Early Changes In The Brain May Occur Decades Before The First Symptoms Of Alzheimer’s Disease Begin To Show.

Early Changes In The Brain May Occur Decades Before The First Symptoms Of Alzheimer's Disease Begin To Show

Does Alzheimer’s disease pathology accumulate in our brains in our younger years without making us symptomatic?

Typically, individuals don’t get evaluated for Alzheimer’s disease (AD) or Mild Cognitive Impairment (MCI) unless they begin to notice a change in their memory or start to have other concerning symptoms that cue them that something may be going on with their brain health.

Research indicates that a decade or more before symptoms of MCI or AD appear, the neuropathological mechanisms associated with the development of Alzheimer’s disease may have already begun.

A recent study was done to evaluate changepoints in a range of biomarkers during preclinical (non-symptomatic) Alzheimer’s disease. Four measures were evaluated in this study including cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), and cognitive testing. The study examined whether these measures had a significant change in relation to the onset of symptoms. The data was drawn from the BIOCARD study conducted at the National Institutes of Health (NIH) and Johns Hopkins University.

The study was made up of 306 cognitively normal individuals. A subset of these individuals progressed to the prodromal (symptomatic) phase of Alzheimer’s disease also called MCI. Approximately 75% of these participants had a first degree relative with AD.

The CSF measures analyzed the biomarkers  Abeta 42, the most toxic form of Abeta, total tau (t-tau), and phosphorylatedtau (p-tau, which make up the tangles in the brain). The MRI measures analyzed the entorhinal cortex, hippocampus, and the amygdala in the brain. The comprehensive neuropsychological battery tested all of the major cognitive domains including memory, executive function, language, visuospatial ability, attention, processing speed, and psychomotor speed. These were completed at baseline and at the onset of symptoms to examine the time association between performances.

Using a changepoint analysis determined whether any of the measures discussed above had a significant changepoint in relation to the onset of clinical AD or MCI symptoms.

Photo: Schematic representation of the changepoint model

All of the measures that were studied had significant changepoints, and all of them preceded the onset of symptoms. The changepoint for CSF t-tau occurred 34 years prior to symptom onset. Although this changepoint appears to be associated with the onset of Alzheimer’s disease symptoms, it does not necessarily correspond to an early effect. All of the cognitive tests had changepoints 10-15 years prior to symptom onset, as well as the remaining CSF measures. The timing of these changepoints varied.

The study results provide a credible indication that a change in the biomarker occurs some number of years before clinical onset. However, an accurate prediction of the timing cannot be made due to the variability between individual experiences. The image below shows the change in hippocampal volume on MRI, and function on PET scan,in a patient with MCI over just a year.

We can expect to see further research in this area in the future due to the fact that it is challenging to  identify biomarker changepoints during the preclinical phase of Alzheimer’s disease.

Sources:
Younes L, Albert M, Moghekar A, Soldan A, Pettigrew C, Miller M. Identifying Changepoints in Biomarkers During the Preclinical Phase of AD. 2018;
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