Alzheimer's has a rich history concerning its definition, based on the multifactorial manifestations of the disease. When discussing Alzheimer's, we are essentially delving into the concept of the "Alzheimer's continuum." This approach simplifies the complexity inherent in the term "continuum."
The most comprehensive and well-defined framework for establishing the parameters of Alzheimer's was established by the NIA-AA in 2018. This framework involves a binary decision: positive or negative for A (Amyloid), T (Tau), and N (Neurodegeneration) (cf. Table 1). This yields 2^3 = 8 biomarker categories, each associated with its specific ATN profile. However, it's important to note that only ATN profiles with positive amyloid are linked to Alzheimer's, ultimately resulting in 4 relevant ATN profiles for the Alzheimer's continuum marked by gray in the table.
Table 1| Source: https://doi.org/10.1016/j.jalz.2018.02.018
By integrating the biological insights outlined in the above table with knowledge of symptoms (such as the type and extent of cognitive impairment), a table detailing various forms of Alzheimer's can be constructed.
Table 2| Source: https://doi.org/10.1016/j.jalz.2018.02.018
Within this framework, mild cognitive impairment (MCI) can signify an early stage of Alzheimer's with prodromal stage of Alzheimer's disease (AD) referred to as MCI due to AD. As symptoms progress from "mild" to moderate and severe, accompanied by the emergence of other dementia-related symptoms, the cognitive stage transitions into the "dementia" category.
In essence, three cognitive stages and four biomarker profiles are linked to the Alzheimer' continuum. However, there's an overlap between two biomarker profiles. This overlap arises because some patient cases might lack neurodegeneration, even if they are categorized as having AD with dementia. Conversely, certain patients may exhibit neurodegeneration but remain entirely symptom-free in terms of cognition.
In summary, excluding the normal AD biomarker profile from Table 2, this results in a total of 3 times 3 = 9 Alzheimer's subtypes within the continuum. Taking into account binary genetic information about individuals (carrier/non-carrier), the potential number of Alzheimer's subtypes could potentially increase to 9 times 2 = 18.