Precision Nutrition for Alzheimer’s Prevention in ApoE4 Carriers

Abstract

The ApoE4 allele is the most well-studied genetic risk factor for Alzheimer’s disease, a condition that is increasing in prevalence and remains without a cure. Precision nutrition targeting metabolic pathways altered by ApoE4 provides a tool for the potential prevention of disease. However, no long-term human studies have been conducted to determine effective nutritional protocols for the prevention of Alzheimer’s disease in ApoE4 carriers. This may be because relatively little is yet known about the precise mechanisms by which the genetic variant confers an increased risk of dementia. Fortunately, recent research is beginning to shine a spotlight on these mechanisms. These new data open up the opportunity for speculation as to how carriers might ameliorate risk through lifestyle and nutrition. Herein, we review recent discoveries about how ApoE4 differentially impacts microglia and inflammatory pathways, astrocytes and lipid metabolism, pericytes and blood–brain barrier integrity, and insulin resistance and glucose metabolism. We use these data as a basis to speculate a precision nutrition approach for ApoE4 carriers, including a low-glycemic index diet with a ketogenic option, specific Mediterranean-style food choices, and a panel of seven nutritional supplements. Where possible, we integrate basic scientific mechanisms with human observational studies to create a more complete and convincing rationale for this precision nutrition approach. Until recent research discoveries can be translated into long-term human studies, a mechanism-informed practical clinical approach may be useful for clinicians and patients with ApoE4 to adopt a lifestyle and nutrition plan geared towards Alzheimer’s risk reduction.

Efficacy and Safety of Ketone Supplementation or Ketogenic Diets for Alzheimer's Disease: A Mini Review

“…Both showed significant improvement after 6 weeks of KD in adults without dementia. The role of ApoE4 could mitigate the effect of ketone energy metabolism, given that ApoE4 differentially impacts insulin resistance, glucose metabolism and microglia ( 26 ). Yet, KD or MCT intake appeared to be more efficient in non- ApoE4 carriers ( 13 , 27 , 28 ).…”

A Review of ApoE4 Interference Targeting Mitophagy Molecular Pathways for Alzheimer's Disease

“…Other rising insights draw more and more interests broadly. The existing investigation of APOE ε4 pathogenesis in AD (Norwitz et al, 2021 ; Serrano-Pozo et al, 2021 ) has expanded beyond Aβ peptide-centric mechanisms to Tau neurofibrillary degeneration, neuroinflammation (Kaur et al, 2019 ; Leng and Edison, 2021 ), synaptic loss (Zhao et al, 2020 ), depression (Rhodes et al, 2021 ; Zhang et al, 2021 ), blood–brain barrier disruption (Rhea and Banks, 2021 ; Zhang and Xie, 2021 ), insulin resistance (Jabeen et al, 2021 ), gut dysfunction (Hoffman et al, 2019 ), oxidative stress (Butterfield and Mattson, 2020 ), and autophagic deficit (Chen et al, 2021 ; Sohn et al, 2021 ; Eran and Ronit, 2022 ); particularly, damaged mitophagy (Simonovitch et al, 2019 ; Schmukler et al, 2020 ; Liang et al, 2021a ; Morton et al, 2021 ; Wang et al, 2021b ). However, the precise molecular mechanisms underlying ApoE4 pathogenic effects during AD have not yet been elucidated.…”

Folate Related Pathway Gene Analysis Reveals a Novel Metabolic Variant Associated with Alzheimer’s Disease with a Change in Metabolic Profile

“…Surprisingly, we found a 70% association of APOE4, rather than the predicted 40%, with AD further reinforcing its high-risk factor status and also indicating potential direct involvement in the condition in the severe cases used in this study. Several recent studies highlight the role of ApoE in several critical processes, including involvement in amyloid plaque and neurofibrillary tangle formation, insulin resistance, decreased amyloid clearance, mitochondrial dysfunction, and autophagy [5,80]. Suggestions have been made for targeted drugs [80] and nutritional and lifestyle changes [5] aimed at ApoE4 processes and pathways to prevent or treat the disease.…”

“…By contrast, late-onset AD is multifactorial, with many genetic risk factors, including APOE4, the highest risk factor for AD, environmental, nutritional, metabolic, and lifestyle factors. No causative genes have been identified for late-onset AD, but non-coding genetic errors have been suggested [2], as well as heritable and non-heritable epigenetic changes, as potential disease onset mechanisms [3], some of which may be offset through nutrition and diet [4,5]. Metabolic disorders have recently been highlighted as a potential cause and target for AD, including insulin signalling dysfunction and brain glucose metabolic disturbances, the latter suggested as hallmarks of AD and underlie the proposition that AD should be regarded as type III diabetes, specifically affecting the brain.…”