Targeting APOE4: A Promising Therapeutic Strategy for Alzheimer Disease

CLINICAL CONVERSATIONS

At the SLEEP 2026 Annual Meeting, Tri Doan, MD, PhD, presented his research on how APOE4 drives early sleep circuit impairments as well as a new therapeutic strategy in treating Alzheimer disease (AD). Following the conference, Psychiatric Times sat down with Doan to further explore this strategy.

Psychiatric Times: Talk to us a little bit about your research and the promising therapeutic strategy for AD.

Tri Doan, PhD: We know that sleep deficits are very common in AD, and they may appear before cognitive decline. The interesting thing is that these deficits are not only the consequences of that disease, but also contribute to the progression of the disease. Indeed, in our published papers, we show that APP/PS1 mice, an Alzheimer’s mouse model, develop sleep impairments starting at 3 to 4 months of age. Right now, we are investigating the impact of APOE4 on the bidirectional relationship between sleep impairments and AD. APOE4 is the strongest genetic risk factor of AD, and after expressing the APOE4 gene in APP/PS1 mice, the animals develop the impairments, affecting not only the quality but also the quantity of sleep. Their sleep duration is shorter and more fragmented, and the brain activities during the deep non-REM sleep are weaker and less synchronized. These impairments appear a month later in APP/PS1 mice without APOE4 gene. It means that APOE4 somehow exacerbates the amyloid related sleep impairments. The study may provide insights on why APOE4 carriers develop dementia decades earlier than non-APOE4 carriers. When the mice are treated with the CN-105, an ApoE-mimetic peptide, we could rescue those impairments in the animals. Ultimately, the study may pave a way for a novel and promising therapeutic approach in AD populations who carry APOE4.

PT: Can you expand on how APOE4and amyloid act together in the brain?

Doan: Right now, we have a lot of hypotheses. APOE4 may accelerate neuroinflammation in the brain, that would enhance the production of amyloid. We know that the presence of soluble A-beta promotes sleep impairments in Alzheimer’s mouse models. That is probably the reason why the co-expression APOE4 and APP/PS1 mutations in the same brain leads to exacerbated sleep disturbances.

PT: What psychopharmacology options seem most promising to you? Maybe you can expand a little bit on zolpidem.

Doan: We have one published paper on zolpidem, in which we prove that when we administer zolpidem to the APP/PS1 mice, we improve their sleep. The sleep duration increases after administration of zolpidem, and the improvement of sleep leads to the slowdown of AD pathologies, and slows the accumulations of amyloid plaques in the brains of the mice. So sleeping pills could be a new therapeutic approach for AD, because we know that if we can improve sleep, we may slow down Alzheimer pathologies. The key point is to find out which sleeping pills work and which do not. Our work on zolpidem has proven that this is one of the sleeping pills that does work—at least in an animal model.

PT: Talk to us about the relationship between sleep and the progression of neurodegenerative diseases. How does circadian regulation assist in slowing AD?

Doan: Yes, that is a very complex system. Slow waves originate in the cortex, but slow oscillations are not the only brain rhythms that contribute to the memory consolidation. They require other brain rhythms, such as the sleep spindles from the thalamus and the sharp wave ripples from the hippocampus. The coupling between these brain rhythms provides the window for memory consolidation during non-REM sleep, so right now our published paper shows that the cortical slow oscillations are impaired in Alzheimer’s mouse models. That is the reason why the coupling of these brain rhythms is also affected. And the impairments of the cortical slow waves are the reason why we think APP/PS1 mice develop cognitive issues, and interestingly, slow wave impairments appear very early. In the APP/PS1 mice, we see the accumulations of amyloid plaques starting at 6 months of age, but the slow wave activities are impaired starting at 3 months of age. It means that the sleep impairments appear very early—before the accumulations of the A-beta plaques.

PT: What future directions do you envision for your research? What are the next steps?

Doan: As I said before, the next step is to find out how APOE4 impacts sleep impairments and AD. With more insights into the molecular mechanisms, we might find out the good therapeutics to target APOE4 carriers at the early stages. Right now, we have the good result with the CN-105, and we want to expand the therapeutic testing to other peptides. Finally, if we could apply those therapeutics to human populations alongside with current anti-amyloid therapies, we could provide more comprehensive treatment for APOE4 carriers.

PT: What do you wish psychiatrists and mental health clinicians knew about this research?

Doan: That is an interesting question. We know that sleep impairments not only appear in patients with AD, but they also appear in a lot of psychiatric disorders, like anxiety and stress disorders. Additionally, the sleep impairments during AD may lead to other psychiatric disorders. They make the patients more stressed. They are also unhappy when their sleep quality decreases. If we can improve sleep, we can slow down AD and help these people live happily. We can improve the quality of life for these patients.

PT: Anything else you would like to share about your research?

Doan: One good thing is that our CN-105 mimetic peptide is currently under investigation in clinical trials. Hopefully, CN-105 will soon be tested in AD population.

Dr Doan is a postdoctoral fellow at Mass General Brigham and Harvard Medical School.

References

1. Kastanenka KV, Hour SS, Shakerdge N, et al. Optogenetic restoration of disrupted slow oscillations halts amyloid deposition and restores calcium homeostasis in an animal model of Alzheimer's disease.PLoS One. 2017;12(1):e0170275.

2. Yu L, Yokomizo S, Doan TH, et al. Zolpidem restores sleep and decreases amyloid in a mouse model. Alzheimers Dement. 2026;22(3):e71175.