Targeting prodromal Alzheimer's disease: too late for prevention?
Authors: Hussein N Yassine
Journal: The Lancet Neurology (2017)

Prodromal Alzheimer's disease is a novel area of research, with clinical research definitions still under development. The LipiDiDiet trial,1Soininen H Solomon A Visser PJ et al.24-month intervention with a specific multinutrient in people with prodromal Alzheimer's disease (LipiDiDiet): a randomised, double-blind, controlled trial.Lancet Neurol. 2017; (published online Oct 30.)http://dx.doi.org/10.1016/S1474-4422(17)30332-0Summary Full Text Full Text PDF PubMed Scopus (134) Google Scholar published in The Lancet Neurology, was one of the first completed trials based on the International Working Group (IWG-1) criteria for prodromal Alzheimer's disease.2Dubois B Feldman HH Jacova C et al.Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria.Lancet Neurol. 2007; 6: 734-746Summary Full Text Full Text PDF PubMed Scopus (3330) Google Scholar The study was a non-pharmacological intervention (medical food Souvenaid) in prodromal Alzheimer's disease. Fortasyn Connect, the active component of Souvenaid, was developed based on the premise that a specific combination of nutrients enhances synaptic functions.3Wurtman RJ Ulus IH Cansev M Watkins CJ Wang L Marzloff G Synaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally.Brain Res. 2006; 1088: 83-92Crossref PubMed Scopus (135) Google Scholar Fortasyn Connect consists predominantly of omega 3 (1500 mg per day of docosahexaenoic acid and eicosapentaenoic acid), phospholipids, choline, high doses of vitamin B (B12, B6, and folic acid), vitamin E, vitamin C, selenium, and uridine monophosphate. Souvenaid is a marketed product of Nutricia and is taken as a once-a-day drink with breakfast. Three Fortasyn Connect trials have been done in patients with mild-to-moderate Alzheimer's disease. In Souvenir I,4Scheltens P Kamphuis PJ Verhey FR et al.Efficacy of a medical food in mild Alzheimer's disease: a randomized, controlled trial.Alzheimers Dement. 2010; 6: 1-10.e1Summary Full Text Full Text PDF PubMed Scopus (222) Google Scholar 225 drug-naive patients with mild Alzheimer's disease participated in a randomised, double-blind, controlled trial of Fortasyn Connect versus placebo for 12 weeks. There was a significant improvement in one of the coprimary outcomes (delayed verbal recall task), but not in the 13-item modified Alzheimer's Disease Assessment Scale cognitive subscale or other cognitive outcomes.4Scheltens P Kamphuis PJ Verhey FR et al.Efficacy of a medical food in mild Alzheimer's disease: a randomized, controlled trial.Alzheimers Dement. 2010; 6: 1-10.e1Summary Full Text Full Text PDF PubMed Scopus (222) Google Scholar The Souvenir II study5Scheltens P Twisk JW Blesa R et al.Efficacy of Souvenaid in mild Alzheimer's disease: results from a randomized, controlled trial.J Alzheimers Dis. 2012; 31: 225-236Crossref PubMed Scopus (219) Google Scholar was a 24-week, randomised, double-blind, controlled trial in 259 drug-naive patients with mild Alzheimer's disease. The primary outcome, neuropsychological test battery (NTB) memory domain Z score, was significantly improved in the active compared with the control group, but the composite NTB total composite Z score was not significantly different.5Scheltens P Twisk JW Blesa R et al.Efficacy of Souvenaid in mild Alzheimer's disease: results from a randomized, controlled trial.J Alzheimers Dis. 2012; 31: 225-236Crossref PubMed Scopus (219) Google Scholar In the S-connect study,6Shah RC Kamphuis PJ Leurgans S et al.The S-Connect study: results from a randomized, controlled trial of Souvenaid in mild-to-moderate Alzheimer's disease.Alzheimers Res Ther. 2013; 5: 59Crossref PubMed Scopus (87) Google Scholar add-on intake of Fortasyn Connect for 24 weeks did not slow cognitive decline in 527 people with mild-to-moderate Alzheimer's disease. In LipiDiDiet,1Soininen H Solomon A Visser PJ et al.24-month intervention with a specific multinutrient in people with prodromal Alzheimer's disease (LipiDiDiet): a randomised, double-blind, controlled trial.Lancet Neurol. 2017; (published online Oct 30.)http://dx.doi.org/10.1016/S1474-4422(17)30332-0Summary Full Text Full Text PDF PubMed Scopus (134) Google Scholar 311 people with prodromal Alzheimer's disease were randomly assigned to Fortasyn Connect or a control isocaloric drink for 24 months. The primary outcome was the change in the NTB composite score. Secondary outcomes included NTB Z scores, progression to Alzheimer's disease dementia, clinical dementia rating sum of boxes (CDR-SB), and atrophy rates on MRI. No statistically significant differences were observed between the active and control groups for the primary outcome or four of the secondary outcomes. Two of the secondary outcomes suggested that Fortasyn Connect had a beneficial response: there was less worsening in CDR-SB in the active group (mean change of 0·56 [SD 1·32]) than in the control group (1·12 [1·72]) with an effect size of 0·33 (p=0·005), and supplementation with Fortasyn Connect slowed hippocampal atrophy rate with an effect size of 0·22 (p=0·005). However, 59 (37%) participants in the control group and 62 (41%) in the active group were diagnosed with dementia during the trial. Several important lessons can be learned from the LipiDiDiet trial. First, LipiDiDiet, together with past trials, does not provide sufficient evidence for the use of Fortasyn Connect in mild or prodromal Alzheimer's disease. The suggestion of benefit in two of the secondary outcomes is encouraging, but needs to be confirmed in further research. Second, most of the participants who were screened were included in the trial, which was attributed to participants primarily coming from memory clinic populations with recent detailed assessments. Although this approach enhanced the selection of this group of individuals, it limits the external validity of this study outside of specialised memory clinics. Third, baseline memory scores were very similar to mild Alzheimer's disease, with a higher-than-expected conversion rate to Alzheimer's disease during the trial. Despite this extent of impairment, changes in the primary outcome were not significant. This result indicates the limitations and challenges of constructing composite outcomes in the absence of validated data relevant to the population studied. Fourth, the intervention appears to be targeting the disease at a late stage. A preplanned analysis in LipiDiDiet suggested that better baseline cognitive function (Mini-Mental State Examination score ≥26) was associated with a better drug placebo response in CDR-SB, hippocampal volume, and the primary endpoint in the per-protocol analysis. Prodromal Alzheimer's disease defined by the IWG-1 criteria2Dubois B Feldman HH Jacova C et al.Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria.Lancet Neurol. 2007; 6: 734-746Summary Full Text Full Text PDF PubMed Scopus (3330) Google Scholar requires evidence of neurodegeneration, such as medial temporal lobe atrophy, for inclusion into the study. As neurodegeneration progresses, the ability of preventive therapies to reverse progression to Alzheimer's disease is attenuated.7Yassine HN Braskie MN Mack WJ et al.Association of docosahexaenoic acid supplementation with Alzheimer disease stage in apolipoprotein E epsilon4 carriers: a review.JAMA Neurol. 2017; 74: 339-347Crossref PubMed Scopus (85) Google Scholar Identification of people at risk of Alzheimer's disease, but who have no evidence of significant neurodegeneration, is crucial to the success of preventive strategies. Sensitive and less invasive biomarkers are needed to correctly identify Alzheimer's disease at its earliest stages for long-term prevention interventions. HNY reports grants from the National Institute of Aging (R01AG055770, R01AG054434), and the Alzheimer's Association (NIRG-15–361854). 24-month intervention with a specific multinutrient in people with prodromal Alzheimer's disease (LipiDiDiet): a randomised, double-blind, controlled trialThe intervention had no significant effect on the NTB primary endpoint over 2 years in prodromal Alzheimer's disease. However, cognitive decline in this population was much lower than expected, rendering the primary endpoint inadequately powered. Group differences on secondary endpoints of disease progression measuring cognition and function and hippocampal atrophy were observed. Further study of nutritional approaches with larger sample sizes, longer duration, or a primary endpoint more sensitive in this pre-dementia population, is needed. Full-Text PDF Open AccessAlzheimer's disease: evolution of research diagnostic criteriaThe diagnosis of Alzheimer's disease in research settings has evolved rapidly over the past decade, with both the International Working Group (IWG) and the US National Institute on Aging and Alzheimer's Association (NIA-AA) contributing to endeavours to integrate biomarkers into research diagnostic criteria. These efforts have been important to distinguish the range of disease stages, from asymptomatic to severe dementia. The NIA-AA work group is now proposing a draft research framework that builds upon the 2011 NIA-AA and 2014 IWG criteria to include biomarkers more comprehensively than previously. Full-Text PDF