High-Fat Diet Could Interrupt Amyloid Clearance



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Date Posted : 2013-06-25


Results of a small pilot study suggest that diet can moderate factors involved in clearing amyloid, the toxic protein linked to the development of Alzheimer's disease (AD), from the brain.

The new proof of concept study showed that a diet high in saturated fat and with a high glycemic index for carbohydrates increases levels of cerebrospinal fluid unbound Aβ, while a healthier diet decreases these fractions.

The breakdown of the process to clear amyloid from the brain is likely a key factor leading to the most common form of AD, according to study author Suzanne Craft, PhD, professor, medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina. The process involves amyloid binding to apolipoprotein E (ApoE); if amyloid is unbound to ApoE or "free," it begins to build up and form toxic clusters called oligomers, she said. This unbound amyloid is referred to as lipoprotein depleted (LD).

"Our study showed that diet affected levels of this lipoprotein depleted amyloid, and that the high saturated fat, high sugar, diet increased levels and the low saturated fat, low sugar, diet reduced levels," said Dr. Craft.

Dr. Suzanne Craft

ApoE is coded for by the APOE gene and, like the gene, comes in 3 forms: ApoE2, which is associated with decreased risk of AD; ApoE3, which is the most common form and is not known to affect AD risk; and ApoE4, which is associated with increased AD risk.

The study was published online June 17 in JAMA Neurology.

Healthy Participants

The study included 27 cognitively normal participants and 20 with amnestic mild cognitive impairment (MCI). Investigators screened out persons with cardiovascular disease, those with high cholesterol levels, and those taking statins, leaving a "super healthy" cohort, said Dr. Craft.

These participants were randomly assigned to 1 of 2 extreme diets:

  • High diet: This diet had a very high glycemic index (greater than 70) and was high in fat. It provided 45% energy from total fat (25% from saturated fat), 35% to 40% from carbohydrates, and 15% to 20% from protein. Typical fare for these participants might include cheeseburgers, soda, and fries.

  • Low diet: Participants in this group ate food with a very low glycemic index (less than 55) and low in fat. This diet consisted of 25% energy from fat (less than 7% from saturated fat), 55% to 60% from carbohydrates, and 15% to 20% from protein. Such a diet might include foods such as poached fish, brown rice, and steamed vegetables.

The diets were equivalent in terms of calories and, because experts meticulously calculated the caloric needs of individual participants, all patients maintained their body weight throughout the 4-week study. Adherence to their diet was excellent for both groups.

After taking blood samples and performing lumbar punctures on each patient at baseline and at the end of the study, researchers measured total levels of ApoE, Aβ 40, Aβ 42 (the 2 forms of Aβ), and insulin, as well as LD fractions containing LD ApoE, Aβ 40, and Aβ 42.

At baseline, the researchers found that those with MCI had a greater fraction of their Aβ in the LD state than the cognitively normal participants and that those carrying the genetic risk factor APOE E4 had a greater fraction than did noncarriers. LD ApoE levels did not differ across diagnostic groups but were higher in the APOE E4 carriers than in noncarriers within each diagnostic group.

Striking Aspect

"One of the striking aspects of the study was that even at baseline, before the diet intervention, we saw that having the risk-increasing allele (E4) was associated with higher levels of the lipoprotein depleted amyloid," said Dr. Craft.

At the end of the study, there were nonsignificant changes in LD Aβ 40 in patients with MCI and those with MCI who were also E4 carriers. However, for LD Aβ 42, there were significant increases in the high diet and significant decreases in the low diet.

This seems to conform with what is known already — that amyloid plaques contain relatively more Aβ 42 compared with Aβ 40, said Dr. Craft.

Diet did not appear to affect LD ApoE in E4 carriers. "Our thought was that with these subjects, this pathology is already in play," explained Dr. Craft. "They already have poorly lipidated ApoE, and that may be pushing them along the pathway to AD. A month of a diet is not potentially going to override that already existing pathology."

The diet, she added, may be mimicking E4. "You could have the high risk by virtue of having the E4 allele, which is associated with bad ApoE protein if you will, or more poorly lipidated protein, and higher lipoprotein depleted amyloid, or, if you don’t have the E4 and you have a bad diet, you may produce the same pathology."

The study showed that the changes in AD-related molecules were inversely correlated with changes in cerebrospinal fluid insulin. In the normal brain, insulin plays an important role in maintaining synapses and memory, but with insulin resistance, high levels of insulin in the blood result in downregulation of insulin transport and a deficiency of insulin in the brain.

"Here, we found that those in the high diet group had lowered insulin in their spinal fluid, and the ones who had it lowered the most were most likely to have the abnormal lipidation of the ApoE and higher levels of the lipoprotein depleted amyloid," said Dr. Craft.

The study results should emphasize the importance of diet in protecting the brain. Until now, said Dr. Craft, the importance of brain health has been "grossly underestimated."

The research also represents an "important step forward" and beyond previous research. "Epidemiological studies are very important for showing us associations, but we've actually intervened and done an experiment where we’ve induced this negative diet and showed a change from baseline in these very important AD-related pathological parameters," said Dr. Craft.

Nevertheless, it's perhaps too early to have a huge impact on clinical practice, she added. "The body of evidence is getting more convincing; the epidemiology is now coming out with a convergent picture of these dietary patterns, the animal literature is coming out with a similar picture, and then studies such as ours are consistent with this. So I think there’s a consistency that physicians could rely on to make recommendations; whether or not it's a prescriptive type of recommendation, I think we're a ways away from that."

One of the complications is that some people whose brains are no longer able to use glucose normally may rely on other sources of energy, such as fat. "It's too early for a one-size-fits-all recommendation," said Dr. Craft. "It might be that the people who are not using glucose need a higher fat diet, and there might be other people who are using glucose and need a lower-fat diet. This is a critical area of study and we need to better understand what these mechanisms are."

Along with her colleagues, she is now looking at how diet affects changes in glucose utilization and blood flow, as well as other biochemical variables.

Small Piece of Causal Chain

Elaborating on comments she made in an accompanying editorial, Deborah Blacker, MD, professor, psychology and epidemiology, Harvard School of Public Health, and director, Gerontology Research Unit, Massachusetts General Hospital, Boston, told Medscape Medical News that the study adds a piece, albeit a small one, to the causal chain that extends from diet to cognitive outcome.

"This is one little piece that adds to the plausibility that these dietary factors might make a difference and that they might make a difference specifically on AD pathology."

Dr. Blacker agreed that the study will not significantly change clinical practice. "Going from showing that something about AD biology seems to move in response to a dietary change in a 4-week period, to changing clinical practice, is a very large leap."

Still, the results are "noteworthy," she said. The study is interesting from a mechanistic point of view, and it adds credibility to the theory that diet affects the brain; in addition, it seems to imply that dietary factors may directly affect AD rather than having an indirect or "add-on" effect through cardiovascular disease.

"That’s not a trivial thing; it’s really quite amazing that they showed that, but exactly what it means will take a long time to sort out."

Dr. Craft and Dr. Blacker have disclosed no relevant financial relationships.

JAMA Neurol. Published online June 17, 2013. Abstract Editorial

:sited from
High-Fat Diet Could Interrupt Amyloid Clearance
   Pauline Anderson, Jun 18, 2013


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