Johnson LA1, Torres ER1, Impey S2,3, Stevens JF4,5, Raber J1,6.
Author information
Abstract
Apolipoprotein E4 (E4) and type 2 diabetes are major risk factors for cognitive decline and late onset Alzheimer's disease (AD). E4-associated phenotypes and insulin resistance (IR) share several features and appear to interact in driving cognitive dysfunction. However, shared mechanisms that could explain their overlapping pathophysiology have yet to be found. We hypothesized that, compared to E3 mice, E4 mice would be more susceptible to the harmful cognitive effects of high fat diet (HFD)-induced IR due to apoE isoform-specific differences in brain metabolism. While both E3 and E4 mice fed HFD displayed impairments in peripheral metabolism and cognition, deficits in hippocampal-dependent spatial learning and memory were exaggerated in E4 mice. Combining genome-wide measures of DNA hydroxymethylation with comprehensive untargeted metabolomics, we identified novel alterations in purine metabolism, glutamate metabolism, and the pentose phosphate pathway. Finally, in E4 mice, the metabolic and cognitive deficiencies caused by HFD were rescued by switching to a low fat diet for one month, suggesting a functional role was associated with reversal of the same metabolic pathways described above. These results suggest a susceptibility of E4 carriers to metabolic impairments brought on by IR, and may guide development of novel therapies for cognitive decline and dementia.
http://www.alzforum.org/news/research-n ... ve-decline
Hi all,
I haven't posted for a while but this Alzforum article came across my radar today. The salient points for me in this study are how many pathways are altered with APOE4. In addition the good news is after 1 month of returning to a low fat diet the mice recouped their losses and returned to baseline. THis echoes the research done by Dr. Bredesen in us humans, showing that even if one strays off of the brain protocol diet, it isn't necessarily "the end" for all neurons, but a warning sign that can be reversed. This also reflects my personal experience with the high fat which I was using more last year. At that time, I was using pretty generous with the coconut oil and nut butters and my numbers showed it. My LDL-P was 1753 now @ 1150 and LDL-C was @161 now 124, and my weight was up +10-15 lbs heavier.
The more I learn about the APOE4 gene the more I am aware of it's far reaching health implications and why every one should be tested for this SNP.
I have been far too busy lately to write too often, but I really appreciate this site so very much . I am referring many clients here since I am testing for APOE4 in my work as a psychiatrist, using a panel designed by Boston Heart Diagnositics that is covered by most health insurances, unfortunately tho not Med-i-cal.
I look forward to our meet up at the FMI Dynamic Brain Conference in June.
Here are a few quotes from the study I found interesting:
The authors analyzed hippocampal epigenetic and metabolomic changes in the mice, looking for pathways most altered in E4s eating the high-fat diet. They found thousands of methylated DNA regions that were unique to the overfed E4s, and were predicted to affect genes involved in numerous cellular processes. Among metabolites, 58 were altered by ApoE genotype and diet, falling into several pathways. In the combined epigenetic/metabolomic dataset, three pathways stood out: purine metabolism, glutamate metabolism, and the pentose phosphate pathway (see image above). All of these processes relate to energy metabolism.
The purine adenosine forms the basis of the energy source ATP. Purine metabolism has previously been reported to go awry in AD (see Sims et al., 1998; Ansoleaga et al., 2015). Purine biosynthesis also produces glutamate as a byproduct. This neurotransmitter links neuronal activity to glucose use, and is found in short supply in ApoE4 mice (see Dumanis et al., 2013). The pentose phosphate pathway (PPP), an alternative to glycolysis, metabolizes sugars to generate five-carbon precursors for various synthesis reactions, including purines. The PPP also helps lower oxidative stress, and is impaired in AD brains (see Palmer et al., 1999; Orešič et al., 2011). However, the mechanisms that connect ApoE4 to any of these processes remain unclear.
The authors wondered whether the harmful changes in memory and metabolism were reversible. They fed a separate group of nine-month-old ApoE4 mice a high-fat diet for five months, followed by a low-fat diet for one. Upon changing diets, the portly mice lost weight and could better metabolize sugar. In cognitive tests, the slimmed-down mice performed like normal controls. Epigenetic markers and metabolites also returned to normal.
