Alzheimer's

Much attention has been given to develop AD treatments based on the amyloid cascade hypothesis; however, none of these drugs had good efficacy at improving cognitive functions in AD patients suggesting that Aβ might not be the disease origin.[2] An increasing body of evidence suggests that age-related dysregulation of neuronal Ca2+ homeostasis may play a proximal role in the pathogenesis of AD as disrupted Ca2+ could induce synaptic deficits and promote the accumulation of Aβ plaques and neurofibrillary tangles.[2]

Increasing numbers of studies suggested that disruption of intracellular Ca2+ homeostasis, especially the abnormal and excessive Ca2+ release from the endoplasmic reticulum (ER) via the ryanodine receptor (RYR), plays important roles in orchestrating the dynamic of the neuropathology of AD and associated memory loss, cognitive dysfunction.[4]

Dyshomeostasis of Ca2+ plays an important role in modulating the pathogenesis of AD by influencing the production and aggregation of Aβ peptides and tau protein phosphorylation and the ways that disrupting the metabolic balance of Ca2+ can affect the learning ability and memory of people with AD[2]

The blood brain barrier is an important factor in Alzheimer's. Loss of some, or most, of blood brain barrier properties during neurological diseases including stroke, multiple sclerosis (MS), brain traumas, and neurodegenerative disorders, is a major component of the pathology and progression of these diseases (Zlokovic 2008; Daneman 2012).[1]

Instances have been seen where only certain regions of the blood brain barrier were found defective, cerebellum, spinal cord, olfactory bulb but not the cortex, striatum, or hypothalamus. [1]

In Alzheimer's, cerebral blood flow is reduced. Amyloid β is transported from the blood to the brain by the receptor for advanced glycation endproducts (RAGE), which is expressed on BBB-ECs. Conversely, both soluble LRP and ApoE are cell-surface Aβ chaperones that associate with clearance receptors and promote extrusion of Aβ from the brain back into the blood through the BBB. In AD, these clearance pathways seem to be altered, which is hypothesized to lead to accumulation of soluble Aβ in the perivascular space and the formation of toxic oligomeric Aβ.[1]

Patients with AD have also been reported to have focal vascular defects in the CNS, such as vascular “regression,” reduced capillary density, accumulation of collagen, perlecan in the basal lamina, reduced mitochondrial content, and loss of TJ and AJ proteins.[1]

Cognitive stimulating therapy improves the memory functions with the same efficacy as galantamine or tacrine1.[5] Spatial training increases the expression of GluA1, PSD93 and PSD95 with a significant upregulation of phosphorylated CaMKII, and decreases the levels of Aβ and tau phosphorylation.[5]

Vitamin K2 is also involved in the synthesis of sphingolipids, an important class of lipids present in high concentrations in brain cell membranes. Initially appreciated for their role as essential structural components of cell membranes, sphingolipids are now known to participate in important cellular events such as signaling, proliferation, differentiation, senescence, transformation and survival of brain cells. In recent years, studies have linked alterations in sphingolipid metabolism to age-related cognitive decline and neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases.10-12[6]

A randomized, double blind, placebo controlled study showed that daily supplementation of 800 μg of oral folic acid for 3 years increased serum folate concentrations, reduced total homocysteine level in plasma, and improved cognitive function. This finding suggests a close association between folic acid and homocysteine and cognitive function (32). Elevated homocysteine may increase risk of Alzheimer’s disease through its deleterious role in endothelial vascular pathogenesis as well as its direct neurotoxic effects. It potentiates the neurotoxicity of β-amyloid, enhances glutamate excitotoxicity, overstimulates N-methyl-D-aspartate (NMDA) receptors, and causes calcium influx into the neurons (5). Furthermore, a high homocysteine concentration as well as folate deficiency may decrease glutathione peroxidase activity and reduce tissue concentrations of antioxidant vitamins, making neurons more vulnerable to oxidative stress (5). In some cross-sectional studies, it was suggested that low serum folate and elevated plasma homocysteine concentrations decline cognition (12, 33). A review by Mattson and Shea described how folic acid and homocysteine were implicated in several neurological diseases. They cited evidence that folic acid might be important for DNA repair in post mitotic neurons. Furthermore, they stated [t]hat homocysteine may induce damage in DNA of mature neurons, contributing to their damage and death. Possible explanations include increased intracellular calcium. Homocysteine may potentiate glutamate toxicity as well. Any or all of these factors might trigger apoptosis (8, 16).[7]

The role of iron in the progression of Alzheimer's has also been investigated, particularly iron dyshomeostasis and ferroptosis (iron-induced apoptosis).[8]

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292164/

[2] https://pubmed.ncbi.nlm.nih.gov/30059692/

[3] https://pubmed.ncbi.nlm.nih.gov/34072743/

[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713908/

[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4377552/

[6] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483258/

[7] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646228/

[8] https://www.mdpi.com/1424-8247/12/2/93

https://pubmed.ncbi.nlm.nih.gov/27233830/

SAMe:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210123/

https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1471-4159.1996.67031328.x

https://pubmed.ncbi.nlm.nih.gov/20573497/

Food:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374314/#B48

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393525/

Calcium:

https://www.cell.com/cell-reports/pdf/S2211-1247(17)31423-7.pdf