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A new study questions the prevailing theory of how Alzheimer’s disease develops. Image Source/Getty Images
  • The results of a new study suggest that increased protein plaque accumulation in the brain may not affect cognition in the way that experts previously thought.
  • The findings challenge prominent theories regarding the onset and progression of Alzheimer’s disease.
  • This research questions the effectiveness of current therapies in treating dementia symptoms.

The Alzheimer’s Association and the National Institute on Aging identify brain amyloidosis, the toxic buildup of the 42-amino acid form of beta-amyloid (Aβ42) into insoluble fibrous plaques, as a marker of dementia.

However, some new evidence suggests that rather than causing neurodegeneration in Alzheimer’s disease, these beta-amyloid deposits might occur as a result of the condition.

Andrea Sturchio, a doctoral student at Karolinska Institute in Sweden, explored this possibility with a team of scientists from the University of Cincinnati in Ohio, Texas Tech University in El Paso, Stanford University in California, and other institutions.

The research appears in the June 2021 edition of EClinicalMedicine.

Since 1992, many neuroscientists have relied on the amyloid cascade hypothesis (ACH) to explain the development of Alzheimer’s disease. ACH blames plaques of Aβ42 for driving the disease’s pathology.

According to the authors of the recent study, proponents of the ACH say that this aggregation triggers a “cascade of neurotoxic events, including intracellular tau accumulation as neurofibrillary tangles and neuroinflammation.” These events result in neuronal cell death and clinical dementia, according to the theory.

However, Sturchio and his team write in their paper that most people with amyloidosis “will not develop dementia during their lifetimes: between the ages of 65 and 85 years, the approximate prevalence of brain amyloidosis increases from 20% to 60%; the prevalence of AD reaches 10% by 85 — five times lower than predicted if amyloid were toxic.”

Further, most Aβ42-targeted therapies have largely failed to halt cognitive decline despite lowering brain amyloid levels.

A 2016 article in Progress in Neurobiology put forward a “loss-of-function” hypothesis to resolve inconsistencies in the ACH.

This hypothesis proposes that when present as soluble, single molecules, beta-amyloid is essential for brain health. However, when it aggregates as plaques, it is no longer soluble and cannot carry out its physiological functions.

The author argues that Aβ42 plaques do not, themselves, cause Alzheimer’s disease-related symptoms. Rather, it is the loss of soluble, single molecule Aβ that causes cognitive decline and Alzheimer’s disease.

On this basis, the author recommends addressing the functional amyloid balance instead of reducing Aβ42 levels overall. Until now, no clinical trial involving humans has evaluated this assumption.

The recent study is the first to test whether high levels of soluble Aβ42, which the team measured in cerebrospinal fluid, correlate with better cognitive performance and larger hippocampal volumes in people with brain amyloidosis.

The researchers chose to measure the hippocampus because this brain region plays a significant role in learning and memory. Earlier research has also shown that hippocampal volume reduces in people with dementia.

Sturchio and his colleagues evaluated 598 participants — all aged 55–90 years with amyloid plaques — from the Alzheimer’s Disease Neuroimaging Initiative between 2010 and 2019.

The researchers selected these individuals based on measurements of Aβ42 derived from positron emission tomography. They adjusted each analysis for age, sex, education, and amyloid levels.

They also examined composite scores for memory and executive function. MRI scans assessed hippocampal volume, as well.

Study participants with normal cognition had higher soluble Aβ42 levels than those with mild cognitive impairment or Alzheimer’s disease.

Regardless of the level of solid brain amyloid plaques, individuals with soluble Aβ42 levels above 800 picograms per milliliter (pg/ml) demonstrated normal cognitive function.

The authors report: “Each standard deviation increase in Aβ42 was associated with greater odds of [normal cognition] than [Alzheimer’s disease]. Higher soluble Aβ42 levels were also associated with better neuropsychological function and larger hippocampal volume.”

The researchers’ data indicate that a reduction in soluble Aβ42 may play a greater part in the onset of Alzheimer’s disease than elevated amyloid levels.

According to the authors, “The reduction in soluble Aβ42 is, in general, described as a consequence of its aggregation into brain amyloid fibrils and plaques, and, thus, it inversely correlates with brain amyloidosis.”

They noticed a weak link between high amyloid plaque load and dementia but a strong connection between low soluble Aβ42 and dementia.

The authors see the cross-sectional design of this analysis as its major limitation. In other words, they only looked at each participant at one point in time rather than following them over months or years.

They also admit that directly measuring soluble Aβ42 in the brain would have yielded more accurate results.

It is worth noting that Dr. Sturchio and several team members are cofounders of Regain Therapeutics. This company owns a provisional patent on methods of preventing or treating protein accumulation.

The Alzheimer’s Association estimates that 6.2 million people in the United States aged 65 and older are living with Alzheimer’s disease. By 2050, that number could more than double to 12.7 million.

Such a sizable burden underscores the critical need for effective therapeutic measures.

As existing treatments only address symptoms without impeding or reversing AD, the study authors hope that their analysis will encourage the exploration of new strategies.

The findings of Sturchio and his team may cast a shadow on Aduhelm, a new brand name version of aducanumab that the Food and Drug Administration (FDA) approved on June 7, 2021. The FDA accelerated its approval of this treatment “based on the surrogate endpoint of reduction of [beta-amyloid] plaque in the brain — a hallmark of Alzheimer’s disease.”

Sturchio suggests a “rescue medicine” approach of evaluating therapies that increase the levels of soluble Aβ42 in individuals with cognitive decline.

He and his collaborators emphasize the need for “true precision medicine” that identifies and targets pathogenic factors at the individual level.