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December 5, 2023:

Comparing Benefits and Risks of New Alzheimer’s Disease Therapies with Lithium Therapy:

If you are one of the 6.7 million people living in the USA with Alzheimer’s disease (AD), a first-degree family member of someone with AD or anyone else that has been waiting for a breakthrough AD therapy, 2023 has been an exciting and confusing year. If you are more interested in new Parkinson’s disease (PD) therapies, it is beneficial to keep abreast of the latest AD developments as the same issues and concerns may soon apply to PD patients.

On the one hand, there have been two new AD therapies recently approved by the FDA for slowing the progressive worsening of cognition that strips AD patients of their ability to remember, perform simple calculations and communicate. These therapies, aducanumab and lecanemab, work by clearing a toxic protein from the brain called beta-amyloid. Aducanumab and lecanemab slow cognitive decline by 22% and 27%, respectively. This is the exciting news.

On the other hand, aducanumab and lecanemab can cause brain swelling and/or bleeding in 41% and 21% of patients, respectively. Finally, the degree of benefit for these therapies, about a 25% reduction in cognitive decline, is so small that patients and families may not even notice any benefit. It will take much more time to determine if these therapies help keep AD patients from progressing to the point where they need nursing home placement. This is the confusing news.

These therapies are also fairly inconvenient. Lecanemab, for example, is administered by intravenous infusion every other week for 18 months. Patients need to receive a brain PET scan and MRI before starting lecanemab and brain MRIs after the 5th, 7th and 14th lecanemab infusions.

The annual cost just for the lecanemab medication is $26,500/year plus the costs of the infusion visits and the brain scans. Medicare will cover 80% of these costs, which will leave patients with at least $5,300/year in out-of-pocket costs after meeting their Part B deductible. Aducanumab therapy is currently not being covered by Medicare due to contradictory results from its two largest clinical trials.

In 2024, another anti-amyloid therapy called donanemab may gain FDA-approval. Donanemab slows cognitive decline in AD by 29% but led to brain swelling and/or bleeding in 36.8% of patients. Additional research on donanemab showed it to slow cognitive decline by 35% in all AD patients studied and by as much as 60% in the subset of AD patients in the earliest stages of the disease. On the other hand, three of the 750 patients receiving donanemab (0.4%) died due to brain swelling or bleeding. Three patients receiving aducanumab and lecanemab have also died but these deaths have not been attributed to side effects from these medications.

In addition, only early AD patients are eligible for any of these anti-amyloid therapies because previous studies showed more advanced patients to obtain no benefit. Other factors can make an AD patient ineligible for these therapies such as being on blood thinner medications or having a history of stroke or seizure. Finally, all three of these anti-amyloid therapies cause the brain to shrink at a faster rate than it already does in AD, which is the opposite of what most experts believe a beneficial AD therapy should do.

With all of this to consider, what is an AD patient to do? Take lecanemab now, if you are eligible, and hope you get some benefit without brain swelling or bleeding or wait for something better, safer and more convenient to become available? This decision is best made on an individual basis after consultation with a neurologist.

This brings us to lithium therapy for AD. As described in the book, The Promise of Lithium, low-dose lithium therapy has been shown in two studies to slow cognitive decline in patients with AD and a pre-AD condition called Mild Cognitive Impairment (MCI). Lithium therapy did not cause any side effects in these studies, is very inexpensive and is taken as an oral pill. Although neither of these two studies checked brain MRIs, lithium therapy (which has been widely used worldwide since the 1960s to treat a psychiatric condition called bipolar disorder) has never been shown to cause brain swelling or bleeding. In addition, lithium therapy has been associated with increased brain volume in contrast to the decreased brain volume (shrinkage) caused by all three anti-amyloid therapies.

The below table summarizes the peer-reviewed, published results for the three anti-amyloid therapies as well as the two lithium trials. Three different cognitive outcomes are included in the table as the trials did not all assess the same outcomes.

Something needs to be emphasized when reviewing this table. Although the results from the lithium studies look impressive compared to the anti-amyloid studies, the first row of data needs to be highlighted. The lithium studies have only enrolled 5-10% of the number of patients as the anti-amyloid studies. This is far too small of a number of patients to make any confident conclusions about lithium therapy for AD. Also, the lithium studies were each derived from a single study site while the anti-amyloid studies were derived from many sites. Positive results from such multicenter studies add much more credibility to the anti-amyloid study results compared to the lithium study results.

What is desperately needed is replication of the lithium study results from an independent study site. Fortunately, that is exactly what the LATTICE trial currently in progress at the University of Pittsburgh is seeking to accomplish. This trial has completed enrollment of 80 MCI patients and is expected to have results in late summer or fall of 2024. Similar to the anti-amyloid trials presented in the above table, the LATTICE trial will assess lithium’s effects on cognition in addition to brain biomarkers. If the LATTICE trial is able to replicate the results from the previous lithium trials, this will provide much stronger evidence supporting the use of low-dose lithium for treating MCI and early AD.

If you are more interested in Parkinson’s disease (PD) therapies than AD therapies, it is beneficial to keep abreast of AD developments as the same issues and concerns may soon apply to PD patients. There are many PD trials currently in progress examining the benefits and side effects of anti-alpha-synuclein therapies. Like beta-amyloid in AD, alpha-synuclein is a toxic protein in PD when it becomes sticky and clumped together in the brain. Therefore, lessons learned from the anti-amyloid AD study results may very well apply to future anti-alpha-synuclein PD study results.

In terms of lithium therapy for PD, the recently published results from our group’s pilot study showed 45mg/day of lithium aspartate therapy to be associated with improvements in several important brain biomarkers among four PD patients. These promising results enabled us to secure funding to enroll an additional 35 PD patients to determine if the pilot study results can be replicated in this larger sample, similar to what the LATTICE trial is seeking to accomplish in AD. If this larger PD study again shows promising results, this will greatly improve our ability to secure funding to support a larger study enrolling 100 or 150 patients to determine if low-dose lithium aspartate therapy slows progression of both PD symptoms and brain biomarkers.

I hope this information helps to inform you in your consideration of any of these therapies.

Thomas Guttuso, Jr., MD

Professor of Neurology

Co-Director, Movement Disorder Center

University at Buffalo

Disclosures: Dr. Guttuso is the author of the book “The Promise of Lithium: How an Over-the-Counter Supplement May Prevent and Slow Alzheimer’s and Parkinson’s Disease” and President of e3 Pharmaceuticals, which manufactures the lithium aspartate dietary supplement, “Lithitate”.

References:

Budd Haeberlein S, Aisen PS, Barkhof F, et al. Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer's Disease. J Prev Alzheimers Dis 2022;9:197-210.
van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer's Disease. N Engl J Med 2023;388:9-21.
Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA 2023;330:512-27.
Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz WF. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry 2011;198:351-6.
Nunes MA, Viel TA, Buck HS. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer's disease. Curr Alzheimer Res 2013;10:104-7.
Gildengers AG. Lithium As a Treatment to Prevent Impairment of Cognition in Elders (LATTICE). Available at: https://clinicaltrials.gov/ct2/show/NCT03185208?term=lithium&recrs=ab&cond=Alzheimer+Disease&draw=2&rank=1. Accessed 07 March 2022.
Guttuso T, Jr., Shepherd R, Frick L, et al. Lithium's effects on therapeutic targets and MRI biomarkers in Parkinson's disease: A pilot clinical trial. IBRO Neurosci Rep 2023;14:429-34.

April 2, 2023:

There is something strange going on with the brain MRI results from the lecanemab Alzheimer’s disease (AD) clinical trials.

What is strange? Lecanemab, in addition to many other drugs that target a brain protein called beta-amyloid, is causing the brain to shrink in AD.

The medical term for shrinkage is atrophy. Brain atrophy reflects neurodegeneration, which is the progressive death of brain cells, and also reflects the worsening of symptoms in AD. As a result, brain atrophy is a well-established “biomarker” of AD. The fact that lecanemab is causing accelerated brain atrophy raises the possibility that use of drugs like lecanemab may accelerate the rate of brain cell death and symptom decline in AD and worsen AD patients’ long-term prognosis.

And yet, lecanemab received “accelerated FDA-approval” on 1/6/23 for treating AD (see my below post on 1/29/23). This accelerated approval was based on the fact the lecanemab clears beta-amyloid from the brain. However, it is not at all clear whether clearing brain beta-amyloid provides benefit to AD patients. On 7/6/23, the FDA will be rending a decision on granting “full FDA-approval” to lecanemab based on the results of a single, 18-month study showing lecanemab to slow cognitive decline in AD by 27%. If lecanemab receives full FDA-approval on 7/6/23, it is highly likely that Medicare and most private insurances will then cover its $26,500/year cost and lecanemab will be widely prescribed and used by AD patients.

How can this be? How can the FDA be ignoring the well-established AD biomarker of brain atrophy and instead focus on brain beta-amyloid levels when considering approval of drugs like lecanemab?

This question and others were raised in an excellent review article published on 3/27/23 by Alves et al. titled, “Accelerated Brain Volume Loss Caused by Anti–β-Amyloid Drugs: A Systematic Review and Meta-analysis”:

https://www.science.org/content/article/promising-alzheimer-s-therapy-and-related-drugs-shrink-brains

Although several anti-beta-amyloid drugs, including lecanemab, accelerate brain atrophy among the group of AD patients receiving these drugs, it is possible that only a subset of AD patients experience these brain MRI changes and others do not. However, the pharmaceutical company that holds these patient-specific data for lecanemab, Eisai, has so far not released them publicly or provided them to Alves et al. despite several direct requests. Those who are paying attention are voicing alarm:

“These data are extremely concerning, and it’s likely these changes are detrimental” says Jonathan Jackson, a cognitive neuroscientist at Massachusetts General Hospital.

“We’re talking about the possibility of brain damage” from treatment, says Scott Ayton, who was an author on the paper published on 3/27/23. “I find it very peculiar that these data, which are very important, have been completely ignored by the field.”

Alves et al. state that “it is conceivable that lowering [beta-amyloid] levels damages the brain by the restriction of a vital function of [beta-amyloid]. The sequence of [beta-amyloid] is highly conserved among vertebrates, and all healthy brains contain [beta-amyloid]. Indeed, the production of [beta-amyloid] requires complex mechanisms that suggest an important reason for its presence.”

As an alternate explanation, Eisai and others have postulated that the reduced brain volume seen in patients receiving lecanemab may be from reduced inflammation resulting in a process called “pseudo-atrophy”. But this is just a theory. Another possibility is that lecanemab is providing short-term, 18-month benefit to cognition at the cost of long-term acceleration in neurodegeneration and symptom progression leading to a worsened overall prognosis. Based on the MRI data Eisai has released to date, this question cannot be answered.

The FDA plans to assemble an advisory committee to review lecanemab’s data. This advisory committee will then issue a recommendation to the FDA on whether to approve lecanemab. Usually, the FDA follows the advice of its advisory committees. However, in a shocking rebuke of this precedent, the FDA approved an AD drug very similar to lecanemab called aducanumab on 6/7/21 despite a near unanimous recommendation against approval from its advisory committee.

Due to this unprecedented event and reports of questionable interactions between the FDA and the pharmaceutical company, Biogen, leading up to FDA approval of aducanumab, a US congressional investigation was launched. The conclusion of this investigation was that the FDA approval of aducanumab was “rife with irregularities” and that there were “serious concerns about FDA’s lapses in protocol”.

In order to avoid another fiasco like what happened with aducanumab, Alves et al. and others are strongly recommending that Eisai voluntarily provide the patient-specific MRI data from their lecanemab trials to researchers, to the FDA and to the FDA’s pending advisory committee. This will allow for a sober and balanced assessment of the brain MRI volume data in the FDA’s overall evaluation of lecanemab.

AD is a grueling and devastating disease for patients and their caregivers and we desperately need treatments that can improve patients’ lives. Nevertheless, we must remember the words of Hippocrates from the 17th century: “first, do no harm”. How horrible it would be if in our haste to offer treatments to AD patients, we end up making them worse than they already are.

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February 8, 2023:

Well, that was fast. "The Promise of Lithium" book was released on 1/31/23 and already there's been a new development in terms of a recently approved treatment for Alzheimer's disease (AD). So, here it is:

On January 6, 2023, the Food and Drug Administration (FDA) approved the drug lecanemab for treating patients with very early AD. This was based on a study showing this drug to slow cognitive decline in AD by 27% compared to patients receiving placebo in addition to its ability to clear a sticky protein called beta-amyloid from the brain. The drug was approved through a special "accelerated approval" pathway that the FDA established to allow patients quick access to new therapies that addressed diseases with an unmet need such as AD. It remains to be determined if the FDA will grant "full approval" to lecanemab and if major insurance companies including Medicare will cover the $26,500 annual price tag.

In "The Promise of Lithium", there are a few sections that review the highly controversial FDA approval of the drug aducanumab for treating AD, which was granted on June 7, 2021. Like lecanemab, aducanumab also cleared beta-amyloid from the brain; however, only one of the two aducanumab studies showed that it slowed cognitive decline in AD. Because of the inconsistencies in the aducanumab studies' results, most experts do not believe that the evidence sufficiently supports FDA-approval of aducanumab and several private insurance companies as well as Medicare have refused to cover the cost of aducanumab.

In addition, both lecanumab and aducanumab can cause brain swelling and brain bleeding. These side effects are usually mild and don't cause any new symptoms in patients; however, potential long term effects of these brain changes caused by lecanemab and aducanumab are still unknown.

In summary, there are now two FDA-approved "disease-modifying" treatments for patients in the very early stages of AD that may slow down the progression of AD symptoms; however, neither has received full FDA approval and neither has received Medicare coverage. Because the vast majority of AD patients are over 65 years old, Medicare coverage will be essential for the wide-spread use of these very expensive therapies. If Medicare does eventually approve coverage for one or both of these drugs, it likely will be restricted to patients recently diagnosed with AD who are still in the earliest stages of the disease.

Although it is exciting for AD patients to finally see some positive news after years of failed clinical trials, there clearly is much more that needs to be done to improve AD patients' lives. First of all, the 27% reduced rate of cognitive decline in early AD shown for lecanemab in a single study is a fairly small treatment effect size. Because of this small magnitude of benefit, it is unclear if lecanemab can provide long-term, meaningful benefit for AD patients. Also, it is unclear how problematic the brain swelling and brain bleeding side effects from both lecanemab and aducanumab will be with long-term treatment. Finally, these findings only apply to early AD patients. It sure would be nice to have something to offer AD patients who are not in the earliest stages to help slow down their disease progression, too.

Fortunately, the LATTICE trial, that is discussed in detail in "The Promise of Lithium", is underway at the University of Pittsburgh with results expected in late 2024. The LATTICE trial seeks to determine if low-dose lithium therapy can slow cognitive decline and brain changes in early AD patients. Previous studies with low-dose lithium in both early and more mid-stage AD have shown positive results with much larger treatment effect sizes than that seen with lecanemab. These studies were also reviewed in great detail in "The Promise of Lithium". Of course, further research is needed but it is very encouraging to see a major lithium study like LATTICE underway.