The first case of Alzheimer’s disease

Yesterday I came across an interesting paper from 2013 in Lancet Neurology that adds important information about the case of Auguste D, the first patient diagnosed with what was later called Alzheimer’s disease. I mentioned this patient in my book. Briefly, she first came under the care of Dr. Alois Alzheimer at age 51 because of rapidly progressive memory loss, hallucinations, and fears that her husband was having an affair with the next-door neighbor, fears that were apparently unfounded. She died five years later, and Dr. Alzheimer was able to examine her brain. He was surprised to find dark blobs outside of nerve cells and smaller dark tangles inside nerve cells.  He reported his findings in 1906 at a conference, but there was little interest from the audience. Soon other pathologists were seeing these dark blobs in brain tissue from demented patients, later identified as amyloid plaques and neurofibrillary tangles. Dementia associated with these pathological findings came to be called Alzheimer’s disease in his honor.

Until the 1970s, Alzheimer’s disease referred only to dementia patients like Auguste D, less than 65 years of age, who were later found to have amyloid plaques and neurofibrillary tangles.  Alzheimer’s disease was considered to be a type of presenile dementia. Demented patients older than 65 were felt to simply have senile dementia thought by many to be a normal consequence of aging. Over the last forty years, the concept of Alzheimer’s disease has evolved. While brain pathology is the same whether the cognitive problems start in the 40s or 70s, the genetics can be different. Three rare gene mutations cause an autosomal dominant form of early Alzheimer’s.  If you have just one copy of the presenilin-1, presenilin-2 or APP gene mutation, you will get Alzheimer’s disease with symptoms starting in the 40s or 50s.  Fortunately, these account for less than 2% of Alzheimer’s cases.  Other Alzheimer’s risk genes, especially having two copies of APOE-4, can sometimes lead to early-onset disease as well. About 60% of people with late-onset Alzheimer’s, beginning after age 65, have at least one copy of the APOE-4 allele.  Many other Alzheimer’s risk genes have been found. With the exception of the presenilin and APP gene mutations, having these risk genes simply increase the chances of getting Alzheimer’s.  Many people with these genes never develop dementia.

In the 2013 Lancet Neurology paper, Ulrich Müller and his colleagues at Justus Liebig University in Giessen, Germany reported their genetic analysis of histopathological tissue recovered from Auguste D’s original autopsy over a hundred years before. They found that she had the presenilin 1 mutation. (For neurologists reading this, she was also an APOE-3 homozygote, providing standard APOE-related risk.) She was doomed from birth to develop Alzheimer’s disease at a relatively young age.  We don’t know if she had children, but if she did each child would have had a 50% chance of inheriting the presenilin 1 mutation and developing early-onset Alzheimer’s.