Alzheimer's Disease


Symptomatic and Disease-Modifying Treatment Pipeline for Alzheimer’s Disease

clinical topic updates by Marwan Noel Sabbagh, MD, FAAN

Until the recent US Food and Drug Administration (FDA) approval of disease-modifying therapies, the treatment armamentarium for patients with Alzheimer’s disease had largely remained unchanged for nearly 2 decades and had largely focused on symptomatic treatment rather than disease modification. This is likely to change, as several promising symptomatic and disease-modifying therapies are currently under investigation.

Expert Commentary
“There is a lot in the pipeline, and I think that we will soon see an increase in the number of available treatments for Alzheimer’s disease.”
— Marwan Noel Sabbagh, MD, FAAN

There have not been many drug approvals for Alzheimer’s disease in recent decades. This is because the FDA approval of Alzheimer’s disease drugs has relied largely on a clinical end point, and clinical end points always take longer to achieve than end points relying on biomarkers or other biological end points. Nevertheless, there are several treatments that are currently under investigation for Alzheimer’s disease.


Available symptomatic drugs, including donepezil hydrochloride, rivastigmine and rivastigmine tartrate, galantamine hydrobromide, and memantine hydrochloride, have modest effects. In our field, we have failed to effectively communicate what these drugs do to patients and why it makes sense to use them. We need to educate patients so they know that these agents may improve the symptoms of memory loss, but they do not fundamentally stop the amyloid, tau, or inflammatory changes. They just make a patient’s symptoms better for a while. Often, the perception is that these drugs do not work because the patient got worse despite taking them, but that is not actually the case. The disease, which is neurodegenerative, marches on whether or not someone is taking the medications.


Several symptomatic treatments are being evaluated in clinical trials. Some of the cognitive enhancers that are in development include nicotinic and muscarinic agonists. There are also several emerging drugs that are being evaluated for neuropsychiatric symptoms, including agitation, hallucinations, paranoia, delusions, and anxiety. Most recently, brexpiprazole (a 5-HT1A and D2 partial agonist and 5-HT2A antagonist) has been FDA approved for dementia-associated agitation in Alzheimer’s disease, and pimavanserin (a 5-HT2A and 5-HT2C inverse agonist and antagonist) is still being investigated as a treatment for symptoms of psychosis, including hallucinations and delusions.


Disease-modifying therapies are also an active area of research. First-generation treatment, such as bapineuzumab, and second-generation treatment, such as aducanumab-avwa and lecanemab-irmb, have taught us many lessons regarding effective therapies and clinical trial design. By applying the lessons that we have learned from these drugs, we are now developing third-generation drugs, such as the anti-amyloid treatment valiltramiprosate, an aggregation inhibitor that is currently in phase 3 trials. The investigational amyloid-beta–targeting therapies appear to work faster and are more aggressive than the first- and second-generation drugs.


It is interesting that the amount of amyloid in one’s brain does not correlate with clinical progression very well; however, it turns out that the spread of tangled tau does, which is why there has also been a lot of focus on trying to target tau. Data from a 2023 phase 1b study of an antisense oligonucleotide called MAPTRx that was injected intrathecally showed, for the first time ever, that cerebrospinal fluid total tau concentrations could be lowered in patients with Alzheimer’s disease. That was very exciting.


In addition, we have seen a resurgence of inflammation as a treatment target in Alzheimer’s disease. NSAIDs and steroids have been studied in Alzheimer’s disease for many years without success. Now, we are once again looking at decreasing inflammation using TNF-α inhibition. Further, drugs that are FDA approved for other diseases are being looked at as possible treatments for Alzheimer’s disease; for example, drugs such as blood pressure and cancer therapies are being repurposed. There is a lot in the pipeline, and I think that we will soon see an increase in the number of available treatments for Alzheimer’s disease.


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Cummings J. New approaches to symptomatic treatments for Alzheimer’s disease. Mol Neurodegener. 2021;16(1):2. Published correction appears in Mol Neurodegener. 2021;16(1):21.


Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F. Alzheimer’s disease drug development pipeline: 2023. Alzheimers Dement (N Y). 2023;9(2):e12385. Published correction appears in Alzheimers Dement (N Y). 2023;9(2);e12407.


Lee D, Slomkowski M, Hefting N, et al. Brexpiprazole for the treatment of agitation in Alzheimer dementia: a randomized clinical trial. JAMA Neurol. 2023;80(12):1307-1316. doi:10.1001/jamaneurol.2023.3810


Mummery CJ, Börjesson-Hanson A, Blackburn DJ, et al. Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial. Nat Med. 2023;29(6):1437-1447. Published correction appears in Nat Med. 2024;30(1):304.


Plantone D, Pardini M, Righi D, Manco C, Colombo BM, De Stefano N. The role of TNF-α in Alzheimer’s disease: a narrative review. Cells. 2023;13(1):54. doi:10.3390/cells13010054


Tian Hui Kwan A, Arfaie S, Therriault J, Rosa-Neto P, Gauthier S. Lessons learnt from the second generation of anti-amyloid monoclonal antibodies clinical trials. Dement Geriatr Cogn Disord. 2020;49(4):334-348. doi:10.1159/000511506

Marwan Noel Sabbagh, MD, FAAN

    Moreno Family Chair for Alzheimer’s Research
    Professor and Vice-Chair of Research
    Department of Neurology
    Barrow Neurological Institute
    Phoenix, AZ