Long-term SSRI use linked to reduced Alzheimer’s pathology but mixed effects on cognition

A new study published in Alzheimer’s & Dementia suggests that long-term use of selective serotonin reuptake inhibitors (SSRIs) may reduce biological markers of Alzheimer’s disease, but their influence on cognitive function appears inconsistent. The findings show that individuals with Alzheimer’s who used SSRIs had lower levels of tau protein in the blood and showed restored activity in a brain region typically impaired by the disease. However, their performance on standard cognitive tests varied depending on the specific measure used.

Alzheimer’s disease is a progressive neurological condition that leads to memory loss, behavioral changes, and ultimately, a loss of independence. One of the main drivers of Alzheimer’s progression is the accumulation of a protein called tau, which forms tangled clumps inside neurons and interferes with their function. Tau pathology is strongly linked to cognitive decline, and researchers have long sought ways to reduce or slow its buildup.

SSRIs are a class of antidepressants commonly prescribed to treat major depressive disorder and anxiety. They work by increasing levels of serotonin, a neurotransmitter that affects mood, sleep, and cognition. The serotonergic system has also been implicated in Alzheimer’s disease, as some of the earliest signs of tau pathology appear in a serotonin-producing brain region known as the dorsal raphe nucleus (DRN). This brainstem region plays a key role in regulating serotonin levels throughout the brain, and its dysfunction is thought to contribute to both depression and Alzheimer’s symptoms.

Given this link, researchers set out to examine whether long-term SSRI use could influence Alzheimer’s pathology, brain metabolism, and cognitive outcomes. They drew on data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a large multi-site study that collects medical, cognitive, and imaging data from people at various stages of cognitive health. The analysis included 191 adults, all of whom had baseline brain scans using 18F-fluorodeoxyglucose (FDG) positron emission tomography, a tool that measures glucose metabolism in brain tissue. Participants also provided blood samples and underwent cognitive testing over a two-year period.

To explore the effects of SSRIs, the researchers divided participants into those who had a documented history of SSRI use and those who did not. They excluded individuals who had ever used other types of antidepressants to isolate the effects of SSRIs. The participants were categorized as cognitively normal or diagnosed with Alzheimer’s disease based on clinical assessments and standard diagnostic criteria. In the group with Alzheimer’s, 65 participants had used SSRIs, while 92 had not.

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One of the primary markers the researchers looked at was phosphorylated tau 181 (p-tau181), a form of tau protein found in the bloodstream that reflects tau accumulation in the brain. Among participants with Alzheimer’s disease, those who used SSRIs had significantly lower levels of plasma p-tau181 compared to non-users. This difference was not observed in cognitively healthy individuals, suggesting that the potential benefit of SSRIs in reducing tau may be specific to those with Alzheimer’s pathology.

Next, the researchers examined how SSRIs affected brain metabolism, focusing on the DRN. In individuals with Alzheimer’s who did not use SSRIs, this brain region showed significantly reduced metabolic activity—an indication of impaired function. In contrast, those with Alzheimer’s who used SSRIs displayed restored activity in the DRN, with glucose metabolism levels similar to those of healthy participants. Interestingly, this effect was not seen in healthy participants who used SSRIs, suggesting that the drug’s impact on DRN function may be specific to disease-related changes.

The team also looked at how SSRI use affected cognitive performance using three standard assessments: the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), and the Clinical Dementia Rating (CDR) sum of boxes. Across the two-year follow-up, MMSE scores declined in all participants with Alzheimer’s, regardless of SSRI use, indicating ongoing cognitive deterioration. However, MoCA scores were slightly higher among SSRI users, suggesting some preservation of certain cognitive functions. CDR scores, which assess the severity of dementia symptoms, increased over time in both groups, with a slightly greater increase in SSRI users.

One unexpected finding was that the relationship between MMSE and MoCA scores shifted in those who used SSRIs. Normally, these two assessments are closely correlated because they measure overlapping aspects of cognition. But in SSRI users, this correlation broke down, possibly pointing to selective effects of the drug on certain cognitive domains or a shift in how these domains are measured. The researchers suggest that future studies should include more specific cognitive tests to determine which areas are most affected by SSRI use in Alzheimer’s patients.

Although the results are promising, the study has several limitations. The researchers were unable to assess the impact of different SSRI types, dosages, or treatment durations due to sample size constraints. They also could not account for other factors that may influence Alzheimer’s progression, such as co-occurring medical conditions, additional medications, or the timing of SSRI initiation relative to the onset of Alzheimer’s symptoms. Because the study was cross-sectional, it also cannot confirm whether SSRI use causes reductions in tau or improved DRN function, or whether people who benefit from SSRIs in these ways are simply more likely to have used them.

Despite these caveats, the findings provide new insights into how a widely used class of antidepressants may influence biological and functional aspects of Alzheimer’s disease. The study supports the idea that SSRI use is associated with lower levels of tau-related pathology and improved activity in a serotonin-rich brain region that plays an early role in disease development. However, the benefits for cognitive performance remain uncertain and may vary depending on how cognition is measured.

Future research will need to clarify whether starting SSRI treatment at specific stages of Alzheimer’s progression offers more benefit, and whether certain subtypes of patients are more likely to respond positively. Longitudinal studies that follow people over time while tracking tau levels, brain function, and detailed cognitive outcomes could help answer these questions.

The study, “SSRIs reduce plasma tau and restore dorsal raphe metabolism in Alzheimer’s disease,” was authored by Dylan J. Terstege, Shaista Jabeen, Alzheimer’s Disease Neuroimaging Initiative, Liisa A. M. Galea, Jonathan R. Epp, and Derya Sargin.