Positive Effects of Soy Lecithin-Derived Phosphatidylserine plus Phosphatidic Acid on Memory, Cognition, Daily Functioning, and Mood in Elderly Patients with Alzheimer’s Disease and Dementia

Cognitive impairment, such as memory loss (dementia), with increasing age is common and distressing to both the aged individual and their family [1, 2, 3]. Due to a gradual decline in cognitive capacity, patients with dementia are no longer able to continue their former regular occupational and social activities. Functional limitation restricts activities that are essential to daily living, such as bathing, dressing, toileting, and eating [4]. The physical and emotional impact of dementia caregiving is estimated to have resulted in healthcare costs of $9.1 billion in the United States in 2012 [5].

A “normal”, gradual, age-associated memory impairment (AAMI), with a decline of memory tasks by 50% or more over adulthood and aging, affects everybody [6]. Superimposed on this normal development, the majority of patients with dementia suffer from either a degenerative disease of the brain, mainly Alzheimer’s disease (AD), or from multiple infarcts of the brain (vascular dementia), or from a combination of the two [6]. In a 65-year-old man, the remaining lifetime risk of AD has been shown to be 6.3%, and the risk developing any dementing illness to be 10.9%; with the corresponding risks for a 65-year-old woman of 12% and 19%, respectively [7].

The distress associated with memory impairments, including AD, has ignited a search for viable treatments, and there have been various pharmacological or nutritional approaches explored to counter dementia [8, 9].

Age-related cognitive deficits have been linked to various mechanisms, including cumulative oxidative stress and age-related changes in cellular metabolism [10]. Many age-related neurochemical changes can be traced to structural and functional alterations in neuronal membranes [11]. A decline of phospholipids—particularly phosphatidylserine (PS) in neuronal membranes—has been associated with memory impairment and deficits in mental cognitive abilities [12, 13]. This has led to the proposal that administration of endogenously occurring phospholipids may prevent or reverse age-related neurochemical deficits [14].

The phospholipids PS and phosphatidic acid (PA) are found in the neuronal membrane in high concentrations and are essential to its functioning, acting as a biological detergent, and keeping fatty substances soluble and cell membranes flexible [15, 16]. PS was also found to reduce oxidative stress in the brain [17], as well as to stimulate neurotransmitter release [18, 19] and to increase brain glucose metabolism [20, 21]. Experiments with PS-supplemented rodents have shown an improvement in memory, learning capacity, and other cognitive parameters [19, 22, 23, 24, 25].

Several human studies have shown the efficacy of bovine brain-derived PS in patients with dementia [26]. For example, AAMI subjects were supplemented by three-month administration of bovine brain-derived PS, 300 mg daily [27]. An improvement on a number of neuropsychological tests was observed in the PS-supplemented subjects relative to those receiving placebo [27]. In a 12-week study with 149 AAMI patients, those supplemented with a bovine brain-derived PS formulation [100 mg PS three times daily (tid)] improved, relative to placebo, in daily life learning and memory tasks [28]. In another 6-month double-blind study, 494 cognitively impaired elderly were supplemented with 300 mg bovine brain-derived PS daily (or placebo), resulting in a significant improvement in behavioral and cognitive parameters in the supplementation group [29].

In a different study, placebo-controlled supplementation of elderly with 100 mg soy-PS six times daily (n = 41, PS-group) for 12 weeks did not reveal any significant cognitive improvements [30]. In contrast, a 12-week pilot study with 30 elderly volunteers suggested that soy lecithin-derived PS (100 mg tid) may have favorable effects on cognitive function in elderly with memory complaints [31]. Also, a different pilot study with 18 AAMI patients demonstrated significant positive effects on cognition [32]. A double-blind, randomized-controlled study investigating the effects of soy lecithin-derived PS on the cognitive functions of elderly Japanese subjects with memory complaints demonstrated (unlike placebo) significantly improved memory scores in PS-treated groups compared to baseline [33]. In different studies, PS-containing preparations were found to selectively dampen stress levels in humans [34, 35, 36], improve learning and perception parameters in children with attention-deficit hyperactivity disorder [37, 38], and improve the calculation speed of athletes [39].

Due to concerns regarding bovine spongiform encephalopathy, the use of PS (and PA) produced by enzymatic conversion of soybean lecithin [40, 41] is considered a safer alternative. Although PS from both sources can be considered safe [42, 43], currently, from a regulatory point of view, only the non-bovine brain-derived PS is allowed as a dietary supplement. The understanding of bovine brain-derived PS limitation initiated development of practical enzymatic conversion of soybean lecithin to PS and PA. The first company to commercially produce soy lecithin-derived PS was Lipogen Ltd. (Haifa, Israel) in 1991. The availability of soy lecithin-derived PS further necessitated clinical testing of the new soy lecithin-derived PS in comparison to the old bovine brain-derived PS.

PS is a structural PL found in neuronal membrane and is essential to its functioning [15, 16]. In various studies, PS (mostly derived from bovine brain) was found to improve cognitive ability and functioning in demented patients (see “Introduction”). However, the use of PS from a vegetative source, free of risk of encephalopathy, is considered advantageous, and the presented human studies were, to the best of our knowledge, the first to use plant-derived PS.

The kinetic analysis in healthy volunteers demonstrated that soy lecithin-derived PS is absorbed and metabolized, with elevated serum levels for at least 1.5 h after an oral dose.

In Study 1 on 72 non-demented, non-depressed, functioning elderly with various degrees of AAMI, the post-supplementation memory testing scores in the PS+PA supplementation group were significantly higher than baseline, with a higher degree of significance compared to the placebo group. Furthermore, when pre- and post-supplementation results of components of the memory test were compared, none of the placebo group’s changes were statistically significant, whereas results for maintaining information, visual memory, and memorizing numbers improved with statistical significance of P < 0.05 within the PS+PA group. The non-significant improvement trends observed in the placebo group may be explained as a learning (test–retest) effect, and/or with the 4–8% of PA also contained within soy lecithin [49].

Comparing both groups, we found that subjects who received PS+PA supplementation and who had scored high on the initial WMS showed more significant memory improvements, whereas those who had scored low did not. A probable explanation may be the rather small size of the study, as well as its relatively short duration. PS+PA was also observed to have clear beneficial effects in patients with dementia, especially if the expected gradual cognitive deterioration is taken into consideration:

In the placebo-controlled, randomized study involving patients with AD (Study 2), a statistically significant positive effect of PS+PA was found on the 7-ADLs functioning index, while a significantly more pronounced deterioration was revealed in the placebo group.

Functioning is considered to be highly important in geriatric practice, since it is strongly associated with pathology, and is a determinant of measurable outcomes, such as morbidity, mortality, hospitalization, and costs, as well as efficacy of interventions and treatments. The association of functioning with quality of life and need of care is well established [50].

The MMSE has a rather low sensitivity to minor changes [51]; accordingly, only slight positive trends after the supplementation of PS+PA could be observed after 2 months. However, the positive trends of PS+PA supplementation on change patterns of functioning and self-reported general condition are encouraging. Significance could possibly not be reached due to the short study duration and the limited sample size.

The data from Study 2 is complemented by the historical prospective data from 68 cognitively impaired elderly dementia patients—especially memory categories and organization skills appeared to improve with PS+PA in pre–post comparison.

The superiority of the PS+PA supplementation can also be derived from the fact that 6 out of 14 (42.9%) patients (or their families) in the PS+PA supplementation group of Study 2 (while still double-blinded) decided to continue the supplementation at their own expense after study termination, compared to none in the placebo group. Similarly, many of those patients with dementia analyzed in a historical prospective manner continued PS+PA supplementation at their own expense for more than a year (data not shown).

In addition to the positive influence on the memory, the study on functioning elderly reveals a positive effect of PS+PA on mood. None of the participants in Study 1 had been initially depressed, since high LDS scores were excluded. Nevertheless, a worsening of mood with time was observed within the placebo group, which was not seen in the PS+PA supplementation group. “Winter blues”, also known as seasonal affective disorder or seasonal depression, is a universal phenomenon in higher latitudes [52, 53]. Since this study started in late summer and ended in winter, we suggest that soy lecithin-derived PS+PA may be advantageous in prevention of “winter blues” and depression. Maggioni et al. [54] reported a positive effect of PS on geriatric depression.

These results go along with strong trends from Study 2 on patients with AD. There were nearly twice as many patients with emotional decline in the placebo group compared to the PS+PA supplementation group, with higher rates of improvement in the PS+PA group. Dementia and mood are highly related, and sometimes dementia is accompanied by depression, thus the effects of PS on mood may be indirect effects due to the positive impact on cognition and memory.

Altogether our results suggest that PS+PA can support memory and cognitive function, which is especially apparent in those who have developed cognition deficiencies. Further investigations should assess a larger sample for a longer duration, so that the full and prolonged effects of PS+PA on cognition, memory, daily functioning, and mood in elderly and patients with dementia can be more thoroughly determined.