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Researchers Identify Three Distinct Subtypes of Alzheimer’s Disease

Finding could mean that each variation would need to be treated differently.

Alzheimer’s disease, long thought to be a single disease, really consists of three distinct subtypes, according to a UCLA study. The finding could lead to more highly targeted research and, eventually, new treatments for the debilitating neurological disorder, which robs people of their memories.

The study further found that one of the three variations, the cortical subtype, appears to be fundamentally a different condition than the other two, said Dr. Dale Bredesen, the study’s author, a UCLA professor of neurology and member of the Easton Laboratory for Neurodegenerative Disease Research.

“Because the presentation varies from person to person, there has been suspicion for years that Alzheimer’s represents more than one illness,” said Bredesen, who also is the founding president of the Buck Institute for Research on Aging. “When laboratory tests go beyond the usual tests, we find these three distinct subtypes.

“The important implications of this are that the optimal treatment may be different for each group, there may be different causes, and, for future clinical trials, it may be helpful to study specific groups separately.”

The subtypes are:

  • Inflammatory, in which markers such as C-reactive protein and serum albumin to globulin ratios are increased.
  • Non-inflammatory, in which these markers are not increased but other metabolic abnormalities are present.
  • Cortical, which affects relatively young individuals and appears more widely distributed across the brain than the other subtypes of Alzheimer’s. It typically does not seem to cause memory loss at first, but people with this subtype of the disease tend to lose language skills. It is often misdiagnosed, typically affects people who do not have an Alzheimer’s-related gene and is associated with a significant zinc deficiency.

The findings of the two-year study, which involved metabolic testing of 50 people, appear in the current issue of the peer-reviewed journal Aging.

No effective therapy for Alzheimer’s exists. And scientists have yet to completely identify the cause, although multiple studies have pointed to metabolic abnormalities such as insulin resistance, hormonal deficiencies and hyperhomocysteinemia, a condition characterized by an abnormally high level of an amino acid in the blood.

In a 2014 paper, Bredesen showed that making lifestyle, exercise and diet changes designed to improve the body’s metabolism reversed cognitive decline in nine out of 10 patients with early Alzheimer’s disease or its precursors.

The current finding grew out of an extensive evaluation of the data from last year’s study, and it could eventually help scientists pinpoint more precise targets for treatments — the same approach that has led to major advances in treating other diseases.

For example, Bredesen explained, researchers have recently been able to develop precise treatments for cancer by sequencing tumor genomes and comparing them to the patients’ genomes to better understand what drives the formation and growth of tumors.

“However, in Alzheimer’s disease, there is no tumor to biopsy,” Bredesen said. “So how do we get an idea about what is driving the process? The approach we took was to use the underlying metabolic mechanisms of the disease process to guide the establishment of an extensive set of laboratory tests, such as fasting insulin, copper-to-zinc ratio and dozens of others.”

Photo of a brain of an alzheimer's patient.

The need for a new approach to treat Alzheimer’s is urgent. It is the most common age-related dementia, and the number of people with the disease in the U.S. is expected to increase to 15 million in 2050, from nearly 6 million today. The cost to treat people in the U.S. with Alzheimer’s and other dementias is expected to be $226 billion in 2015 alone, and could reach $1.1 trillion in 2050. The image is for illustrative purposes only.

Going forward, Bredesen and his team will seek to determine whether the subtypes have different underlying causes, and whether they respond differently to potential treatments.

The need for a new approach to treat Alzheimer’s is urgent. It is the most common age-related dementia, and the number of people with the disease in the U.S. is expected to increase to 15 million in 2050, from nearly 6 million today. The cost to treat people in the U.S. with Alzheimer’s and other dementias is expected to be $226 billion in 2015 alone, and could reach $1.1 trillion in 2050.

About this Alzheimer’s disease research

Funding: The study was funded by the National Institutes of Health (AG165070, AG034427 and AGO36975), the Mary S. Easton Center for Alzheimer’s Disease Research at UCLA, the Douglas and Ellen Rosenberg Foundation, the S.D. Bechtel, Jr. Foundation, the Joseph Drown Foundation, the Alzheimer’s Association, the Accelerate Fund, the Buck Institute and Marin Community Foundation, the Michael and Catherine Podell Fund, Craig Johnson, Allan Bortell and Michaela Hoag.

Source: Kim Irwin – UCLA
Image Credit: The image is in the public domain
Original Research: Full open access research (pdf) for “Metabolic profiling distinguishes three subtypes of Alzheimer’s disease” by Dale E. Bredesen in Aging. Published online August 31 2015 doi:Unavailable


Abstract

Metabolic profiling distinguishes three subtypes of Alzheimer’s disease

The cause of Alzheimer’s disease is incompletely defined, and no truly effective therapy exists. However, multiple studies have implicated metabolic abnormalities such as insulin resistance, hormonal deficiencies, and hyperhomocysteinemia. Optimizing metabolic parameters in a comprehensive way has yielded cognitive improvement, both in symptomatic and asymptomatic individuals. Therefore, expanding the standard laboratory evaluation in patients with dementia may be revealing. Here I report that metabolic profiling reveals three Alzheimer’s disease subtypes. The first is inflammatory, in which markers such as hs-CRP and globulin:albumin ratio are increased. The second type is non-inflammatory, in which these markers are not increased, but other metabolic abnormalities are present. The third type is a very distinctive clinical entity that affects relatively young individuals, extends beyond the typical Alzheimer’s disease initial distribution to affect the cortex widely, is characterized by early non-amnestic features such as dyscalculia and aphasia, is often misdiagnosed or labeled atypical Alzheimer’s disease, typically affects ApoE4-negative individuals, and is associated with striking zinc deficiency. Given the involvement of zinc in multiple Alzheimer’s-related metabolic processes, such as insulin resistance, chronic inflammation, ADAM10 proteolytic activity, and hormonal signaling, this syndrome of Alzheimer’s-plus with low zinc (APLZ) warrants further metabolic, genetic, and epigenetic characterization.

“Metabolic profiling distinguishes three subtypes of Alzheimer’s disease” by Dale E. Bredesen in Aging. Published online August 31 2015 doi:Unavailable

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