A review of the TGF-β1 pathway in Alzheimer’s disease and depression: Possible restoration potential of antidepressants

Alzheimer’s Disease (AD), the most common type of dementia, is increasing rapidly in prevalence, while Major Depressive Disorder (MDD), the most frequent psychiatric condition, continues to pose significant global healthcare challenges. Recent hypotheses suggest that AD and MDD might be interrelated, potentially sharing common pathophysiological mechanisms. One possible central link is the Transforming Growth Factor-beta 1 (TGF-β1) pathway. Reduced TGF-β1 levels, a cytokine involved in inflammatory responses, have been observed in both conditions. In AD, diminished TGF-β1 might contribute to neurodegeneration and apoptosis, whereas in MDD it might lead to neurotransmitter dysregulation. The + 10C/C genotype of TGF-β1 may increase susceptibility to both disorders. Additionally, the detection of cortical β-amyloid (Aβ) in non-demented depressed patients and elevated Aβ levels in depressed AD patients compared with non-depressed AD patients might indicate overlapping mechanisms. These findings have led to growing interest in whether antidepressants, including SSRIs, SNRIs, TeCAs, TCAs, and ketamine, might have therapeutic potential in AD. Some preclinical and early clinical studies suggest that certain antidepressants, such as SSRIs (fluoxetine, sertraline, fluvoxamine, vortioxetine), SNRIs (venlafaxine), and ketamine, may exert neuroprotective effects or modulate Aβ toxicity. However, the evidence remains inconsistent and sometimes contradictory. Moreover, possible adverse effects, including the risk that long-term antidepressant use might worsen cognitive decline or accelerate cellular aging via pathways such as PI3K/Akt/mTOR, have been reported. These uncertainties highlight the need for further rigorous investigation to determine whether antidepressants could represent a viable therapeutic strategy in Alzheimer’s Disease.