Alzheimer’s disease prevention: Can antidepressants lend a hand?

The selective serotonin reuptake inhibitor (SSRI) escitalopram holds promise in the prevention of Alzheimer’s disease (AD), reducing amyloid-β-42 (Aβ₄₂) levels in cerebrospinal fluid (CSF) and brain tissue in older adults with normal cognitive function, according to recent evidence.

“We show that escitalopram administered at two different doses (20 and 30 mg) and for either 2 or 8 weeks was associated with a decrease in the level of CSF Aβ₄₂,” said lead study investigator Dr Yvette Sheline of the University of Pennsylvania in the US.

“The mechanism for this reduction is through serotonin (5-hydroxytryptamine [5-HT]) receptor subtypes 5-HT4, 5-HT6, and 5-HT7, to activate a signaling pathway that culminates in an upregulation of α-secretase activity to suppress Aβ₄₂ generation,” she explained. [Mol Neurodegener 2016;11:45]

In the study, Sheline and her team randomly assigned 114 cognitively healthy older adults aged 50–84 years to receive either escitalopram (20 mg daily for 2 weeks or 8 weeks, or 30 mg daily for 8 weeks) or placebo. They measured Aβ levels in CSF samples collected using lumbar punctures before and after treatment.

Compared with placebo, SSRI treatment resulted in a significant decrease in CSF Aβ₄₂ (difference, 9.4 percent, 95 percent confidence interval [CI], 4.9–14.2 percent; p<0.001). The combined escitalopram doses produced an average reduction of 6.0 percent as opposed to a 3.5-percent increase noted with placebo. [Neurology 2020;doi:10.1212/WNL.0000000000010725]

Looking at individual dosing regimens, the 8-week course at either 20 or 30 mg yielded modest but meaningful reductions in Aβ₄₂ (–7.8 percent and –6.1 percent, respectively) relative to placebo (p=0.002 and p=0.007). However, the change observed with the 2-week 20-mg regimen (–3.8 percent, respectively) did not achieve significance.

In the entire population, the escitalopram-induced Aβ₄₂ reduction was smaller among participants with positive baseline Aβ status (CSF Aβ₄₂ levels <250 pg/mL)—an indirect indicator of amyloid deposition in the brain—than among those with negative baseline amyloid status (CSF Aβ₄₂ levels >250 pg/mL).

“It is important to note that reducing the rate of plaque accumulation is unlikely to be a viable treatment strategy for individuals who have already developed dementia, as there is little evidence that progression of their disease is dependent on the progression of their amyloid deposition,” Sheline pointed out.

“Thus, some studies, but not all, find that SSRIs do not slow the course of AD or improve the cognitive function of AD patients. To the extent that many people in the amyloid-negative group may never develop brain Aβ deposition it will be critical to determine how biomarker changes can be used to indicate a need for initiating treatment,” she added. [Age Ageing 2016;45:448-456; J Alzheimers Dis 2018;65:793-806]

These findings by Sheline and colleagues are consistent with recent data from an Alzheimer mouse model, where a 4-month course of escitalopram, administered via drinking water, reduced Aβ levels in the interstitial fluid of the brain by 25 percent. The authors attributed this reduction to an increase in α-secretase cleavage of amyloid precursor protein. [Neurology 2020;doi:10.1212/WNL.0000000000010733]

Furthermore, there was a decrease in plaque load of 28 percent with 2.5 mg/kg/day and 34 percent with 5 mg/kg/day. At the higher dose, escitalopram was not able to remove existing plaques but completely hampered individual plaque growth over time.

Despite the encouraging data, Sheline acknowledged that it is still unclear whether the relatively modest reduction in CSF Aβ₄₂ observed in cognitively healthy older adults could translate to clinical benefits.

“If a greater reduction could be demonstrated for the higher 30-mg dose, or for a longer duration of exposure, or for a different SSRI more specific for the relevant 5-HT subtypes, the feasibility might be higher,” Sheline said. “In considering higher doses in an older adult population, caution is warranted given potential cardiac effects including increased QTc interval.”