The "LEARn" (Latent Early-life Associated Regulation) model integrates environmental risk factors and the developmental basis of Alzheimer's disease, and proposes remedial steps

Abstract

The neurodegenerative disorder Alzheimer's disease (AD) is the 6th leading cause of death in the USA. In addition to neurological and psychiatric symptoms, AD is characterized by deficiencies in S-adenylmethionine (SAM), vitamin B12, and folate. Deficiency in these nutrients has been shown to result in gene promoter methylation with upregulation of AD-associated genes. While some cases of AD are due to specific mutations in genes such as presenilin 1 (PSEN) and the amyloid-beta peptide precursor protein (APP), these familial AD (FAD) cases account for a minority of cases. The majority of genetic contribution consists of risk factors with incomplete penetrance. Several environmental risk factors, such as cholesterol and diet, head trauma, and reduced levels of exercise, have also been determined for AD. Nevertheless, the majority of risk for AD appears to be established early in life. We propose to explain this via the LEARn (Latent Early-life Associated Regulation) model. LEARn-AD (LAD) would be a "two-hit" disorder, wherein the first hit would occur due to environmental stress within the regulatory sequences of AD-associated genes, maintained by epigenetic changes such as in DNA methylation. This hit would most likely come in early childhood. The second hit could consist of further stress, such as head trauma, poor mid-life diet, or even general changes in expression of genes that occur later in life independent of any pathogenesis. Given that the primary risk for LAD would be maintained by DNA (hypo)methylation, we propose that long-term nutritional remediation based on the LEARn model, or LEARn-based nutritional gain (LEARnING), beginning early in life, would significantly reduce risk for AD late in life.

Fig. 1. Pathways to AD, FAD, SAD, LAD

Three pathways are posited that can lead to pathogenic conditions such as AD. In the familial AD (FAD) pathway, genotype results directly in AD. This pathway explains a minority of AD cases. In the sporadic (SAD) pathway, genotype or somatic genotype have minimal input (excluding cases of FAD), and it is direct, non–latent response to environmental insults (such as metal toxicity or head trauma) that lead to AD. In the LEARn AD (LAD) pathway, environment induces epigenetic marker shifts in critical gene sequences, resulting in potentially pathogenic, but latent, somatic epitype(s). These somatic epitypes would undergo “second hit” environmental effects that result in disease.

Fig. 2. The HCY/SAM cycle

B) Dietary folate and B12 facilitate the conversion of HCY to methionine, which is then converted to SAM. SAM can also be directly supplemented. SAM provides methyl groups for transfer to DNA by DNA methylases and is converted to S–adenosylhomocysteine in the process. Low levels of HCY drive conversion of S–adenosylhomocysteine to HCY, which is then reconverted to methionine. A) Pathogenic (reverse) pathway. Lack of folate and B12 permit accumulation of homocysteine (HCY), which is converted to S–adenosylhomocysteine. High levels of S–adenosylhomocysteine block transfer of methyl groups from S–adenylmethionine (SAM) to DNA or other substrates.

Fig. 3. Deregulation of BACE1 promoter from B12/folate deficiency

Under nutrient–deficient conditions, the HCY/SAM cycle runs in “reverse”, resulting in reduced DNA methylation efficiency. Lack of methylation of critical CpG dinucleotides prevents binding of methyl–DNA binding proteins (MDBP) and permits binding of transcription factors such as SP1. SP1 binding drives increased gene expression, which ultimately results in elevated amyloidogenesis.

Fig. 4. Regulation of BACE1 promoter following B12/folate or SAM supplementation

Methylation deficiency can be remediated by dietary supplementation with B12, folate, and/or SAM. This would drive the HCY/SAM cycle “forwards” and provide more abundant methyl groups for transfer to substrates such as CpG dinucleotides. Methylated CpG would permit binding of MDBP, which would inhibit binding of SP1. Inhibition of SP1 binding would regulate gene expression and reduce levels of BACE1 and amyloidogenesis.