations on the diagnosis of dementia and mild cognitive impairment from Alzheimer disease however, these guidelines do not address the treatment of Alzheimer disease and do not recommend the clinical use of biomarkers.52,53

What Is Alzheimer’s Disease

Alzheimers disease is a brain disorder that cannot be stopped or reversed. The disease severely affects memory, thinking, learning and organizing skills and eventually affects a persons ability to carry out simple daily activities. Alzheimers disease is not a normal part of the aging process.

Alzheimers is a disease whose symptoms worsen over time. In fact, scientists believe the disease process may go on for 10 years or longer before the first symptoms of Alzheimers disease appear.

When memory problems do begin to be noticeable, they are often identified as mild cognitive impairment . At this stage, intellectual function is affected but the ability to function and live independently remain intact as the brain compensates for disease-related changes.

In some people, MCI can hold steady at this stage. However, people with MCI are at high risk for progressing to dementia. Alzheimers disease is the most common form of dementia. With dementia, in contrast to MCI, daily function is affected.

As dementia due to Alzheimers disease progresses to late stages, affected individuals cannot carry on a conversation, recognize family and friends, or care for themselves.

Treatment For Moderate To Severe Alzheimers

A medication known as memantine, an N-methyl D-aspartate antagonist, is prescribed to treat moderate to severe Alzheimers disease. This drugs main effect is to decrease symptoms, which could enable some people to maintain certain daily functions a little longer than they would without the medication. For example, memantine may help a person in the later stages of the disease maintain his or her ability to use the bathroom independently for several more months, a benefit for both the person with Alzheimer’s and caregivers.

Memantine is believed to work by regulating glutamate, an important brain chemical. When produced in excessive amounts, glutamate may lead to brain cell death. Because NMDA antagonists work differently from cholinesterase inhibitors, the two types of drugs can be prescribed in combination.

The FDA has also approved donepezil, the rivastigmine patch, and a combination medication of memantine and donepezil for the treatment of moderate to severe Alzheimers.

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The Devastation Of Alzheimers Disease

With all this said, we are extremely aware of the gradual and cumulative devastation that Alzheimers disease causes, as patients lose their memory and cognitive functioning over time. In late-stage disease, people can no longer hold a conversation or respond to their environment. On average, a person with Alzheimers disease lives four to eight years after diagnosis, but some patients can live up to 20 years with the disease.

The need for treatments is urgent: right now, more than 6 million Americans are living with Alzheimers disease and this number is expected to grow as the population ages. Alzheimer’s is the sixth leading cause of death in the United States.

Although the Aduhelm data are complicated with respect to its clinical benefits, FDA has determined that there is substantial evidence that Aduhelm reduces amyloid beta plaques in the brain and that the reduction in these plaques is reasonably likely to predict important benefits to patients. As a result of FDAs approval of Aduhelm, patients with Alzheimers disease have an important and critical new treatment to help combat this disease.

Cognitive Enhancing Agents For Treatment Of Alzheimers Disease

Current symptomatic therapies

Four cholinesterase inhibitors and one N-methyl-D-aspartate receptor antagonist have been approved by the FDA for the treatment of AD. One ChE-I — tacrine — is no longer available on the market the three available ChE-Is are donepezil , rivastigmine , and galantamine . The NMDA receptor antagonist is memantine . Clinical trials show that these agents produce improvement on the AD Assessment Scale cognitive subscale in the range of 1.5 to 3 points with corresponding changes on the Mini Mental State Examination . Meta-analyses demonstrate consistent benefit compared to placebo on measures of function and global ratings . Drug-placebo differences persist for a least 1year in double-blind trials . Cholinesterase inhibitors and memantine have similar effects with improvements above baseline on measures of cognition and global function and temporary stabilization of activities of daily living . Most studies show amelioration of current neuropsychiatric symptoms with reduced emergence of new neuropsychiatric symptoms following treatment with symptomatic agents .

Clinical trial methodology for symptomatic cognitive enhancing agents

Overview of recent trials for cognitive enhancing agents

Fig. 1

Number of cognitive enhancing agents for Alzheimers disease in Phase 2 and Phase 3 clinical trials 20162020

Cognitive enhancing drugs with novel mechanisms of action in clinical trials

Table 1 Phosphodiesterase inhibitors assessed in clinical trials

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Reminiscence And Life Story Work

Reminiscence work involves talking about things and events from your past. It usually involves using props such as photos, favourite possessions or music.

Life story work involves a compilation of photos, notes and keepsakes from your childhood to the present day. It can be either a physical book or a digital version.

These approaches are sometimes combined. Evidence shows they can improve mood and wellbeing.

Find out how to live well with dementia and more useful information in the NHS Dementia Guide.

Page last reviewed: 05 July 2021 Next review due: 05 July 2024

Current Landscape In Treatment Research For Ad

No new drug has been approved by FDA for AD since 2003 and there are no approved DMTs for AD, despite many long and expensive trials.22,28 As a matter of fact, more than 200 research projects in the last decade have failed or have been abandoned.10 Nevertheless, drug pipeline for AD is still full of agents with mechanisms of action that target either disease modification or symptoms.4,10 Some of the recent failures of anti-amyloid agents in phase 3 clinical trials in patients with early-stage, mild, or mild-to-moderate stage AD were semagacestat,29 bapineuzumab,30 solanezumab31 and in similar trials of -secretase inhibitors lanabecestat,32 verubecestat,33 and atabecestat.34

The National Institute on Aging and the Alzheimers Association proposed a new framework for research,39 which requires the application of amyloid, tau, and neurodegeneration biomarkers to clinical trials, succeeds in precise classification of patients in AD stages, and can be used to assist clinical trials design.

Tau positron emission tomography , neurofilament light, and neurogranin are the new biomarkers that are increasingly used by clinical trials.40

In this review, agents currently studied as potential DMTs will be discussed. Furthermore, an approach to a future precision medicine multifactorial therapeutic model based on biomarkers profile, genetic analysis, neuropsychologic evaluation, and neuroimaging accomplished with risk factors restriction will be attempted.2,3

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Other Adjunct Treatments For Alzheimers

Other drugs used off-label in Alzheimerâs treatment include:

• Anticonvulsants. Carbamazepine and gabapentin are anti-seizure drugs often prescribed for epilepsy. Theyâre also sometimes used to treat agitation in Alzheimerâs.
• Anti-Parkinsonâs drugs. Certain drugs used to treat Parkinsonâs disease are being tested to see if they can help with Alzheimerâs symptoms. Rotigotine and rasagiline increase the levels of brain chemicals that help nerve cells communicate.

Show Sources

Alzheimerâs Association: âMedications for Memory, Cognition and Dementia-Related Behaviors,â âTreatments for Sleep Changes,â âDepression,â âTreatments for Behavior.â

National Institute on Aging: âWhat Happens to the Brain in Alzheimer’s Disease?â âHow Is Alzheimer’s Disease Treated?â

Neuropsychiatric Disease and Treatment: âTreatment of behavioral and psychological symptoms of dementias with psychopharmaceuticals: a review.â

University of California San Francisco: âMedications & Dementia.â

World Journal of Psychiatry: âPharmacological management of behavioral symptoms associated with dementia.â

FDA: âUnderstanding Unapproved Use of Approved Drugs “Off Label.â

Belsomra.com.

Currently Studied Dmts For Ad

Amyloid-related mechanismsDMTs

The crucial step in AD pathogenesis is the production of amyloid , which forms SPs . The A derives from a protein overexpressed in AD, APP through sequential proteolysis by -secretase in the extracellular domain and -secretase in the transmembrane region. Full-length APP is first cleaved by -secretase or -secretase. The APP cleavage by -secretase leads to nonamyloidogenic pathway, whereas APP cleavage by -secretase leads to amyloidogenic pathway. Sequential cleavage of APP by BACE1 in the extracellular and -secretase in the transmembrane area results in the A production. Major sites of -secretase cleavage usually occur in positions 40 and 42 of A, thus A40 and A42 oligomers are the main products of the sequential APP cleavage, as the amyloidogenic pathway is favored in neurons because of the greater plentifulness of BACE1. On the contrary, the nonamyloidogenic processing is more favored in other cells without BACE1 predominance.5

Consequently, anti-amyloid DMTs have focused on 3 major MOAs: reduction of A42 production , reduction of A-plaque burden , and promotion of A clearance .10

Reduction of A42 production

-secretase inhibitors

BACE inhibitors

Two BACE inhibitors are still elaborated: elenbecestat in phase 2 and umibecestat in phase 3.4 The later agent is studied in asymptomatic individuals at risk of developing AD .45

-secretase modulators

Reduction of A-plaque burden

Aggregation inhibitors

Promotion of A clearance

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What Are The Symptoms Of Alzheimers Disease

Symptoms of Alzheimers disease vary from person to person and worsen over time. Symptoms of the disease include:

• Memory loss. This is usually one of the first symptoms of Alzheimers disease.
• Putting objects in odd places
• Confusion about events, time and place
• Repeating questions

For more information on the stage of disease, click here.

Medications For Sleep Disorders

There are several types of medications that can be used to treat sleep disorders, including hypnotics, sedatives, and wake-promoting agents.

Hypnotics are medications that induce sleep. The most common hypnotic medication is zolpidem . Other hypnotic medications include eszopiclone , zaleplon , and ramelteon .

Sedatives are medications that help to relieve anxiety and promote relaxation. The most common sedative medication is diazepam . Other sedative medications include alprazolam and lorazepam .

Wake-promoting agents are medications that help to increase alertness and combat fatigue. The most common wake-promoting agent is modafinil . Other wake-promoting agents include armodafinil and methylphenidate .

Medications that can be used safely to treat both Alzheimer’s disease and sleep disorders include cholinesterase inhibitors, memantine, antidepressants, antipsychotics, and hypnotics.

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Other Important Aetiological Mechanisms

Vascular disease

While traditionally it was felt that vascular disease was the underlying factor in the development of VaD, it is clear that vascular burden also plays a role in AD pathogenesis, and that there is significant overlap between these two dementia subtypes. Vascular risk factors, such as high BMI, smoking, hypercholesterolemia and hypertension, have been associated with an increased risk of developing clinical AD. While vascular lesions such as cerebral amyloid angiopathy and white matter hyperintensities are common in patients with AD, hypertension is also associated with the development of specific neuropathological hallmarks of AD such as NFTs, and this association appears to be stronger when hypertension is present in mid rather than late life. Thus, vascular disease may directly affect amyloid plaques or NFTs by increasing their formation or reducing their elimination from the brain.

Given these findings, it would seem to follow that control of vascular risk factors may slow the rate of decline of cognition in patients with AD however, this is not yet supported by data from randomised controlled trials.

Diabetes and hyperinsulinaemia

These findings have led to the theory that drugs used in diabetes may be able to modify the pathophysiology of AD and a study of intranasal insulin as a therapy in mild cognitive impairment and AD is currently being conducted after encouraging results from small pilot studies.

Apolipoprotein gene

Neuroinflammation

Current Management Of Ad

A multifactorial tailored management of AD is attempted nowadays based in the following components:

FDA-approved AD medications

The AChEIs donepezil, galantamine, rivastigmine, and the NMDA antagonist memantine are the only FDA-approved AD medications.10

AChEIs attempt at reducing the breakdown of acetylcholine levels in the brain of the patients with AD by inhibiting the responsible enzyme acetylcholinesterase in the synaptic cleft.5 Thus, AChEIs enhance central cholinergic neurotransmission and finally tend to mitigate decline in cognition at least during the first year of treatment. Further decline occurs, but even temporary discontinuation of these drugs results in rapid decline and is associated with greater risk of nursing home placement.16

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What Causes Alzheimers Disease

Alzheimers disease is caused by the abnormal build-up of proteins in the brain. The build-up of these proteins called amyloid protein and tau protein leads to cell death.

The human brain contains over 100 billion nerve cells as well as other cells. The nerve cells work together to fulfill all the communications needed to perform such functions as thinking, learning, remembering, and planning. Scientists believe that amyloid protein builds up in the brain cells, forming larger masses called plaques. Twisted fibers of another protein called tau form into tangles. These plaques and tangles block the communication between nerve cells, which prevents them from carrying out their processes. The slow and ongoing death of the nerve cells, starting in one area of the brain then spreading to other areas, results in the symptoms seen in patients with Alzheimers disease.

Moderate To Advanced Alzheimers Disease

Ebixa® has been conditionally approved to treat symptoms in people with moderate to advanced Alzheimers disease. Aricept has been approved to treat symptoms in people with mild to moderate and advanced Alzheimers disease.

Neurotransmitters send messages across the space between nerve cells. As Alzheimers disease progresses, the neurotransmitter glutamate leaks out of nerve cells and is reabsorbed at levels that are toxic to the cell. Memantine hydrochloride, known by the trade name Ebixa®, works by blocking the reabsorption of glutamate into nerve cells.

Ongoing research suggests that there may be greater benefit to using cholinesterase inhibitors and memantine hydrochloride together. However, more and larger trials are needed to confirm these results.

Medications are also available to help manage symptoms such as sleep disruption. Talk to your doctor to determine whether other medications may be helpful for you or the person you are caring for.

Medications for people diagnosed with Alzheimers disease are only available by prescription to those under the care of a doctor.

Note: In areas of Canada where Alzheimer medications are now covered, individuals must meet specific clinical criteria for entitlement. These medications are covered by most private insurance plans.

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Early Onset Alzheimers Disease

Although age is the main risk factor for Alzheimers disease, this is not just a condition that affects older adults.

According to the Alzheimers Association, early onset Alzheimers disease affects around 200,000 U.S. adults under the age of 65 years. Many people with this condition are in their 40s or 50s.

In many cases, doctors do not know why younger people develop this condition. Several rare genes can cause the condition. When there is a genetic cause, it is known as familial Alzheimers disease.

What The Data Show

The late-stage development program for Aduhelm consisted of two phase 3 clinical trials. One study met the primary endpoint, showing reduction in clinical decline. The second trial did not meet the primary endpoint. In all studies in which it was evaluated, however, Aduhelm consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion. It is expected that the reduction in amyloid plaque will result in a reduction in clinical decline.

We know that the Peripheral and Central Nervous System Drugs Advisory Committee, which convened in November 2020 to review the clinical trial data and discuss the evidence supporting the Aduhelm application, did not agree that it was reasonable to consider the clinical benefit of the one successful trial as the primary evidence supporting approval. The option of Accelerated Approval was not discussed by the Advisory Committee. As mentioned above, treatment with Aduhelm was clearly shown in all trials to substantially reduce amyloid beta plaques. This reduction in plaques is reasonably likely to result in clinical benefit. After the Advisory Committee provided its feedback, our review and deliberations continued, and we decided that the evidence presented in the Aduhelm application met the standard for Accelerated Approval. We thank the Advisory Committee for its independent review of the data and valuable advice.

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