The clinical diagnosis of probable Alzheimer disease has been the rule over the past 50 years. Clinicians identify a typical clinical picture, with progressive memory and behavioural deterioration, the investigation makes sure there are no other treatable causes, and it remains a probable diagnosis until post-mortem examination confirms it. Even the MRI findings of atrophy, which appear relatively late in the course of the dementia, are not total proof of the diagnosis.
Some 30 years ago biomarkers in the cerebrospinal fluid became available for the changes in amyloid and tau metabolism that take place in the brain of people with Alzheimer’s disease. They are markers in the cerebrospinal fluid of the appearance of neuritic plaques and neurofibrillary tangles. But laboratories report wide differences in results of abeta 42 and phospho tau protein, leading to some resistance in their clinical use.
It was in 2004 that amyloid plaques could be identified in living persons through C11-PET scans. Soon many fluoro-based ligands with a longer half-life became available, including florbetapir, flutemetamol and florbetapen. With these the exams became much more practical and became more widely available. Recently tau ligands became available and their reliability in aiding diagnosis was established.
With the confirmation and demonstration of practical use in clinical practice, the criteria for diagnosing Alzheimer disease were updated in 2011 to include a preclinical phase, followed by mild cognitive impairment and finally progressive dementia. In the preclinical phase only PET and cerebrospinal changes are present, without any symptoms. This approach has been in use mainly in research, and means that people with mild cognitive impairment can be included in therapeutic trials when amyloid deposits appear on PET scan, and amyloid and tau metabolism is altered in the cerebrospinal fluid.
The natural history of Alzheimer disease has been divided now in 6 phases, or 6 stages. Stages 1 and 2 are in the preclinical stage; 3 is mild cognitive impairment; 4, 5 and 6 are in the progressive dementia phase. Subjective cognitive decline, a syndrome that was more related with depression, has been associated with the presence of biomarkers, and the possibility of development into Alzheimer disease.
Jack et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurology 2010, 9:119-128
Ronald C Petersen. How early can we diagnose Alzheimer disease. Neurology 2018, 91: 395-402
Dr Paulo Bittencourt
