Great info. From attending the MPI Cognition physician training, I know that Dr. Bredesen wants his patients’s calcium levels closer to the bottom of the reference range.
FWIW, I fell down the ApoE4/Calcium dysregulation rabbit hole a few months ago after reading the paper below. It may be especially important for our population to pay attention to this. ApoE4 upregulates the activity of mitochondria-associated ER membranes.http://www.ncbi.nlm.nih.gov/m/pubmed/26 ... from=apoe4
In addition to the appearance of senile plaques and neurofibrillary tangles, Alzheimer's disease (AD) is characterized by aberrant lipid metabolism and early mitochondrial dysfunction. We recently showed that there was increased functionality of mitochondria-associated endoplasmic reticulum (ER) membranes (MAM), a subdomain of the ER involved in lipid and cholesterol homeostasis, in presenilin-deficient cells and in fibroblasts from familial and sporadic AD patients. Individuals carrying the ε4 allele of apolipoprotein E (ApoE4) are at increased risk for developing AD compared to those carrying ApoE3. While the reason for this increased risk is unknown, we hypothesized that it might be associated with elevated MAM function. Using an astrocyte-conditioned media (ACM) model, we now show that ER-mitochondrial communication and MAM function-as measured by the synthesis of phospholipids and of cholesteryl esters, respectively-are increased significantly in cells treated with ApoE4-containing ACM as compared to those treated with ApoE3-containing ACM. Notably, this effect was seen with lipoprotein-enriched preparations, but not with lipid-free ApoE protein. These data are consistent with a role of upregulated MAM function in the pathogenesis of AD and may help explain, in part, the contribution of ApoE4 as a risk factor in the disease.
From my notes:
An exploration of mitochondria-associated ER membrane (MAM) function reveals that calcium is an integral part of this bioenergetic signaling process involving mitochondria. APOE dose-dependently increases intracellular free calcium: E4>E3>E2. APOE-ε4 homozygotes have the MOST intracellular calcium followed by heterozygotes, etc. Mitochondria, the batteries in our cells, don't like too much calcium. Excess intracellular calcium leads to cellular death which may underlie ε4 carriers inherent mitochondrial dysfunction.
Recent studies indicate that impaired contact between MAM and mitochondria might underlie the pathology of several human neurodegenerative diseases, including Alzheimer's disease. Moreover, MAM has been implicated in modulating glucose homeostasis and insulin resistance, as well as in some viral infections.
Magnesium, of course, is the antagonist of calcium. Magnesium deficiency implies an inherent Mg/Ca imbalance. Exploring this lead me to the calcium hypothesis of Alzheimer's disease.
I still have lots more to explore here, but suspect that it might be especially important for ε4 carriers to avoid a magnesium deficiency and we may indeed benefit by maintaining higher levels.