Rare, Aggressive Form of Early-Onset Alzheimer’s Discovered

Alzheimer's Disease CT Scan
CT images of the brain from two siblings and a cousin with familial Alzheimer’s disease who harbored the Uppsala APP mutation. Credit: M. Pagnon de la Vega et al., Science Translational Medicine (2021)

A team of scientists have discovered a genetic mutation that causes an early-onset and aggressive form of Alzheimer’s disease.

Although Alzheimer’s disease most commonly occurs in those aged 65 years and above, a rare, early-onset form of the disease also exists. Early-onset Alzheimer’s disease usually shows up by age 40 or 50. Symptoms include forgetfulness, inability to perform complex but familiar tasks, trouble recalling certain words, difficulty with normal work or household activities, and behavioural changes. The buildup of proteins – amyloid and tau – are often considered the cause of the disease. However, why this protein buildup occurs is still uncertain.

Now, a team of international scientists, led by neurobiologists in Sweden, have discovered a genetic mutation that can cause an extremely rare and aggressive form of the disease. The mutation, the Uppsala APP deletion, has so far only been found in one family. Moreover, according to researchers, the resultant form of Alzheimer’s is aggressive, rapid and starts at a much younger age.

Affected individuals have an age at symptom onset in their early forties, and suffer from a rapidly progressing disease course.

Dr. María Pagnon de la Vega, study author

The family involved in the study had several members affected by memory loss and cognitive decline. Physicians at Uppsala University Hospital had treated several of the family members for nearly identical symptoms and diagnosed them with early-onset Alzheimer’s disease.

Early-onset Alzheimer's Disease
Electron microscopy and three-dimensional density reconstructions of amyloid fibrils resulting from the Uppsala APP mutation. Credit: M. Pagnon de la Vega et al., Science Translational Medicine (2021)

The Uppsala APP Deletion

The team of researchers conducted genetic analysis, structural biological research, studies of amino acid and protein chemistry, and mass spectrometry to confirm the genetic mutation. Their analysis further revealed that all carriers carried the APP gene deletion in a specific string of amino acids part of the amyloid precursor protein. The gene deletion led to a total of six amino acids missing.

According to researchers, the mutation accelerates the formation of amyloid plaques in the brain, which then destroy neurons. Thus, resulting in neurocognitive decline.

Symptoms and biomarkers are typical of Alzheimer’s disease, with the exception of normal cerebrospinal fluid.

Dr. María Pagnon de la Vega, study author

Study authors believe this rare form of early-onset Alzheimer’s disease is autosomal dominant. However, there is no evidence of other families carrying the Uppsala APP deletion. Further research us required to learn more about this rare disease.


María Pagnon de la Vega et al, The Uppsala APP deletion causes early onset autosomal dominant Alzheimer’s disease by altering APP processing and increasing amyloid β fibril formation, Science Translational Medicine (2021). DOI: 10.1126/scitranslmed.abc6184

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