Researchers Create a Model for the Progression of Alzheimer’s Disease

Scientific researchers have proposed a hypothetical model of the cascade of events typically observed in the brain preceding a clinical diagnosis of Alzheimer’s disease. Their work is published in the journal Lancet Neurology.


Based on data from studies of Alzheimer’s disease across many laboratories, the researchers’ model relates biomarkers of Alzheimer’s disease to the stage of the disease. Biomarkers are measurable indicators of specific changes in the brain that are characteristic of Alzheimer’s disease. 

Researchers constructed the model so that biomarkers of beta-amyloid plaques become abnormal first, before any symptoms of brain degeneration occur, and before any clinical symptoms are present. This is similar to the results reported from many scientific studies. Then, biomarkers of injury, dysfunction, and degeneration of the brain become abnormal.

Progression of Alzheimer’s disease

There is strong evidence in the scientific literature that Alzheimer’s disease progresses in stages. The first stage is widely accepted to be the formation of beta-amyloid plaques in the brain of people who are cognitively normal. This is followed by a time lag, the length of which differs for each person. The second stage is that people develop a mild cognitive impairment, which involves memory loss. The third stage is dementia, where injury, dysfunction, and degeneration of the brain are observed in a clinical setting. While not everyone with a mild cognitive impairment will go on to develop dementia, the current clinical diagnosis for Alzheimer’s disease requires a diagnosis of dementia.

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Biomarkers for Alzheimer’s disease

The biomarkers used as the basis for the model were either biochemical in nature or imaging-based.  Examples of biochemical markers used are two protein biomarkers found in cerebrospinal fluid (CSF). CSF tau indicates a neuronal injury, and a particular form of CSF amyloid-beta is a biomarker for the presence of beta-amyloid plaques in the brain. Examples of imaging-based biomarkers used are structural MRI, which measures decreases in brain volume, and amyloid PET imaging, which is another biomarker for beta-amyloid plaques in the brain.

Biomarkers become abnormal in a time-dependent, ordered way

Data from the scientific literature suggests that the biomarkers for Alzheimer’s disease do not become abnormal at the same time. Rather, the data suggest that biomarkers progressively become abnormal and that they become abnormal in a systematic, ordered way.

The relationship between biomarkers and clinical symptoms

Many reports in the scientific literature provide evidence that both biomarkers for beta-amyloid plaques and biomarkers for degeneration of the brain typically become abnormal before clinical symptoms are present. When cognitive symptoms do begin to be detectable in a clinical setting, these symptoms correlate to the biomarkers related to degeneration of the brain, and not to the biomarkers related to beta-amyloid plaque formation. 

As many as two in five older individuals have substantial beta-amyloid plaques, indicated by amyloid PET and CSF tau biomarkers. However, the data show that it is possible to have these plaques and at the same time show no sign of cognitive impairment and no sign of decreased brain size on MRI biomarkers. Some studies have suggested that these plaques can accumulate in the brain for decades before there is any evidence of clinical symptoms. Biomarkers for the presence of beta-amyloid plaques in the brain typically reach a plateau before there is any evidence on an MRI of a decrease in brain size or any indication of cognitive impairment.

By the time people have developed a mild cognitive impairment, MRI and CSF tau biomarkers have already become abnormal. Several studies provide evidence that the CSF tau biomarker becomes abnormal before MRI biomarkers show a decline in brain size. For MRI biomarkers, the rate at which brain size has decreased depends on the stage of Alzheimer’s disease. For people who show no symptoms of cognitive impairment, their decline in brain size is the least. Individuals with a mild cognitive impairment have an intermediate rate of brain decline, and people who have been diagnosed with Alzheimer’s disease see the greatest rate of brain size decrease. Thus, a decrease in the size of the brain, present as an abnormal MRI biomarker, is indicative of a later stage of Alzheimer’s disease.

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The goal of this model was to relate the biomarkers of Alzheimer’s disease to the stages of the disease. Based on their model, a number of scientific hypotheses related to the time-dependent changes in biomarkers at different disease stages have emerged. These hypotheses can be tested in future research studies. One example is that the authors of the model hypothesize that people with co-morbidities, such as vascular disease, may see a shift in the curve representing the presence of beta-amyloid plaques in the brain such that these plaques appear at an earlier time in an individual’s life. Additionally, the model provides a common framework so that researchers from various disciplines can relate their results to the results of others. The proposed model also has implications for clinical trials related to Alzheimer’s disease. The authors suggest using a combination of biomarkers to appropriately screen people as to whether they meet the inclusion criteria to participate in the trial.