The Silent Stalker – Alzheimer’s Changes the Brain Years Before First Symptoms

Twenty-five years before the first clinical symptoms, Alzheimer’s disease has already produced permanent changes in the brain. New research published in the New England Journal of Medicine traces the timeline of the disease, challenging current perceptions about this devastating form of dementia.

Most cases of Alzheimer’s are sporadic, meaning that they arise in a seemingly random fashion, without a family history or other identifiable cause. However, a small proportion — approximately 1% — of individuals with Alzheimer’s have a special genetically inherited form. The Dominantly Inherited Alzheimer Network (DIAN) was formed to facilitate the study of families carrying these genetic mutations; members have been recruited from across the US, as well as Australia and the United Kingdom. While the 128 subjects in the current study are presently asymptomatic (showing no signs of dementia), approximately half of them are expected to eventually develop clinical Alzheimer’s disease.

Children who inherit one of these three mutations leading to Alzheimer’s disease tend to develop signs of dementia at approximately the same age as their parents. This allowed researchers at Washington University in St Louis to work backwards to construct a timeline of the changes in the brain seen with Alzheimer’s disease.

The earliest biomarkers of Alzheimer’s are associated with the formation of beta-amyloid plaques. Plaques represent clumps of a specific protein (beta-amyloid) intermixed with neurons (brain cells). Beta-amyloid plaques are believed to interfere with communication between nerve cells, and possibly trigger nerve cell damage. Twenty-five years before the expected onset of Alzheimer’s symptoms, the level of amyloid proteins decreases in the cerebrospinal fluid (CSF).

Fifteen years before the onset of symptoms, beta-amyloid plaque formation begins. These plaques are visible on noninvasive PET-CT scans of the brain. Atrophy, or shrinking of the brain tissue, also begins around this time.

Ten years before the onset of clinical Alzheimer’s, parts of the brain become hypometabolic, or less active. There is also subtle impairment in episodic memory, a subtype of long-term memory involving the recollection of specific events.

Furthermore, the appearance of these markers is specific for Alzheimer’s disease; family members without the Alzheimer’s mutations demonstrate no changes in brain chemistry or structure. This suggests that biomarkers may eventually be used to screen for Alzheimer’s in asymptomatic individuals, much like blood glucose levels are used to screen for diabetes or PSA levels for prostate cancer.

In a news release from Washington University, first author Randall Bateman, MD stated “As we learn more about the origins of Alzheimer’s to plan preventive treatments, this Alzheimer’s timeline will be invaluable for successful drug trials.”

The researchers plan to start clinical trials later this year aimed at blocking the formation of beta-amyloid plaques. The hope is that targeting Alzheimer’s at this early preclinical stage, before significant memory loss and impairment take hold, may represent the best chance for effective prevention and treatment.


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Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, & Trojanowski JQ (2010). Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet neurology, 9 (1), 119-28 PMID: 20083042

Image via John Wollwerth / Shutterstock.

Margaret McKernan, MD, PhD

Margaret McKernan, MD, PhD, is a practicing diagnostic radiologist and medical writer. She holds an MD/PhD degree in neuroscience from the University of Texas Medical Branch, and completed her graduate medical training in radiology at Wake Forest University Baptist Medical Center and Massachusetts General Hospital.
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