Maintenance of Cognitive Performance and Mood for Individuals with Alzheimer’s Disease Following Consumption of a Nutraceutical Formulation: A One-Year,Open-Label Study

INTERVENTION

As in prior studies [6–10], NF consisted of 400μg folic acid, 6μg B12, 30 IU alpha-tocopherol, 400 mg SAM (200 mg active ion), 600 mg NAC, and 500 mg ALCAR, prepared by Nutricap Labs (Farmingdale, NY 11735) at USP grade under FDA-approved, cGMP conditions, with 2 tablets/daily dose. Participants received NF under open-label conditions for 12 months.

TRIAL REGISTRATION

This study was registered with ClinicalTrials.gov (NCT01320527) and the Alzheimer’s Association (alz.org/Trialmatch).

INCLUSION/EXCLUSION CRITERIA

Inclusion criteria were personal physician’s diagnosis (probable AD and/or senile dementia of the Alzheimer type) and approval to participate, ability to swallow pills, availability of a personal or professional caregiver, and signed consent from the participant or health-care proxy. Exclusion criteria were inability to swallow pills and known or suspected bipolar disorder (for which SAM is contraindicated) [11].

PARTICIPANT DEMOGRAPHICS

Individuals diagnosed with AD (n = 24; aged 78.4±5.7 years, 13.9±2.1 years education, baseline MMSE 19.6±6.0).

OUTCOME MEASURES

Primary outcome was defined as cognitive performance, ascertained by participant performance on Clox-1 and the Dementia Rating Scale [12, 13]. Secondary outcomes were defined as BPSD and daily function, ascertained by caregiver completion of the Neuropyschiatric Inventory (NPI) and the Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADL) [14, 15]. Tests were completed at baseline, and at 3-month intervals until 12 months. Primary analysis was Intention-To-Treat; all enrolled participants were included in analysis, subject to attrition. All instruments have established reliability and validity.

RANDOMIZATION AND MASKING

The protocol was approved by the New England IRB (Newton, MA) and by respective IRBs.

STUDY ENDPOINTS

Based on prior efficacy, the protocol specified that all participants would receive NF in an open-label extension for the duration of the 12-month study.

STATISTICAL ANALYSES

Data were independently analyzed by statisticians (CM and RP) not involved in data acquisition. Statistical methods included paired Student’s t tests (2-tailed) of individual participant performance versus baseline, unpaired 2-tailed t tests of NF and placebo cohorts, and Cohen’s effect size. Effect size was calculated for each respective cohort according to the formula: [(cohort mean at treatment time) - (cohort mean at baseline)]/standard deviation at baseline of the entire participant pool; p values <0.05 and effect sizes >0.2 were considered significant [16]. Participants/caregivers completing each test varies both among tests and sampling intervals; see figure legends.

Participants did not display any significant or clinical change in cognitive performance over the course of 12 months. Caregivers reported no significant or clinical change in BPSD or daily function over the course of 12 months (Fig. 1). No serious adverse events were reported for any participants.

In prior studies where participants diagnosed with AD received NF de novo, participants randomized to NF improved in cognitive performance and BPSD within 3–6 months, and either maintained that improvement or displayed continued improvement over 12 months. Participants initially randomized to placebo did not improve or declined; however, following crossover to NF, these participants demonstrated improvement or maintenance paralleling that of participants initially randomized to NF [6–10].

The present study included a cohort with AD that had already been consuming NF prior to initiation of monitoring of cognitive performance and BPSD. Unlike individuals receiving NF de novo, participants in the present study did not display a significant change in cognitive performance or BPSD over 12 months. The lack of an increase may be anticipated, since any increase they might have displayed could have occurred prior to enrollment in this study. Notably, however, they displayed no significant decrease in cognitive performance or BPSD over the course of 12 months, which contrasts with the routine decline observed for participants receiving a placebo for 12 months (Fig. 2) [8, 17–34]. It is recognized that this comparison is compromised since the participants in the present study were aware that they were receiving NF, while randomized participants did not share the same certainty.

These findings extend prior studies on the efficacy of NF in multiple studies from 2008 to 2015 [6–10]. A limitation of our analyses is that participants were not fully categorized according to prior or concurrent supplement/vitamin consumption or general nutritional intake. It is noteworthy that sustained cognitive and behavioral performance was maintained herein despite these caveats. The efficacy of NF may be maximized when combined with the so-called “Mediterranean diet,” which has beneficial effects [35] and other lifestyle modifications [4]. Maintenance of acetylcholine levels by NF components in murine models of AD neuropathology [36] holds the possibility that NF may augment acetylcholinesterase therapy. In this regard, administration of a combination of supplements may be essential to augment pharmacological approaches. Consistent with this possibility, a different antioxidant formulation provided significant improvement in cognitive function when administered in combination with donepezil versus donepezil alone [37]. In addition to providing benefit for cognitive performance, NF maintained and activities of daily living for as long as 28 months (the longest period tested thus far) [6], supporting the notion that nutritional approaches can positively impact the quality of life for individuals with AD.