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Mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) is the first disease stage when symptoms may become apparent to individuals living with AD, their loved ones, and their doctors.1
Individuals with MCI due to AD have subtle problems in one or more cognitive domains with an underlying Alzheimer's pathology. These cognitive problems do not interfere with an individual's ability to carry out basic activities of daily living (ADL).3-5
Early detection of MCI provides an opportunity to diagnose AD early in the disease course before clinical progression to dementia stages.4-6
The World Health Organization (WHO) also supports a paradigm shift towards an earlier AD diagnosis to preserve brain functions for as long as possible.7
The Time Frame for Early AD Detection and Diagnosis is Limited3
Early detection of MCI due to AD allows patients additional time to prepare for the future and to adopt appropriate lifestyle changes which can reduce the risk of further cognitive decline and preserve activities of daily living (ADL).2
Preserved ADL
Impaired ADL due to
functional decline
Onset of first MCI signs:
Subjective Cognitive Decline (SCD)
COGNITIVE FUNCTION
Normal
Ageing
Up to 20 years
~2-6 years
~4-8 years
Mild
Moderate
Severe
YEARS
Evidence of AD pathology - amyloid beta (Aβ) plaques, phosphorylated tau aggregates (NFT, neurofibrillary tangles)
Cognitive decline
Behavioural and psychological changes
Functional decline
Adapted from Sperling et al. (2011)8-11
Progression to AD Dementia from MCI due to AD
Approximately 60% of people with MCI due to AD* will
progress within 2-3 years to AD dementia12
MCI due to AD
AD Dementia
Individuals in the MCI due to AD stage
Individuals progressed to AD dementia
* n=308 and n=353 people with MCI due to AD according to IWG-2 and NIA-AA criteria, respectively.
The National Alzheimer's Coordinating Center in the US provided patient-level longitudinal data from 3291 unique patients with information on the full spectrum of the individuals' disease progression. The transition probability from MCI-AD individuals with positive amyloid beta status to mild AD dementia or worse was reported to be as high as 21.8% per year.13
Clinical MCI Subtypes
MCI can be defined as amnestic (aMCI) or non-amnestic (na-MCI). A clinical presentation with memory impairment is characterized as aMCI, whereas individuals with naMCI have impairments in one or more non-memory cognitive domains (e.g., executive functions, attention, language, visuospatial function) na-MCI is probably less common than amnestic MCI.14,15 Both subtypes can be categorized further to single-domain or multiple-domain subtypes.16,17
Individuals with aMCI have a higher likelihood of progressing to AD dementia while naMCI is rather associated with reversible causes or a higher risk of progression to early-onset AD or to non-AD dementia, such as dementia with Lewy bodies, frontotemporal lobar degeneration, Parkinson disease with dementia, vascular dementia, or primary progressive aphasia.14-18
Cognitive complaint
Reported by the patient, an informant, or clinician
Not normal for age or individual person
Normal functional activities
Mild Cognitive Impairment
Amnestic
Single domain
Impairment of only episodic memory
or
Multiple domain
Impairment of episodic memory and in one or more additional domains
Higher risk of progressing to AD dementia
Non-Amnestic
Single domain
Impairment of only one non-memory domain
or
Multiple domain
Impairments in more than one non-memory domain
Higher risk of early-onset AD or conversion to non-AD dementia
Adapted from Petersen RC. 201616
The MCI phenotype (aMCI vs. naMCI) and the number of affected domains (single vs. multiple) have important implications for understanding the extent of the underlying AD pathology, disease severity, and likelihood of progression to dementia.17
MCI Symptoms Are Not Part of
Normal Ageing
The detection of MCI signs and symptoms and the differential diagnosis between MCI due to AD and MCI due to other causes is challenging. Consequently, MCI due to AD is often underdiagnosed and overlooked.19 In addition it can be difficult to differentiate MCI from the decline in cognitive abilities seen with normal ageing.20
In MCI due to AD, episodic memory and executive functions are often the first domains to be impaired.21 Although cognition is the core affected feature, mild neuropsychiatric symptoms (NPS) including disturbances in mood, perception, motivation and behaviour may coexist.22 In some individuals, the primary complaint may be neurobehavioural rather than cognitive.4 NPS are associated with poorer outcomes and greater caregiver burden.22-24
Cognitive Symptoms
Clinical hallmarks of MCI due to AD
Memory
Executive Function
Attention
Language
Visuospatial Function
Alzheimer’s Disease3,21,25
- Increasingly persistent forgetfulness of recent conversations, names, important events or newly learned information
- Becoming increasingly repetitive, e.g. repeating questions after a very short interval, or repeating behaviours and routines
- Worsening ability to retrace steps and find misplaced objects that occurs more frequently over time
- Continually impaired judgment and decision-making, leading to difficulty solving problems
- Increasing difficulty following sequential tasks in social or work settings, like planning an event, working with numbers or cooking a meal
- Regularly losing track of thoughts
- Impaired concentration and taking much longer to do things than before
- Decline in overall attention skills
- Difficulty with processing information, language interpretation, and communication, like stopping mid-conversation and not continuing
- Having trouble naming objects
- Struggling to follow a conversation
- Having difficulty judging distance, color, or contrast, leading to impaired perception of objects and faces
- Trouble with spatial relationships and confusion with time or place
Normal Ageing3
- Simple forgetfulness, now and then, e.g. difficulties recalling a list of items to purchase at the grocery store
- Sometimes forgetting names or appointments, but remembering them later
- Losing things from time to time, but being able to retrace steps to find them
- Slight decline in problem-solving and reasoning, about things that are less familiar
- Planning skills for everyday tasks remains normal, but can be slower when multitasking or when executing a new task
- Slight decline in the ability to concentrate and focus on specific stimuli, and to perform multiple tasks simultaneously, such as talking on the phone while preparing a meal
- Sometimes having trouble finding the right word
- Slight decline in verbal fluency
- Visuospatial abilities, like object perception and spatial perception, remain mostly intact
- Slight decline in perception of spatial orientation
Neurobehavioural Symptoms
Mood and Behaviour
Alzheimer’s Disease3,21,25
- Changing general behavior, perception or personality, like becoming more easily upset in uncomfortable situations
- Acting more irritable, anxious, or experiencing low moods more frequently
Normal Ageing3
- Developing very specific ways of doing things
- Becoming irritable when a routine is disrupted
Clinical assessment of a patient with a cognitive complaint or informant concern, and further investigation of cognitive domains is essential for physicians to differentiate between normal ageing and other causes of cognitive decline.19,20
Cognitive Symptoms
Clinical hallmarks of MCI due to AD
Memory
Alzheimer’s Disease3,21,25
- Increasingly persistent forgetfulness of recent conversations, names, important events or newly learned information
- Becoming increasingly repetitive, e.g. repeating questions after a very short interval, or repeating behaviours and routines
- Worsening ability to retrace steps and find misplaced objects that occurs more frequently over time
Normal Ageing3
- Simple forgetfulness, now and then, e.g. difficulties recalling a list of items to purchase at the grocery store
- Sometimes forgetting names or appointments, but remembering them later
- Losing things from time to time, but being able to retrace steps to find them
Executive Functions
Alzheimer’s Disease3,21,25
- Continually impaired judgment and decision-making, leading to difficulty solving problems
- Increasing difficulty following sequential tasks in social or work settings, like planning an event, working with numbers or cooking a meal
Normal Ageing3
- Slight decline in problem-solving and reasoning, about things that are less familiar
- Planning skills for everyday tasks remains normal, but can be slower when multitasking or when executing a new task
Attention
Alzheimer’s Disease3,21,25
- Regularly losing track of thoughts
- Impaired concentration and taking much longer to do things than before
- Decline in overall attention skills
Normal Ageing3
- Slight decline in the ability to concentrate and focus on specific stimuli, and to perform multiple tasks simultaneously, such as talking on the phone while preparing a meal
Language
Alzheimer’s Disease3,21,25
- Difficulty with processing information, language interpretation, and communication, like stopping mid-conversation and not continuing
- Having trouble naming objects
- Struggling to follow a conversation
Normal Ageing3
- Sometimes having trouble finding the right word
- Slight decline in verbal fluency
Visuospatial Function
Alzheimer’s Disease3,21,25
- Having difficulty judging distance, color, or contrast, leading to impaired perception of objects and faces
- Trouble with spatial relationships and confusion with time or place
Normal Ageing3
- Visuospatial abilities, like object perception and spatial perception, remain mostly intact
- Slight decline in perception of spatial orientation
Neurobehavioral Symptoms
Mood and Behavior
Alzheimer’s Disease3,21,25
- Changing general behavior, perception or personality, like becoming more easily upset in uncomfortable situations
- Acting more irritable, anxious, or experiencing low moods more frequently
Normal Ageing3
- Developing very specific ways of doing things
- Becoming irritable when a routine is disrupted
Clinical assessment of a patient with a cognitive complaint or informant concern, and further investigation of cognitive domains is essential for physicians to differentiate between normal ageing and other causes of cognitive decline.19,20
What’s next
Diagnosis of MCI due to Alzheimer’s
Disease
An Alzheimer's diagnosis strategy must combine clinical assessment and biomarker evaluation.
References
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3.Alzheimer’s Association. Alzheimer’s Association Report: 2021 Alzheimer’s disease facts and figures. Alzheimer’s Dement. 2021 Mar;17(3):327-406.
4.Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA Research Framework: To-ward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535-562.
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7.World Health Organization (WHO). Global action plan on the public health response to dementia 2017-2025. www.who.int/publications/i/item/9789241513487. Accessed January, 2022.
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13.Potashman M, Buessing M, Levitchi Benea M, et al. Estimating Progression Rates Across the Spectrum of Alzheimer's Disease for Amyloid-Positive Individuals Using National Alzheimer's Coordinating Center Data. Neurol Ther. 2021;10(2):941-953.
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19.Galvin JE. Using Informant and Performance Screening Methods to Detect Mild Cognitive Impairment and Dementia. Curr Geriatr Rep. 2018;7(1):19-25.
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23. Ismail Z, Smith EE, Geda Y, et al. Neuropsychiatric symptoms as early manifestations of emergent dementia: Provisional diagnostic criteria for mild behavioral impairment. Alzheimers Dement. 2016;12(2):195-202.
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25.Winblad B, Palmer K, Kivipelto M, et al. Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med. 2004; 256:240–246.