In November 1901, Dr. Alois Alzheimer, a German psychiatrist made his first examination of a 51-year old woman experiencing language impairment, disorientation, memory problems and hallucinations. Despite her relatively young age, he diagnosed the patient as suffering of “senile dementia”. The patient died on April 1906. Since he had never seen a similar case before, Dr Alzheimer obtained the permission to perform an autopsy of her brain. He sampled thin slices of the brain tissue, stained them with silver stain and examined them under the microscope. He observed two types of abnormal deposits inside and between the nerve cells that had never been described before in anyone so young of age. He defined it as “a particular malady of the cerebral cortex”. The two kind of deposits seen in the microscope were the “amyloid plaques “and the “neurofibrillary tangles “which still today are considered to be two characteristic hallmarks of the pathology of the AD. The first official definition of the disease as Alzheimer’s disease (AD) appeared for the first time in 1910 in the book “Psychiatrie”, written by another German psychiatrist named Emil Kraepelin. The definition included neurological and behavioral symptoms as well as pathological changes in the brain,

 More than seventy year later, in 1984, the National Institute of Neurological and Communication Disorders and Stroke (NINCDS) and the Alzheimer Association (ADRDA) of United States reformulated the requirements for the diagnosis of AD considering as sufficient, characteristics of dementia”, memory changes and another cognitive impairment” with no requirement of brain pathology. In 2007, an International Working Group (IWG) introduced a new concept of a special type of AD called “amnestic of hippocampal type “.These patients exhibit early memory deficits related to a lesion of the hippocampus ,a brain structure which has a major role in learning and memory. For the rare autosomal genetic mutation of AD, together with MRI atrophy, specific markers in the cerebrospinal fluid (CSF) and low cerebral glucose metabolism with PET scan were required.

 Since 2007 the definition of AD has changed six times alternating requirements of cognitive impairment together with pathophysiological markers such as beta-amyloid and tau to requirement of only biomarkers without amnestic or non-amnestic symptoms.

According to the most recent definition of AD described in the 2021 paper of Dubois et al., the basic criteria for diagnosis go back to the original ones described by Alzheimer himself in 1906, recognizing as important sign of the disease both cognitive symptoms and markers (CSF or PET ) of the presence of beta-amyloid and tau  brain.

 In clinical practice this translates into a combination of laboratory  tests (plasma or CSF) and neuroradiological tests (CT scan or MRI ), together with neuropsychological testing combined with a careful clinical evaluation The diagnostic evaluation of AD will continue to evolve in time and become  more exact and more reliable as  more reliable biomarkers of pathology will  become available.

In an ultimate analysis, the question of diagnosing AD and the relative importance of biomarkers will be clarified only when a therapy of the disease will be available.

Review written by Ezio Giacobini MD, PhD.

Article published in The Lancel Neurology, 29 April 2021, Dubois B. et al., Clinical diagnosis of Alzheimer’s disease: recommendations
of the International Working Group,