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Alzheimer's disease (AD) is a multifaceted, slowly progressing, irreversible neurodegenerative brain disease with a long preclinical phase (up to 20 years) and an average clinical duration of 8 to 10 years.3,4
The AD Continuum
The progression of AD typically spans several stages, and the rate of disease progression varies from person to person.
AD starts with a long asymptomatic stage, called preclinical AD, followed by a symptomatic stage before dementia, called mild cognitive impairment (MCI), which eventually progresses to dementia, varying from mild to severe.1 Based on the National Institute on Ageing and Alzheimer’s Association (NIA-AA), Alzheimer’s Disease is defined as a continuous process in both cognitive and biomarker domains rather than as three separate clinical entities. Biomarkers are grouped into those of amyloid beta (Aβ), tau, and neurodegeneration (A-T-N).2-4
Today there is greater awareness that AD is a continuum from the preclinical stage to the severe dementia stage. In clinical practice it is extremely useful to refer to the individual stages in order to use the appropriate diagnostic and therapeutic interventions.2
Preclinical AD
MCI due to AD
Mild Dementia
Moderate Dementia
Severe Dementia
Preclinical AD
DURATION: Up to 20 years
This is the stage of disease before symptoms become apparent, but in which changes in the brain occur. Neuropathological build-up of amyloid plaques starts developing in the medial temporal lobe.6
Asymptomatic: No cognitive decline or functional impairment, other than consistent with typical ageing. Neuropsychological testing is normal, and activities of daily living (ADL) are not impaired.1,2
Biomarker evidence: Amyloid beta (Aβ), tau-mediated neuronal injury, and dysfunction.2,3
Mild cognitive impairment (MCI) due to AD (i.e. prodromal AD)
DURATION: ~2-6 YEARS
It occurs in people with evidence of pathophysiological changes and a noticeable decline in cognition that may be visible to friends and family, but not yet severe enough to significantly interfere with daily functioning as the brain compensates for changes1,2
Symptoms: Episodic memory loss, i.e. forgetting recent events and conversations or struggling to follow a series of steps. Executive function, attention, language, and visuospatial function also start to become impaired.1,6 In addition, neuropsychiatric symptoms (NPS) are also common in MCI. Mild NPS include apathy, irritability, anxiety, depression, or disinhibition. Mild behavioral impairment (MBI) is another term used to describe the very early NPS evidenced prior to cognitive decline.7
At the MCI stage, people show preserved activities of daily living (ADL) or very mild problems in instrumental ADL (IADL) - they are not considered demented.2,9 A meta-analysis of the prevalence of MCI, regardless of etiology, found that the prevalence increased from 6.7% in patients aged 60 to 64 years to 25.2% in patients aged 80 to 84 years.8
Biomarker evidence: Amyloid beta (Aβ), tau-mediated neuronal injury and dysfunction, changes in brain structure with associated impairment of memory and/or other cognitive domains.2,3
Dementia due to AD (mild, moderate, severe)
DURATION: ~4-8 YEARS
This includes three steps of disease progression characterized by Alzheimer’s-related brain changes and further decline, including worsening cognitive symptoms and functional impairment. The classification as mild, moderate, or severe primarily reflects the degree to which symptoms interfere with one’s ability to carry out everyday activities measured by basic activity of daily living (ADL) and instrumental ADL (IADL). This functional impairment means that individuals are no longer fully independent which is the primary feature differentiating dementia from MCI.2,9 Neuropathology spreads to frontal and parietal lobes affecting all cognitive domains and progresses to involve all brain lobes with a profound deficit in all cognitive domains.6
Mild AD dementia
Symptoms: At the mild AD dementia stage, due to substantial progressive cognitive impairment affecting several domains, people require some assistance with ADL, but individuals maintain at least some level of independent functioning. Evident functional impact on daily life mainly affects instrumental activities.2 Neuropsychiatric symptoms (NPS) are common in dementia and include disturbances in mood, perception, and behaviour. They are often referred to as behavioral and psychological symptoms of dementia (BPSD).
Biomarker evidence: Amyloid beta (Aβ), tau-mediated neuronal injury and dysfunction, changes in brain structure with associated impairment of memory and/or other cognitive domains, and clinical function.2,3
Dementia due to AD (mild, moderate, severe)
DURATION: ~4-8 YEARS
This includes three steps of disease progression characterized by Alzheimer’s-related brain changes and further decline, including worsening cognitive symptoms and functional impairment. The classification as mild, moderate, or severe primarily reflects the degree to which symptoms interfere with one’s ability to carry out everyday activities measured by basic ADL and IADL. This functional impairment means that individuals are no longer fully independent which is the primary feature differentiating dementia from MCI.2,9 Neuropathology spreads to frontal and parietal lobes affecting all cognitive domains and progresses to involve all brain lobes with a profound deficit in all cognitive domains.6
Moderate AD dementia
Symptoms: Moderate AD dementia is typically the longest stage of the disease, when people may have difficulties communicating and experience increased confusion, making it difficult to perform everyday activities. Individuals experience extensive functional impact on daily life with impairment in basic activities. They are no longer independent and require frequent assistance with daily life activities.1,2 Neuropsychiatric symptoms (NPS) are common in dementia and include disturbances in mood, perception, and behaviour. They are often referred to as behavioral and psychological symptoms of dementia (BPSD).
Biomarker evidence: Amyloid beta (Aβ), tau-mediated neuronal injury and dysfunction, changes in brain structure with associated impairment of memory and/or other cognitive domains, and clinical function.2,3
Dementia due to AD (mild, moderate, severe)
DURATION: ~4-8 YEARS
This includes three steps of disease progression characterized by Alzheimer’s-related brain changes and further decline, including worsening cognitive symptoms and functional impairment. The classification as mild, moderate, or severe primarily reflects the degree to which symptoms interfere with one’s ability to carry out everyday activities measured by basic ADL and IADL. This functional impairment means that individuals are no longer fully independent which is the primary feature differentiating dementia from MCI.2,9 Neuropathology spreads to frontal and parietal lobes affecting all cognitive domains and progresses to involve all brain lobes with a profound deficit in all cognitive domains.6
Severe AD dementia
Symptoms: People with severe AD dementia require constant caregiving as they may lose awareness of their surroundings and experience loss of physical abilities. Neuropsychiatric symptoms (NPS) are common in dementia. They are often referred to as behavioral and psychological symptoms of dementia (BPSD). Severe symptoms include agitation, aggressiveness, aberrant vocalizations, hallucinations, and euphoria. Individuals are bedridden and need full-time care. Over time, pathology spreads to regions of the brain that control basic functions such as heart rate, leading ultimately to death due to AD or death due to a complication caused by AD.1,2
Biomarker evidence: Amyloid beta (Aβ), tau-mediated neuronal injury and dysfunction, changes in brain structure with associated impairment of memory and/or other cognitive domains, and clinical function.2,3
Preclinical AD
MCI due to AD
Mild Dementia
It is recognized that a person with mild cognitive impairment (MCI) is at an increased risk of developing AD. Based on analysis from several cohorts, approximately 60% of subjects with MCI and underlying AD pathology progressed to Alzheimer’s disease-type dementia within 2-3 years.11,12 However, current clinical practice often does not recognize a person as having AD until the disease has progressed significantly and dementia is evident.5,8
Diagnosis of AD at later stages means that the decision-making of the person with AD may be impacted, as behavioral problems and impairments in ADL are already present. A timely diagnosis of MCI due to AD provides HCPs, patients, and care partners with an opportunity to help manage the disease and plan for the future.7
WHAT'S NEXT
Pathophysiological Hallmarks of
Alzheimer's Disease
It is now recognized that pathophysiological changes of Alzheimer's disease may begin up to 20 years prior to clinical manifestations.