Antidepressants May Reactivate Areas Of The Brain Affected By Alzheimer's

Researchers have found that antidepressants called SSRIs (such as fluoxetine and sertraline) can have positive effects on the brains of people with Alzheimer's. These drugs appear to reduce a protein linked to the disease (tau) and improve the functioning of an important area of ​​the brain called the dorsal raphe nucleus. However, the effects on memory and thinking are mixed, and more studies are needed to fully understand how these drugs can help.

Alzheimer's disease (AD) is a neurodegenerative condition that causes progressive deterioration of cognitive functions, such as memory, attention and language. One of the most important elements in its progression is the abnormal accumulation of proteins in the brain, such as tau and beta-amyloid. These proteins form tangles and plaques that interfere with communication between neurons and lead to the death of these cells.

One of the first places in the brain to show signs of these changes is the dorsal raphe nucleus (DRN), a region located in the brain stem, at the back of the neck. This area is particularly important because it is the brain's main source of serotonin, a neurotransmitter critical for regulating mood, sleep, and cognition.

Serotonin is widely known for its role in depression, and so drugs that increase its availability, called selective serotonin reuptake inhibitors (SSRIs), are often used as antidepressants.

Previous studies have shown that dysfunction in the serotonergic system (i.e., the system that uses serotonin as a messenger) is linked to the early onset of changes typical of Alzheimer's disease, including the accumulation of tau protein in the dorsal raphe nucleus.

Furthermore, depression is a common condition in people with Alzheimer's, which reinforces the hypothesis that there is a biological connection between these systems.

Given this scenario, researchers at the University of Calgary, Canada, set out to investigate whether the use of the SSRI drug could affect the development of Alzheimer's disease, influencing the presence of abnormal proteins and brain function.

To do this, they used data from a large research database called ADNI (Alzheimer's Disease Neuroimaging Initiative), which gathers brain imaging scans and clinical information from thousands of people followed over many years.

The participants included in this study were classified as cognitively normal or diagnosed with Alzheimer's, and only those who had specific imaging scans and a history of SSRI use were analyzed.

The study focused specifically on how the brain “spends energy” in an area of ​​the dorsal raphe nucleus. To understand this expenditure, doctors use a test called PET-FDG, which works like a “sugar thermometer” in the brain: they inject a special form of glucose (FDG) and, during the tomography, they see where this sugar is consumed.

Regions that use a lot of energy shine brighter in the image, while those that are functioning less appear cooler. This makes it possible to know whether the dorsal raphe nucleus, responsible for producing serotonin, is active or “turned off” in patients with Alzheimer’s, giving an idea of ​​how that part of the brain is working (or not) in the disease.

In patients with Alzheimer’s, a significant drop in the metabolism of the dorsal raphe nucleus was observed, which means that this region is functioning below normal. However, in patients who had been taking SSRI drugs for a long time, this metabolic activity in the dorsal raphe nucleus was restored, suggesting that antidepressants can reactivate the functioning of this area.

Another important finding was related to the tau protein, especially the form called p-tau181, which is used as a marker for Alzheimer's disease. In individuals who used SSRIs, levels of this protein in the blood were lower, which suggests a possible reduction in the formation of the pathological tangles that characterize the disease.

This indicates that the use of these drugs may be related to a lower burden of the disease, at least at the molecular level.

This figure shows how the use of SSRI antidepressants (selective serotonin reuptake inhibitors) can affect the activity of a region of the brain called the dorsal raphe nucleus (DRN), especially in people with Alzheimer's. The image is divided into three parts: (A) shows that people with Alzheimer's who did not take SSRIs (compared to healthy people who did not take them) have lower metabolic activity in the DRN, that is, this region is functioning less, which appears in light blue in the images. (B) shows that people with Alzheimer's who used SSRIs have increased activity in the dorsal raphe nucleus (DRN) compared to Alzheimer's patients who did not use these drugs. This increased function appears in yellow/orange, suggesting that SSRIs can help "reactivate" this part of the brain affected by the disease. (C) shows that in people without Alzheimer's, the use of SSRIs does not significantly alter the activity of the dorsal raphe nucleus (DRN), that is, in healthy brains, the medication does not cause major changes in this region.

On the other hand, when researchers looked at the effects of SSRIs on cognition (mental functions such as memory, attention and reasoning), the results were mixed. While some tests showed improved cognitive performance, others showed no significant changes.

This means that while SSRIs may have promising biological effects on the brain, their direct impact on memory and thinking is not yet fully predictable.

In summary, this study suggests that long-term use of SSRI antidepressants may have a beneficial effect on some of the brain changes that occur in Alzheimer's disease, especially by restoring metabolism in early affected regions and by reducing tau protein levels.

However, their effects on cognition are not consistent, and more research is needed to fully understand how these drugs can be used in the context of preventing or treating Alzheimer's.

READ MORE:

SSRIs reduce plasma tau and restore dorsal raphe metabolism in Alzheimer's disease

Dylan J. Terstege, Shaista Jabeen, Alzheimer's Disease Neuroimaging Initiative, Liisa A. M. Galea, Jonathan R. Epp, and Derya Sargin

Alzheimer’s & Dementia. Volume 21, Issue2 February 2025 e14579

https://doi.org/10.1002/alz.14579

Abstract:

Tau pathology impacts neurodegeneration and cognitive decline in Alzheimer's disease (AD), with the dorsal raphe nucleus (DRN) being among the brain regions showing the earliest tau pathology. As a serotonergic hub, DRN activity is altered by selective serotonin reuptake inhibitors (SSRIs), which also have variable effects on cognitive decline and pathology in AD. We examined N = 191 subjects with baseline 18F-fluorodeoxyglucose positron emission tomography and plasma biomarker data to study the effects of SSRIs on tau pathology, cognitive decline, and DRN metabolism. Plasma phosphorylated tau 181 (p-tau181) was lower with SSRI use. The effect of SSRIs on cognition varied by cognitive assessment. The DRN was hypometabolic in AD patients relative to healthy controls; however, SSRI use restored the metabolic activity of this region in AD patients. Long-term SSRI use may reduce the pathological presentation of AD but has variable effects on cognitive performance.