Approved Alzheimer's Drugs

I rarely report on drugs, but because I do have a number of early reports on the four drugs approved for use with Alzheimer’s, I wanted to provide this update.

The four drugs are donepezil, rivastigmine, galantamine and memantine. This review is said to be the first to rank their comparative safety and effectiveness. It used evidence from 142 clinical trials published between 1996 and 2015. The number of patients in each study ranged from 13 to 2,045, and the review evaluated a total of 33,889 patients.

Donepezil was the most effective medication for Alzheimer's dementia across all effectiveness outcomes, including cognition, behavior and overall health, according to the study. It was also the only cognitive enhancer that produced effects that could be observed clinically, not merely statistically.

However, patients who took donepezil were more likely to experience side effects including nausea, vomiting and diarrhea than those who received a placebo.

Previous research found that these drugs don’t improve cognition or function in people with MCI, and these patients experience significantly more nausea, diarrhea, vomiting and headaches.

https://www.eurekalert.org/pub_releases/2017-09/smh-srs092817.php

Memantine plus care program dramatically better at reducing Alzheimer's symptoms than drug alone

A small study found that combining a specific care management program with memantine multiplied the drug’s ability to improve daily function by about 7.5 times.

The Comprehensive, Individualized, Person-Centered Management program (CI-PCM) includes caregiver training, residence assessment, therapeutic home visits, and caregiver support groups.

In the 28-week, blinded, randomized controlled trial, 10 patient-caregiver groups enrolled in the CI-PCM were compared against 10 pairs receiving standard community care. All patients were taking memantine. Participants were assessed at the end of the trial using a recognized tool called Functional Assessment Staging (FAST), which measures losses in the ability of a person to independently carry out daily activities, such as dressing, bathing and toileting.

Caregiver training included "memory coaching" that teaches patients how to accomplish skills they lost.

The findings were presented July 16 at the Alzheimer's Association International Conference 2017 in London.

https://www.eurekalert.org/pub_releases/2017-07/nlmc-dcw071317.php

Tricco, A. C., Ashoor, H. M., Soobiah, C., Rios, P., Veroniki, A. A., Hamid, J. S., … Straus, S. E. (2018). Comparative Effectiveness and Safety of Cognitive Enhancers for Treating Alzheimer’s Disease: Systematic Review and Network Metaanalysis. Journal of the American Geriatrics Society, 66(1), 170–178. https://doi.org/10.1111/jgs.15069

Data from a ten-year study involving 345 Alzheimer's patients has found that cholinesterase inhibitors work better with those who don't have the gene CHRFAM7A. The gene is a fusion between a gene that codes for an Alpha 7 receptor for acetylcholine, and a kinase, a type of enzyme. It is not present in the animals genetically engineered to provide Alzheimer's models, but is present in 75% of humans.

Three of the four available Alzheimer’s drugs work by stimulating all receptors that respond to acetylcholine. More specific drugs for Alpha 7 have been in development for over 10 years but have yet to be successful.

The Alpha 7 receptor is one of the receptors binding amyloid beta.

More research is needed to confirm these preliminary findings.

https://www.eurekalert.org/pub_releases/2019-07/uab-sfc071719.php

https://www.futurity.org/alzheimers-disease-drugs-chrfam7a-2108902/

Scientists fix APOE4 gene in human brain cells

Research using human brain cells has found that the APOE4 protein is slightly misshapen and can’t function properly. It breaks down into disease-causing fragments, resulting in a number of problems, including the accumulation of the protein tau and of amyloid peptides.

The presence of APOE4 does not change the production of amyloid beta in mouse neurons, so this is a crucial species difference which shows why our animal models are of limited value.

Further research confirmed that it was specifically the presence of APOE4, and not the absence of the more common allele, APOE3, that promotes Alzheimer’s.

The human APOE4 neurons were treated with compounds developed to change the structure of the apoE4 protein so it resembles the APOE3 protein. This treatment eliminated the signs of Alzheimer's disease, restored normal function to the cells, and improved cell survival.

https://www.eurekalert.org/pub_releases/2018-04/gi-sfg040818.php

The first study was presented at the annual Alzheimer's Association International Conference (AAIC) in Los Angeles, July 2019.

[4416] Wang, C., Najm R., Xu Q., Jeong D-eun., Walker D., Balestra M. E., et al.
(2018).  Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector.
Nature Medicine. 24(5), 647 - 657.

Most of the (few) approved Alzheimer’s drugs are cholinesterase inhibitors — that is, they stop the breakdown of the neurotransmitter acetylcholine. A new study explains why they help. It appears they allow signals to enter the brain with more precision and less background noise.

The study involved 13 healthy young adults, some of whom were given the cholinesterase inhibitor galantamine, before listening to a series of modulating tones while focusing on a simple concentration task. The patterns of neural activity demonstrated by those on the drug most closely fit a model in which the signals coming into the brain were sharpened. This was something of a surprise, since it has been generally assumed that the effects would be most pronounced in the ‘higher-order’ processing regions.

The findings are an interesting reminder of the importance of sensory perception for optimal cognition. It should be noted, though, that this sharpening of the signal did occur in an environment in which the stimuli were predictable.

http://www.eurekalert.org/pub_releases/2013-05/vt-taf050713.php

[3407] Moran, R. J., Campo P., Symmonds M., Stephan K. E., Dolan R. J., & Friston K. J.
(2013).  Free Energy, Precision and Learning: The Role of Cholinergic Neuromodulation.
The Journal of Neuroscience. 33(19), 8227 - 8236.

Older news items (pre-2010) brought over from the old website

 

Mixed pathology of dementia indicates combination therapies needed

Data from the Medical Research Council's Cognitive Function and Ageing Study, including post-mortem study of the brains of 456 participants, has enabled researchers to estimate the contribution of each type of pathology to dementia in the population as a whole. The main pathological contributors to dementia were age (18%), small brain (12%), amyloid plaques (8%) and neurofibrillary tangles (11%), small blood vessel disease (12%), multiple vascular pathologies (9%), and hippocampal atrophy (10%). Other significant factors include cerebral amyloid angiopathy (7%) and Lewy bodies (3%). The findings support to the need for a range of strategies, and combination therapies, tailored to the particular needs of the patient. It also points to why particular therapies may be more successful with some individuals but not others.

Matthews, F. E., Brayne, C., Lowe, J., McKeith, I., Wharton, S. B., & Ince, P. (2009). Epidemiological Pathology of Dementia: Attributable-Risks at Death in the Medical Research Council Cognitive Function and Ageing Study. PLoS Med, 6(11), e1000180. doi: 10.1371/journal.pmed.1000180. Full text available at http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000180

http://www.eurekalert.org/pub_releases/2009-11/plos-utp110409.php

Recommended: Use of antipsychotic drugs for dementia patients should be curtailed

A report just out from the U.K. Department of Health has concluded that as many as 144,000 dementia patients are being given anti-psychotic drugs unnecessarily, and that excessive use of the medication causes an estimated 1,800 deaths and almost as many strokes every year. It recommended that the use of the drugs could be cut by two-thirds over the course of the next three years, but urged carers and family not to act hastily, warning that stopping prescriptions immediately for many patients could be dangerous.

http://www.guardian.co.uk/society/2009/nov/12/anti-psychotic-drugs-kill-dementia-patients
http://news.bbc.co.uk/2/hi/health/8356423.stm

Risk of abnormally slow heart rate twice as high in those taking Alzheimer's drugs

Data from 1.4 million Canadians aged 67 and older has revealed that older patients hospitalized with bradycardia were more than twice as likely to have recently started on a cholinesterase inhibitor such as donepezil for Alzheimer's disease compared to those without bradycardia. Bradycardia is an abnormally slow resting heart rate (under 60 beats per minute). Although it can be asymptomatic, it can also cause fainting, palpitations, shortness of breath, or even death. Although there are three cholinesterase-inhibiting drugs approved for use in Canada, most had been prescribed donepezil. The findings add weight to recent guidelines suggesting that doctors should not prescribe cholinesterase inhibitors for dementia patients as a matter of course, but weigh the potential risks and benefits.

Park-Wyllie, L. Y., Mamdani, M. M., Li, P., Gill, S. S., Laupacis, A., & Juurlink, D. N. (2009). Cholinesterase Inhibitors and Hospitalization for Bradycardia: A Population-Based Study. PLoS Med, 6(9), e1000157. doi: 10.1371/journal.pmed.1000157. Full text available at http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000157

http://www.eurekalert.org/pub_releases/2009-10/smh-roa100109.php

Dementia drugs have greater side-effects than thought

A very large study has found that use of cholinesterase inhibitors (the Alzheimer’s drugs Aricept, Exelon and Reminyl) is associated with increased rates of fainting, slowed heartrate, pacemaker insertion, and hip fracture. Both the injuries incurred from falling and the risks from pacemaker implants are "downstream consequences" of not recognizing that fainting and slowed heartrate may be a consequence of taking these drugs.

Gill, S.S. et al. 2009. Syncope and Its Consequences in Patients With Dementia Receiving Cholinesterase Inhibitors: A Population-Based Cohort Study. Archives of Internal Medicine, 169 (9), 867-873.

http://www.eurekalert.org/pub_releases/2009-05/qu-ddm052709.php

Benefit of combination therapy for Alzheimer's

The first long-term study of the real-world use of Alzheimer's drugs has found that extended treatment with Alzheimer's disease drugs can significantly slow the rate at which the disorder advances, and combination therapy with two different classes of drugs (cholinesterase inhibitors and memantine) is even better at helping patients maintain their ability to perform daily activities. The results showed significant differences in the rate of symptom progression among all three groups – with the smallest level of decline in those receiving combination therapy. Cholinesterase inhibitors are approved for use in mild to moderate dementia, while memantine has been approved for advanced dementia. But these findings suggest there may be an advantage in prescribing both types of drugs as initial treatment.

Atri, A. et al. 2008. Long-term Course and Effectiveness of Combination Therapy in Alzheimer Disease. Alzheimer Disease & Associated Disorders, 22(3), 209-221.

http://www.eurekalert.org/pub_releases/2008-09/mgh-scb092208.php

Drugs may not delay onset of dementia

A review of six clinical trials that had addressed the use of cholinesterase inhibitors (donepezil, rivastigmine and galantamine) with MCI patients has found that in none of the trials did the use of the drugs significantly reduce the rate of progression from MCI to dementia.

Raschetti, R., Albanese, E., Vanacore, N. & Maggini, M. 2007. Cholinesterase inhibitors in mild cognitive impairment: A systematic review of randomised trials. PLoS Medicine, 4(11), e338. Full text available at http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0040338

http://www.eurekalert.org/pub_releases/2007-11/plos-dmn112207.php

Negative review of recommended Alzheimer's drugs

A review of the 22 published, double-blind, randomised trials of the three cholinesterase inhibitors currently recommended for Alzheimer’s disease (donepezil, rivastigmine, and galantamine) has found considerable flaws in the methodology of all trials, and concluded that “Because of flawed methods and small clinical benefits, the scientific basis for recommendations of cholinesterase inhibitors for the treatment of Alzheimer's disease is questionable.”

Kaduszkiewicz, H., Zimmermann, T., Beck-Bornholdt, H-P. & van den Bussche, H. 2005. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. British Medical Journal, 331, 321-327.

Anti-inflammatory function of Alzheimer's disease drugs revealed

Current Alzheimer’s drugs focus on preventing the breakdown of acetylcholine. Acetylcholine-producing cells are among the first to die in Alzheimer's patients. Research has also shown that the brains of Alzheimer's patients are characterized by excessive immune activation and inflammation, which are induced by overproduction of an inflammation-producing protein called interleukin-1 and related compounds. Now a new study has found that current Alzheimer's drugs cause a marked reduction in the production of interleukin-1. The findings suggest a new interpretation of why acetylcholine is important; when the acetylcholine increases (as a result of the drug), there is a reduction of the production of interleukin-1. The study also describes the use of a new drug (EN101) which produces these effects in a more efficient way than known heretofore by destroying the molecular antecedent (messenger RNA) of the enzyme, rather than simply blocking the enzyme's activity.

Pollak, Y., Gilboa, A., Ben-Menachem, O., Ben-Hur, T., Soreq, H. & Yirmiya, R. 2005. Acetylcholinesterase inhibitors reduce brain and blood interleukin-1 g production. Annals of Neurology, 57(5), 741-745.

http://www.eurekalert.org/pub_releases/2005-07/thuo-afo072805.php

Drugs used to treat Alzheimer's in nursing homes are worsening sufferers' illness

A study of 93 patients with dementia has found that quetiapine, an anti-psychotic drug commonly used in nursing homes to treat agitation and related symptoms in people with Alzheimers' disease, actually worsens patients' illness, significantly speeding up their rate of cognitive decline. Unfortunately, quetiapine had been regarded as one of the safer of the antipsychotic drugs available. There have been safety concerns with the two most commonly used antipsychotic drugs in people with dementia, risperidone and olanzapine, because of increased risk of stroke. Participants in the trial who were taking rivastigmine showed little or no worsening of their illness. Neither drug had any effect on agitation.

Ballard, C. et al. 2005. Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: Randomised double blind placebo controlled trial. British Medical Journal, 330, 874-7.

http://www.eurekalert.org/pub_releases/2005-02/bmj-dut021605.php

Research clarifies how Alzheimer's medicines work

New research clarifies how cholinesterase inhibitors alleviate mild-to-moderate Alzheimer's. When scientists chemically blocked receptors for an important neurotransmitter called acetylcholine, even healthy young people found it significantly harder to learn and remember – especially in the face of interference. Cholinesterase inhibitors slow the breakdown of acetylcholine. The finding also helps explain why Parkinson's disease, dementia due to multiple strokes, multiple sclerosis and schizophrenia, are all also associated with memory problems — all these conditions, like Alzheimer’s, are associated with lower levels of acetylcholine in the brain.

Atri, A., Norman, K.A., Nicolas, M.M., Cramer, S.C., Hasselmo, M.E., Sherman, S., Kirchhoff, B.A., Greicius, M.D., Breiter, H.C. & Stern, C.E. 2004. Central Cholinergic Receptors Impairs New Learning and Increases Proactive Interference in a Word Paired-Associate Memory Task. Behavioral Neuroscience, 118 (1).

http://www.eurekalert.org/pub_releases/2004-02/apa-rch020904.php