Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder that is the most common type of dementia. The diagnosis of Alzheimer’s disease largely remains a clinical diagnosis in practice, using the criteria like the ones below. However, we expect that biomarkers will enter routine practice instead of as a research framework especially as new therapeutic agents are developed.

2011 NIA-AA criteria for probable Alzheimer’s disease dementia: These criteria for clinical diagnosis were put forth by workgroups of the National Institute on Aging and Alzheimer’s Association in 2011.

1. Meets criteria for dementia
2. Insidious onset. Symptoms have a gradual onset over months to years
3. Clear-cut history of worsening of cognition by report or observation.
4. The initial and most prominent cognitive deficits are evident on history and examination in one of the following categories:
   • Amnestic presentation: It is the most common syndromic presentation of AD dementia. The deficits should include impairment in learning and recall of recently learned information. There should also be evidence of cognitive dysfunction in at least one other cognitive domain.
   • Nonamnestic presentations:
     • Language presentation: The most prominent deficits are in word-finding, but deficits in other cognitive domains should be present.
     • Visuospatial presentation: The most prominent deficits are in spatial cognition, including object agnosia, impaired face recognition, simultanagnosia, and alexia. Deficits in other cognitive domains should be present.
     • Executive dysfunction: The most prominent deficits are impaired reasoning, judgment, and problem solving. Deficits in other cognitive domains should be present.

2011 NIA-AA criteria for possible Alzheimer’s disease dementia:

1. Atypical course: Meets the core clinical criteria in terms of the nature of the cognitive deficits for AD dementia, but either has a sudden onset of cognitive impairment or demonstrates insufficient historical detail or objective cognitive documentation of progressive decline.
2. Etiologically mixed presentation: Meets all core clinical criteria for AD but has either
   • concomitant cerebrovascular disease, defined by a history of stroke temporally related to the onset or worsening of cognitive impairment; or the presence of multiple or extensive infarcts or severe white matter hyperintensity burden; or
   • features of Dementia with Lewy bodies other than the dementia itself; or
   • evidence for another neurological disease or a non-neurological medical comorbidity or medication use that could have a substantial effect on cognition.

• Atypical phenotypes/nonamnestic presentations of Alzheimer’s disease:
  • Atypical phenotypes have been estimated to comprise 6% of cases of late-onset AD (after age 65).
  • Atypical phenotypes include:
    • Posterior cortical atrophy AD
    • Lopogenic variant primary progressive aphasia
    • Behavioral AD
    • Dysexecutive AD
    • Corticobasal syndrome AD

• Early onset Alzheimer’s disease (EOAD):
  • EOAD is diagnosed when someone presents with AD before the age of 65, in contrast to late-onset AD which refers to the syndrome diagnosed after age 65 (also known as LOAD, or more commonly simply referred to as AD).
  • Besides the age cutoff between EOAD and LOAD, there are often significant differences in the clinical presentation and the clinical course.
    • The progression of disease is often faster in EOAD.
    • People with EOAD are more likely to present with nonamnestic or atypical presentations of AD, including lopogenic variant primary progressive aphasia and posterior cortical atrophy.
  • About 5% of people with AD have EOAD.

• Autosomal dominant Alzheimer’s disease:
  • Autosomal dominant AD is characterized by diagnosis of AD in at least three individuals of at least two generations.
  • It accounts for less than 1% of cases of AD.
  • APP, PSEN1, PSEN2 are three of the main genes associated with dementia, with PSEN1 being the most common gene found in autosomal dominant AD.
  • It is almost exclusively early-onset.
  • The vast majority of people with a family history of AD do not need genetic testing for autosomal dominant AD! Your suspicion should be raised if there is a family history of at least two first-degree relatives with EOAD, especially if onset of EOAD was at age 60 or under (***need to confirm this). If you are concerned, you should refer the patient and family to a genetic counselor; do not perform genetic testing by yourself.

• Research framework for Alzheimer’s disease: In 2018, the National Institute on Aging and Alzheimer’s Association published a research framework to help standardize research around biomarkers associated with AD. This framework sets a classification system for diagnosis of AD by biomarkers within the categories of amyloid, tau, and neurodegeneration; the authors refer to this as the AT(N) classification system. This system is not currently used in clinical practice for diagnosis of AD, but we expect it may be incorporated into clinical practice in the future.