Can Metabolic Testing Distinguish Alzheimer's Subtypes?

Pauline Anderson

September 24, 2015

Metabolic testing sorts patients with Alzheimer's disease (AD) into three sub-categories — inflammatory, noninflammatory, and cortical — each with distinct pattern of metabolic disturbance and cognitive impairment, a new study suggests.

"We're saying that what you call Alzheimer disease is really the result of metabolic imbalances," said the paper's author, Dale E. Bredesen, MD, professor, neurology, University of California at Los Angeles, and founding president and CEO, Buck Institute for Research on Aging. "We describe three different metabolic conditions, all labeled Alzheimer disease."

The third subtype, in which patients have a cortical rather than subcortical presentation, with non-amnestic features, and often very low serum zinc levels, is fundamentally different from the other two types and deserves further attention, said Dr Bredesen.

Dr Dale E. Bredesen

But others caution that the concept that metabolic testing can differentiate subtypes of AD is, at this point, only a hypothesis.

The new report was published in the August issue of Aging.

Dr Bredesen said that doctors don't typically do an extensive metabolic workup because they believe AD is primarily a neurodegenerative disorder. "The standard has been to wait as long as possible because people believe nothing can be done," he told Medscape Medical News.

"We believe it should be the opposite: that people should be checking as early as possible, just like you would get your cardiovascular risk factors checked." He would advocate that patients over age 40 years should have metabolic testing.

Metabolic Enhancement

Dr Bredesen has already reported that a personalized program called MEND (metabolic enhancement for neurodegeneration) that is aimed at correcting conditions such as hormone imbalance, zinc and vitamin deficiency, and impaired insulin resistance, as well as addressing stress and sleep issues, can reverse cognitive decline (Aging. 2014;6:707-717).

In this new paper, he used case studies to illustrate three subtypes of AD. Under the inflammatory category, he said patients typically have markers of systemic inflammation such as high C-reactive protein (CRP) and interleukin-6. "The pathology of AD includes inflammatory microglia and activated astroglia and many but not all patients with AD show evidence of systemic inflammation as well," he writes.

Patients in this category present with amnestic symptoms that are backed up by imaging studies showing hippocampal atrophy, he said.

Patients with noninflammatory AD are often slightly older than those in the first category and may have the apolipoprotein E ε4 (APOE4) risk allele, said Dr Bredesen. As with the first subtype, patients in this category tend to present with amnestic syndrome, with tests showing temporal-parietal reductions in glucose utilization.

For this group, Dr Bredesen described alternative associations to inflammation, including insulin resistance, hypovitaminosis D, hyperhomocysteinemia, and hormonal loss associated with early oophorectomy. For each of these, there are theoretical mechanisms to support contributions to AD pathogenesis.

"Homocysteine, for example, has been shown to exert multiple effects that may contribute to cognitive decline, such as increasing tau phosphorylation."

Cortical Category

In the third subcategory of AD, instead of losing the ability to form new memories at the initial presentation, patients have lost long-term memory maintenance, said Dr Bredesen.

He believes these patients represent a group that is distinct from the more typical amnestic presentation in several respects, including:

  • Early symptom onset, typically in the fifth decade;

  • Lack of family history;

  • APOE4-negative status in most cases;

  • Cortical atrophy on MRI (and in some cases cerebellar atrophy) rather than hippocampal atrophy; and

  • Reductions in glucose utilization beyond the typical temporal-parietal distribution shown with fludeoxyglucose positron emission tomography.

Dr Bredesen noted that unlike in the other categories, patients in this third group often have very low serum zinc levels. Zinc, he said, plays a role in several processes related to AD, including insulin resistance and inflammation.

"That's why we thought this is something to look at carefully; people haven't talked about zinc as a critical player in AD."

He also emphasized the cortical rather than subcortical presentation, and the nonrelationship with APOE4, among patients in this third group. "In fact, it may be that APOE4 is a protection against type 3, but we don't have enough numbers to know that yet."

Classification of AD into subtypes according to metabolic profiling may be useful for therapeutic trials, said Dr Bredesen.

No Strong Evidence

Approached for a comment, Keith Fargo, PhD, director of scientific programs & outreach, Alzheimer's Association, stressed that the idea that three distinct subtypes of Alzheimer's disease can be distinguished by metabolic testing is a hypothesis that has not yet been established by strong research.

The article, said Dr Fargo, is based on eight case studies, which is not enough to draw conclusions that are generalizable to medical practice.

"At this time, there is no reason for doctors to use this concept or change their current clinical practice," said Dr Fargo. "Doctors should continue to perform all appropriate assessments and tests to make sure they are aware of and treating any conditions and/or deficiencies their patients may be experiencing." 

Asked whether zinc deficiency might be a factor in AD, Dr Fargo said this is not firmly established because some studies have suggested it may play some role while others indicate that it does not.

He cited the large Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL), which investigated the biomarkers, cognitive characteristics, and health and lifestyle factors that determine subsequent development of symptomatic AD. The study showed that serum zinc decreased with age in general but was not associated with whether a person had normal cognition, mild cognitive impairment, or AD.

"The idea that zinc may play a role in Dr Bredesen's proposed cortical subtype cannot be ruled out by the AIBL study, but nonetheless should be thought of as very provisional at this point."

Dr Bredesen has disclosed no relevant financial relationship. The Alzheimer's Association has funded Dr Bredesen in the past but did not fund the current study.

Aging. 2015;7:595-600. Abstract


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