This study of non-demented older adults found that ginseng intake had a benefit on AD-specific cognition, i.e., the delayed episodic memory. It also showed that APOE4 had a moderating effect on the association between ginseng intake status and delayed episodic memory cognition, and that ginseng intake had a benefit on the delayed episodic memory cognition in APOE4-negative but not APOE4-positive subjects. This may reflect interactions among ginseng intake, APOE4, and AD or related cognitive decline.
This study found that the benefit of ginseng intake was observed mainly on memory, not on non-memory, and it was more prominent in delayed episodic memory than immediate episodic memory. The earliest cognitive change in patients who will develop AD is episodic memory decline, particularly in delayed episodic memory decline.[2–7] Therefore, our results suggest that ginseng intake acts mostly on delayed episodic memory decline and may play a clinically significant role in early AD-related cognitive decline.
Previously, neuroprotective effects of ginseng on the pathological and clinical process of AD was reported, which may explain the mechanism underlying the relationship between ginseng intake and early AD-related cognitive decline.[29] In cell and animal models, ginseng acted on AD by regulating multiple signaling pathways, such as, the phosphatidylinositol 3-kinase/protein kinase B, adenosine-monophosphate activated-protein kinase/mammalian target of rapamycin, and nuclear factor kappa B pathways, in order to block or improve pathological processes, such as Aβ accumulation, tau phosphorylation, neuroinflammation, neurotrophic factors, apoptosis, and mitochondrial dysfunction in AD.[29] One preclinical study using an AD model revealed that ginseng treatment significantly improved learning and memory performance at 14 months of age and reduced brain senile plaques at this age.[30] In vitro experiments also found that ginseng treatment reduced Aβ 40 and 42 concentrations.[30] Another preclinical study in a transgenic mouse AD model found that long-term ginseng treatment attenuated Aβ deposition and short- and long-term memory impairment.[31] In a human model, two clinical trials investigating the effects of ginseng intervention on AD patients showed a significant improvement in global cognitive function.[32, 33] Based on the preclinical findings, ginseng improves cognitive features of AD patients via AD pathologies, i.e., Aβ accumulation and tau phosphorylation. In human, however, the precise mechanism of ginseng in the pathologies of AD in the prevention and treatment of AD remain unclear.
The present study found that APOE4 status moderated the relationship between ginseng intake and delayed episodic memory cognition, showing a significant negative association between ginseng intake and delayed episodic memory cognition in subjects without APOE4, but not those with APOE4. This may reflect associative interactions between ginseng intake, the APOE4 isoform, and AD-related cognitive decline. There may be differences in Aβ clearance depending on the APOE isoform, which can be explained by interactive effect of ginseng. As APOE4 is less effective than APOE3 and APOE2 at stimulating Aβ clearance, APOE4 could significantly inhibit the removal of Aβ compared to non-APOE4.[34] Therefore, the protective effect of ginseng on AD-related cognition might be prominent in the APOE4-negative group because the neuroprotective effect of ginseng may be offset by APOE4 in the shared Aβ clearance pathway.[35] In addition, the benefit of ginseng may be masked in that APOE4 led to blood–brain barrier dysfunction, predicting cognitive decline.[36]
The present study also found that ginseng intake was associated with a higher delayed EMS in the high duration (≥ 5 years) and midlife onset (< 65 years) groups. Regarding the high duration effect of ginseng on delayed EMS, two studies were similar to ours. A randomized open-label study indicated that long-term ginseng treatment for up to 2 years improved the cognitive deficit in AD patients.[37] A population-based prospective cohort study of older Koreans also revealed that the high-use group (≥ 5 years) had a higher global cognitive score than the no-use group, which means that ginseng use for longer than 5 years may benefit cognitive function in late life.[19] Regarding the effect of ginseng intake with midlife onset on delayed EMS, a human study supported our finding of a highly significant association between increasing age and decreased Aβ turnover rates, i.e., 2.5-fold longer half-life over five decades of age.[38] These changes in Aβ kinetics associated with aging present opportunities for treatment strategies, such as ginseng as an early intervention in middle age rather than old age.
Limitations
Our study had several limitations. First, as it was cross-sectional in its design, causal relationships could not be inferred, which would require long-term prospective studies. Second, it did not measure brain AD pathology biomarkers, e.g., Aβ, tau, and APOE4-related metabolic biomarkers. These should be analyzed in future studies of the link between the ginseng intake and AD or related cognitive decline in APOE-negative older adults. Third, there was a possibility of recall biases in the ginseng intake history. Therefore, we evaluated the ginseng intake history in non-demented older adults using intensive interviews by researchers, not a questionnaire. Furthermore, information accuracy was ensured by interviewing reliable informants. Lastly, the dose effect of ginseng intake was not analyzed using the amount of ginseng taken. Challenges exist to measure the actual amount of ginseng intake because commercial ginseng products do not consistently or clearly indicate amounts of active ginseng component. Subsequent human studies quantifying ginseng intake are needed.