Gains in Our Knowledge of Preclinical Alzheimer's

Martha Snyder Taggart, BrightFocus Editor, Science Communications
  • Science News
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Research Backs a New Treatment Frontier

This research was supported by BrightFocus

For the Alzheimer’s community, new drugs cannot come fast enough. In recent years, trials of disease-modifying drugs have been disappointing, yet they’ve brought valuable knowledge about the optimal timing for when Alzheimer’s can be stopped. Today, there’s a sense that a breakthrough is near. There’s a quantum leap of activity aimed at slowing down Alzheimer’s decades before symptoms appear.

This new frontier of research aimed at finding treatments for “preclinical” Alzheimer’s is reviewed by Reisa Sperling, MD, and colleagues, in a special issue of Neuron (Sperling et al, Neuron, 2014). Sperling, a Harvard researcher and 2010-14 BrightFocus grantee, has built herself a large soapbox to stand on in the research world. With support from BrightFocus and others, she’s become an authority on use of amyloid imaging and other ways to detecting the disease in its earliest stages.  

More recently, with Paul Aisen, MD, of the University of California, San Diego, she designed the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) trial, the largest Phase 3 clinical trial of a disease-modifying drug for preclinical Alzheimer’s. She also leads A4, described below and in an earlier News Update. 

In their Neuron article, Sperling et al comprehensively review the entire body of research findings—their own and others’—about preclinical Alzheimer’s. They describe its course as “a 20-year-long progression of amyloid accumulation and neurodegeneration” that is well entrenched by the time symptoms become recognizable. Alzheimer’s decades-long residence in the brain may explain why earlier trials of disease-modifying therapies failed, because they were started too late. It’s thought that by the time a person reaches the stage of mild cognitive impairment (MCI), which is still prior to an Alzheimer’s diagnosis, substantial neuron loss has already occurred and the “pathophysiological cascade” associated with Alzheimer’s, like a train in motion, is running rampant through the brain.

The only thing that will stop it, most experts believe, is early intervention. Here are some key points—and remaining questions—raised by Sperling and colleagues.

Amyloid Accumulation as Driving Mechanism.

Most evidence points to beta amyloid (Aβ) peptide accumulation as the main culprit in preclinical Alzheimer’s, and that’s the biomarker being used to screen potential candidates for inclusion in the A4 trial. However, the issue of whether amyloid accumulation actually drives the disease process is far from settled. “It remains to be proven in sporadic, late-onset Alzheimer’s disease that Aβ accumulation is sufficient to incite the downstream pathological cascade … and to ultimately result in cognitive impairment and dementia,” Sperling et al advise. At several points in their review, they back up this assertion with evidence about the role of other key players—including Tau, and “suspected non-Alzheimer pathology”— that depart from the hypothesis.


The association between , Tau, and cognitive decline is still unclear, and to some extent a “chicken and egg” question. Tau imaging has lagged behind that of Aβ, and experts part ways over whether Aβ or Tau is responsible for atrophy in some brain regions. Sperling et al assert that “it is likely that Aβ accelerates the spread of Tau …disrupting function and initiating neurodegeneration,” ultimately leading to cognitive decline.  Knowledge gained from Tau PET scans and other imaging will help to settle this question. “Until very recently, this critical spread and intensification of Tau pathology has been invisible to all but the neuropathologist,” they note.

Staging of Preclinical Disease

 Sperling took part in a 2011 workgroup that developed a hypothetical staging for preclinical Alzheimer’s disease based on biomarkers and imaging results. That 2011 document has been further adapted by Sperling et al to describe four stages of preclinical disease: Stage 0—No biomarker abnormalities; Stage 1—asymptomatic amyloidosis; Stage 2—amyloidosis plus neurodegeneration; and Stage 3—amyloidosis, plus neurodegeneration, plus subtle cognitive decline.

Neurological “Reserve”

It is hypothesized that the capacity to tolerate Alzheimer’s pathology for longer periods without exhibiting clinical symptoms may be an important determinant of cognitive abilities in aging and may interact with Aβ to modulate risk. Yet these authors say there’s a “tipping point,” that, once reached, is followed by rapid decline once compensatory mechanisms begin to fail.

Glossary Terms

  • Mild cognitive impairment (MCI)  is a condition between normal age-related memory loss and dementia. Individuals with MCI have persistent memory problems (for example, difficulty remembering names and following conversations and marked forgetfulness) but are able to perform routine activities without more than usual assistance. Individuals with MCI are at risk of developing Alzheimer's disease or other forms of dementia.

  • Anti-amyloid agents can decrease the production of beta-amyloid, prevent the accumulation of beta-amyloid, or increase removal of beta-amyloid from the brain.

  • Evidence points to beta amyloid (Aβ) peptide accumulation as a culprit in preclinical Alzheimer’s disease.

  • Amyloid is a general term for protein fragments that the body produces normally. Beta amyloid is a protein fragment snipped from an amyloid precursor protein (APP). In a healthy brain, these protein fragments are broken down and eliminated. In Alzheimer's disease, the fragments accumulate to form hard, insoluble plaques.

  • Amyloid is a general term for protein fragments that the body produces normally. Beta amyloid is a protein fragment snipped from an amyloid precursor protein (APP). In a healthy brain, these protein fragments are broken down and eliminated. In Alzheimer's disease, the fragments accumulate to form hard, insoluble plaques.

  • The neurofibrillary tangles found in Alzheimer's disease consist primarily of a protein called tau, which forms part of a structure called a microtubule. The microtubule helps transport nutrients and other important substances from one part of the nerve cell to another. In Alzheimer's disease, however, the tau protein is abnormal and the microtubule structures collapse. Abnormal tau formations, known as “tauopathy,” have been associated with a number of neurodegenerative disorders.