Alzheimer’s disease (AD), the most common form of dementia, is a progressive neurogenerative disease characterized by memory loss and decline of cognitive function. Despite extensive treatment efforts, AD remains incurable and novel therapies to prevent, slow down or delay the onset of the disease are urgently needed. Without effective therapies, the number of patients with dementia worldwide is estimated to reach more than 130 million by 2050 (Cummings et al., 2016).

Given the need for disease-modifying therapies for AD, drug repurposing may be a promising approach. Preclinical studies indicate that antidepressants, particularly selective serotonin reuptake inhibitors (SSRI), have beneficial effects on AD-related biomarkers including amyloid plaques, one of the major pathological hallmarks in AD (Cirrito et al., 2011, 2020; Sheline et al., 2014). Neuritic plaques consist of aggregated Abeta peptides that are formed within neurons by sequentially cleavage of the amyloid precursor protein (APP). Dysregulation of Aβ production and Aβ clearance leads to accumulation of hydrophobic Aβ forms and the formation of extracellular plaques (Chen et al., 2017; Guo et al., 2020). While the pathway of APP processing is well-characterized, mechanisms of its regulation are not yet fully understood. APP processing can be modulated by several signaling pathways including NMDA, acetylcholine and serotonin signaling systems. Serotonin receptors (5-HTr) might affect APP processing and Aβ levels. In vitro studies could show that activation of 5-HTr2a, 5-HTr2c, and 5-HTr4 increases non-amylogenic APP processing (Nitsch et al., 1996; Robert et al., 2001; Pakaski et al., 2005; Shen et al., 2011). In addition, treatment with SSRI reduced Aβ levels and amyloid plaque burden in different mouse models of AD (Tucker et al., 2005; Nelson et al., 2007; Cirrito et al., 2011, 2020). Furthermore, beneficial effects of antidepressant medication on cognition could be shown in depressed patients, while there was no effect on non-depressed individuals (Prado et al., 2018).

However, whether chronic SSRI-treatment influences amyloid burden and cognition in humans remains unclear. A few studies suggest a possible positive benefit of SSRI treatment on the risk of developing AD, whereas the effect on amyloid burden remains controversial (Kessing et al., 2009; Cirrito et al., 2011; Bartels et al., 2018, 2020).

The aim of this study is the evaluation of the influence of SSRI-treatment on amyloid burden in ¹⁸F-Florbetapir positron emission tomography (PET) in cognitively normal and cognitively impaired individuals.

Data used in this study were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database.¹ The ADNI was launched in 2003 as a public-private partnership, led by Principal Investigator Michael W. Weiner, MD. The primary goal of ADNI has been to test whether serial magnetic resonance imaging (MRI), positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment (MCI) and early Alzheimer’s disease (AD). ADNI is a multicentered project that aims to improve clinical research on AD unifying data on demographics, clinical and cognitive assessments as well as on genetic, biochemical and imaging biomarkers. Standardized protocols and unlimited data access allow analysis of an enormous amount of data from more than 1800 patients that have been included to the ADNI database to date. Groups of AD patients, patients with mild cognitive impairment (MCI), and cognitively normal elderly controls were included in four phases starting in 2004.

Amyloid plaques are a major pathological hallmark of AD and the modulation of plaques, APP processing, and related signaling pathways has been a research focus for novel AD-therapies for many years. The role of different neurotransmitter systems in the development of AD is still unclear. Recent evidence suggests that the serotonergic system, that has mainly been studied in mood disorders so far, might play a role in the pathogenesis of AD (Cirrito et al., 2011; Ramos-Rodriguez et al., 2013).

Mid-life or late-life depression is considered a risk factor for the development of AD. However, whether depression is a prodromal symptom or a true etiologic risk factor for AD remains controversial. Both, AD and depression share similar neuropathological changes as neuroinflammation, elevated oxidative stress markers and synaptic dysfunctions and an increased cortical amyloid burden is also seen in patients with a lifetime history of depression (Chung et al., 2015; Herbert and Lucassen, 2016; Mahgoub and Alexopoulos, 2016).

Therefore, the modulation of serotonergic systems with SSRIs might be a potential treatment option for AD patients with or without a history of depression.

Several preclinical studies demonstrated beneficial effects of SSRI-treatment on AD-pathologies in different mouse models of AD suggesting a modulation of APP processing by SSRIs. Cirrito et al. (2011) first showed a serotonin-dependent reduction of Aβ levels in the brain interstitial fluid (ISF) in APP/PS1 mice after short-term treatment with citalopram or fluoxetine. Furthermore, reduced cortical and hippocampal plaque burden as well as decreased Aβ levels in ISF and cerebrospinal fluid (CSF) were also detected after chronic citalopram administration (Cirrito et al., 2011). Beneficial effects on plaque load and Aβ-levels following citalopram treatment could also be confirmed by a couple of other studies (Sheline et al., 2014; Wei et al., 2017; Zhang et al., 2018). Sheline and colleagues demonstrated a reduced formation of plaques as well as decreased growth of preexisting plaques in APP/PS1 mice after 28 days of citalopram treatment (Sheline et al., 2014). Similar to the results obtained after citalopram treatment, several studies demonstrated that fluoxetine treatment decreases amyloid plaques and soluble Aβ levels in the brain in different AD mouse models (Cirrito et al., 2011; Wang et al., 2014, 2016; Qiao et al., 2016; Jin et al., 2017; Ma et al., 2017; Sun et al., 2017; Zhou et al., 2019). Furthermore, there is limited evidence that paroxetine has also beneficial effects on the AD pathology as Nelson et al. (2007) showed reduced accumulation of tau-protein and cortical Aβ1-40 levels after chronic paroxetine treatment in 3xTg mice and Olesen et al. (2017) detected a reduction of plaque load in the hippocampus of APP/PS1-mice (Nelson et al., 2007; Olesen et al., 2016, 2017). In addition, escpitalopram was able to reduce tau-hyperphosphorylation in cultures of Aβ1-42 treated hippocampal neurons of fetal brains obtained from rats (Wang et al., 2016) and in a recent study, Cirrito and colleagues showed a significantly reduced plaque load in APP/PS1 mice after 28 days of escpitalopram treatment (Cirrito et al., 2020).

While these preclinical results hint to a beneficial effect of SSRIs on AD-pathologies, studies on their impact in humans are very limited. Bartels et al. (2018) showed that long-term use of SSRIs delayed the conversion from MCI to AD in patients with a previous depression for 3 years (Bartels et al., 2018). Similarly, Burke et al. (2018) showed that the risk of cognitively normal patients with a prior history of depression developing AD was neutralized by SSRI treatment compared to untreated patients (Burke et al., 2018). A retrospective study of Down syndrome patients with a previous history of depression showed that SSRI use for more than 90 days significantly delayed the onset of dementia (Tsiouris et al., 2014).

Sheline et al. (2014) demonstrated a significant reduction of Aβ production and CSF Aβ concentration after a single high dose application of citalopram in healthy volunteers (Sheline et al., 2014). However, it should be noted that the study was performed on young participants, presumably before plaque formation while our cohort was much older. However, in a recent study, the same group showed that short-term longitudinal treatment of escitalopram decreases CSF Aβ42 levels in cognitively normal older adults (Sheline et al., 2020).

In the current study, we could not detect any differences of amyloid burden or cognition between patients with SSRI treatment compared to untreated patients regardless of a previous depression.

So far, only two studies have evaluated the effects of SSRI-treatment on amyloid burden using amyloid-PET showing controversial findings. Brendel et al. (2018) showed no significant reduction of amyloid deposition in ¹⁸F-Florbetapir-PET between SSRI-treated and untreated MCI and AD patients with a prior history of depression (Brendel et al., 2018). Results are in line with our findings, as we did not detect significant differences in amyloid burden between SSRI-treated and untreated patients in a comparable patient cohort. In addition, we did not find any significant differences in MCI and AD groups without prior depression nor in cognitively normal patient groups with or without depression. Consistent with our findings, in a previous study by Bartels et al. (2018) CSF Aβ levels were unaffected by SSRI treatment in MCI patients with a history of depression.

In contrast to those findings and to our findings, Cirrito et al. (2011) showed a significant lower cortical binding of the ¹¹C-labeled amyloid tracer Pittsburgh Compound-B (¹¹C-PiB) in cognitively normal patients that have received fluoxetine, citalopram or escitalopram treatment (mean duration 35 months) compared to patients with no history of SSRI use. The Thioflavin-S derivate ¹¹C-PiB was the first amyloid tracer applied in human PET studies with high sensitivity and specificity for the detection of amyloid plaques. Limitations of the ¹¹C-labeld tracer due to its availability and short half-life were overcome with the development of ¹⁸F-labeled amyloid tracers, including ¹⁸F-Florbetapir. ¹⁸F-labeled tracers show comparable binding properties and clinical performance to ¹¹C-PiB and therefore, differences cannot be mainly explained by the use of different amyloid tracers (Johnson et al., 2013; Barthel and Sabri, 2017; Villemagne et al., 2017). In the study by Cirrito et al. (2011), all participants that took SSRIs had a history of depression while our cohort also included patients that used SSRI due to other reasons than depression which might be the main reason of discrepant results. However, after separating participants with and without history of depression, there were no differences between SSRI+ and SSRI− subjects in our cohort.

We could show that the duration of SSRI treatment correlated inversely with amyloid burden in both, cognitively normal and cognitively impaired patients, consistent with the findings of Cirrito et al. (2011). The time of onset and duration of exposure to SSRIs seems to be a crucial factor as SSRI-treatment might have preventive properties reducing Aβ accumulation. Hypothesizing that SSRIs influence Aβ metabolism promoting the non-amylogenic APP processing pathway leading to a lower amount of soluble neurotoxic Aβ forms and lower amyloid plaque burden, only long-term treatment might contain AD pathologies in a protective way. Furthermore, the development of AD pathologies takes many years and only short-term treatment might not be sufficient in order to reduce Aβ accumulation. This theory is supported by the results of a large Danish population-based study in which patients who received only one prescription of SSRI antidepressants had an increased rate of dementia compared to subjects unexposed to antidepressants, while continued long-term antidepressant treatment (six to nine prescriptions) was associated with a reduced rate of dementia (Kessing et al., 2009). Additional factors that might be modulated by long term SSRI-treatment include depressive symptoms, stress and neuroinflammation with a possible beneficial effect on cognition.

Preclinical studies indicate that the decrease of Abeta levels after SSRI treatment is dose-dependent (Cirrito et al., 2011; Sheline et al., 2014). A dose-dependent decrease of Abeta levels was first demonstrated by Cirrito et al. (2011) as they showed a reduction of ISF Aβ-levels by 12–16% using 5 mg/kg of citalopram while 10 mg/kg reduced Aβ-levels by 24%. However, in our cohort, we could not detect a dose-effect on the cerebral amyloid load in ¹⁸F-Florbetapir-PET. One possible explanation of theses divergences might be an inter-individual variation in the efficacy of SSRI-treatment. Thus, the dose of SSRI treatment may vary greatly between individual patients and bias a grouped analysis.

It has previously been shown that the ApoE ε4 allele influences the response to different antidepressants in geriatric depression. Murphy et al. (2003) showed that patients carrying the ε4 allele showed a rapid onset of the noradrenergic and specific serotonergic antidepressant mirtazapine action, whereas paroxetine-treated patients with the ε4 allele were slow to respond (Murphy et al., 2003). However, ApoE genotype had no effect on the treatment outcome with SSRIs in the current study. Although, ApoE4 carriers showed significantly higher SUVR compared to non-carriers in cognitively impaired patients as well as in cognitively normal subjects.

Limitations of this study include the retrospective setting. Especially inconsistencies in SSRI-treatment protocols (doses, type of SSRI, duration of treatment) have to be considered as an important limitation. Furthermore, more detailed information on the number and extent of depressive episodes were not available in the dataset. In addition, inconsistencies between the groups regarding the history of depression might have led to a possible bias. Another limitation is the limited number of patients in some of the studied sub-groups.

Overall, the effect of SSRI-treatment on AD-pathologies in humans remains controversial. While preclinical studies and first clinical data showed promising results, a beneficial effect neither on amyloid load nor cognition could be confirmed so far.

The effect of SSRI-treatment on AD-pathologies remains unclear. However, preclinical data and the negative correlation between the time of SSRI treatment and amyloid load continue to suggest a possible beneficial effect of SRRI-treatment on the pathogenesis of AD. A controlled randomized prospective study on the effect of SSRIs on AD-pathologies is necessary in order to overcome limitations of previous studies evaluating treatment effects in a dose- and time-controlled manner. Furthermore, more information of the mechanism of action of SSRI-treatment are needed, including secondary and tertiary preventive properties, e.g., possible modulation of depressive symptoms and stress of SSRIs in the development of AD.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

All ADNI participants provided informed written consent, which was approved by each site’s Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.

CB and YB designed the project, analyzed the data, and wrote the manuscript. Both authors contributed to revising the manuscript and approved the final version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.