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Evidence-Based Reviews

Mild cognitive impairment: How can you be sure?

Use evidence-based cognitive and functional tests to differentiate MCI from dementia and normal healthy aging.

Vol. 7, No. 4 / April 2008

Mr. R, age 67, presents with what he describes as uncharacteristic “memory loss” that is affecting his ability to run his accounting business. He and his wife relate that he was doing well until approximately 9 months ago, when he started showing difficulties remembering clients’ names and addresses.

His wife became extremely concerned when he made serious accounting errors in a 1-month period that resulted in the loss of a longtime customer. Mr. R has become easily distracted and absentminded as well, and his wife reports he is misplacing things around the house.

Screening for mild cognitive impairment (MCI) is not recommended for asymptomatic, cognitively healthy older persons, but memory complaints in individuals age >50—especially when corroborated by a reliable informant—warrant further assessment. Your challenge is to determine whether subtle cognitive changes in patients such as Mr. R are part of normal aging, caused by medical or mental illnesses, or a harbinger of Alzheimer’s disease (AD) or another dementia.

Although no treatments can yet prevent dementia, substantial new research is defining the MCI diagnosis for clinicians. This article describes:

  • the evolving understanding of MCI and its subtypes
  • risk factors for converting from MCI to AD
  • an evidence-based work-up (including functional, cognitive, and neuropsychological testing)
  • neuroprotective strategies for patients with an MCI diagnosis, including evidence on cholinesterase inhibitors, vitamin E, and anti-inflammatory agents.

MCI’s evolving definition

MCI is characterized by subjective and objective cognitive decline greater than expected for an individual’s age and education but less than the functional deficit required for a dementia diagnosis. MCI is proposed to identify persons with early but pathologic cognitive impairment that has a high risk to progress to AD and possibly other dementias.

MCI is thought to be a transitional state between normal aging and dementia.1 Its estimated prevalence in the general population is 19% among individuals age <75 and 29% in those age >85.2

MCI subtypes. Some experts view MCI as a single entity, whereas others suggest amnestic (aMCI) and nonamnestic (nMCI) subtypes.1,3 Each subtype is further divided into single and multiple cognitive domains. So, for example, the diagnosis would be:

  • aMCI-single cognitive domain for memory impairment only
  • aMCI-multiple cognitive domains for memory impairment plus nonmemory deficits, such as in language, executive function, or visuospatial function
  • nMCI-single or multiple cognitive domains for nonmemory deficits without memory impairment.

MCI subtypes may have different outcomes for progression to dementia, and all progressive dementias may have their own predementia states.4 Vascular MCI, for instance, is thought to result from cerebrovascular disease and is proposed to describe a prodrome of vascular dementia.5

Determining a patient’s MCI subtype is still a research activity and calls for comprehensive neuropsychological testing. MCI patients perform at least 1.5 standard deviations below the average for age- and education-matched healthy individuals on objective measures of memory.1

Conversion to dementia

In longitudinal population studies patients with MCI have shown an 11% to 33% risk of developing dementia within 2 years, whereas 44% reverted to normal 1 year later. Reasons for reversibility may include variable definitions of MCI among the longitudinal studies and the possibility that patients who recovered or improved may have had reversible causes of dementia.1

When patients with MCI are followed over time, they progress not only to AD but also to non-AD dementias. For example, patients with Parkinson’s disease (PD) and MCI may be at higher risk of progressing to dementia than cognitively intact PD patients.6 MCI patients with the e4 allele of the apolipoprotein E gene (ApoE e4) are at increased risk to convert from MCI to AD.7

Individuals with aMCI (Table 1)8 progress to AD at a rate of 10% to 15% per year, compared with 1% to 2% per year in normal elderly persons. The Mayo AD research center studies reported a conversion rate of up to 80% from aMCI to AD within 6 years.9

Research focuses on identifying preclinical AD states and potential targets for intervention using disease-modifying therapies. Some experts consider MCI to be the earliest clinical manifestation of AD, at least in a subgroup of patients.

Identifying markers to predict which patients are likely to convert from MCI to dementia also is a major research objective. In addition to ApoE status (Table 2),7,9-15 predictors of conversion may include:

  • hippocampal atrophy13
  • reduced metabolism in the temporoparietal cortex and posterior cingulum14
  • elevated CSF tau and the 42 amino acid form of ß-amyloid (Aß 42).15

Research techniques such as structural neuroimaging, positron-emission tomography, functional magnetic resonance imaging (fMRI), and cerebrospinal fluid biomarkers have not been defined for clinical use, however.

Neuropsychiatric symptoms. Individuals with MCI and neuropsychiatric symptoms may be at particular risk for progressing to dementia. Agitation or depression are more prevalent in persons with MCI than in normal elderly but less prevalent than in those with dementia (Table 3).10,16

The cross-sectional, community-based Cardiovascular Health Study showed one or more neuropsychiatric symptom in:

  • 16% of normal healthy elderly
  • 43% of MCI patients
  • 75% of dementia patients.16

Depression (20%), apathy (15%), and irritability (15%) were the neuropsychiatric symptoms reported most frequently in MCI patients, compared with apathy (36%), depression (32%), and agitation/aggression (30%) in dementia patients.

Sleep disturbances and anxiety in persons with MCI may predict progression to AD.10 A baseline high frequency of apathy in aMCI patients has been associated with progression to AD within 1 year.11

Table 1

Amnestic MCI: Proposed diagnostic criteria

Subjective memory impairment, preferably corroborated by a reliable informant

Reduced performance on objective memory tests, compared with persons of similar age and educational background

Typical general cognitive function

Intact basic activities of daily living and intact or minimally impaired instrumental activities of daily living

Absence of dementia

MCI: mild cognitive impairment

Source: Reference 8

Table 2

Factors shown to predict conversion from MCI to dementia


Predictors of conversion


Cognitive: Amnestic MCI
Neuropsychiatric: Depression, apathy, and possibly nighttime behaviors and anxiety

Neuropsychological tests

Clock-drawing test, Trail-Making Test B, Symbol Digit Modalities Test, Delayed 10-Word List Recall, New York University Paragraph Recall Test (Delayed), ADAS-Cog total score


MRI: Entorhinal cortex and hippocampal atrophy
PET: Medial temporal region, parietotemporal association cortex, and posterior cingulate hypometabolism
fMRI: Abnormal hippocampal, posterior cingulate, and medial temporal region activation on memory tasks

CSF markers

Increase: t-tau, p-tau
Decrease: Aß 42

Genetic markers

ApoE e4 carriers

ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive subscale; ApoE e4: apolipoprotein E gene, e4 allele; CSF: cerebrospinal fluid; MCI: mild cognitive impairment; MRI: magnetic resonance imaging; fMRI: functional MRI; PET: positron-emission tomography

Source: References 7,9-15

Table 3

Neuropsychiatric symptoms: Rising prevalence mirrors cognitive deterioration in elderly patients*

Neuropsychiatric symptoms

Normal elderly


Mild AD

Depressed mood/dysphoria




Nighttime behaviors/sleep




















Eating/appetite disturbance








Aberrant motor behavior
















* 0 = 0%; +/- = 1% to 5%; + = 6% to 10%; ++ = 11% to 20%; +++ = 21% to 40%

MCI: mild cognitive impairment; AD: Alzheimer’s disease

Source: References 10,16

Depression and MCI

Depression and cognitive complaints overlap considerably in older adults. Depressed patients without dementia show persistent cognitive deficits even after depression remits. In some patients, new-onset geriatric depression is considered a prodrome of MCI and AD. Given that AD neuropathologic changes precede clinical symptoms by many years, depression and AD have been proposed as different clinical manifestations of AD pathology.17

Among patients with MCI, 20% meet criteria for major depression and 26% for minor depression. Symptoms often include sadness, poor concentration, inner tension, pessimistic thoughts, lassitude, and insomnia.18

Depressed MCI patients are at higher risk of developing dementia than those without depression, especially if cognitive measures do not improve after depression is treated.12 Similarly, cognitively intact older persons who develop depression are at increased risk for MCI, particularly if they carry the ApoE e4 genotype.19

In the only study in which MCI patients’ neuropsychiatric symptoms have been treated, 39 elderly patients with depression and MCI received open-label sertraline, ≤200 mg/d, for 12 weeks. Among the 26 patients who completed the trial, 17 showed moderate improvement in depressive symptoms, attention, and executive function, and 9 showed no response.20

Recommendation. In clinical practice, antidepressant treatment—usually a selective serotonin reuptake inhibitor (SSRI), with or without psychotherapy—is recommended for the MCI patient with comorbid major depression.

CASE CONTINUED: No signs of depression

Mr. R’s medical, neurologic, and substance use history is unremarkable. Family history includes AD in a paternal aunt diagnosed at age 82. Mr. R reports no history of mood, sleep, or appetite changes and no psychotic symptoms. He shows no deficits in activities of daily living (ADL), although his wife recently took over paying household bills after he forgot to make a payment.

Evidence-based workup

Functional assessment. In the differential diagnosis of MCI, give special attention to functional impairment, which points toward dementia. ADL generally are preserved in MCI, and minimal deterioration is seen in instrumental activities of daily living (IADL). A relatively easy way to assess function is to use the Alzheimer’s Disease Functional Assessment and Change Scale (ADFACS), which is based on 16 ADL and IADL items (Table 4).21

A substantial functional decline precludes an MCI diagnosis, although the degree of functional decline can be difficult to assess in older adults with physical limitations caused by medical comorbidities.

Cognitive assessment. Because most individuals with MCI score in the normal range on the Folstein Mini-Mental State Examination (MMSE), the modified MMSE (3MS)22 may be more sensitive for detecting MCI. The 3MS retains the MMSE’s brevity (≤10 minutes to administer) but incorporates 4 additional items, has more graded scoring responses, and broadens the score range to 0 to 100. The clock-drawing test also is sensitive for MCI, especially in detecting early visuoconstructional dysfunction.

The Montreal Cognitive Assessment (MoCA) is a 10-minute, 30-point scale designed to help clinicians detect MCI (see Related Resources). The MoCA usually is given with the modified MMSE for a comprehensive cognitive assessment.

Nasreddine et al23 administered the MoCA and MMSE to 94 patients who met clinical criteria for MCI, 93 patients with mild AD, and 90 healthy cognitively normal elderly persons, using a cutoff score of 26. MoCA showed:

  • 90% sensitivity for detecting MCI (compared with 18% for the MMSE)
  • 87% specificity to exclude normal elderly persons.

The average MoCA score in patients with AD was much lower than in individuals with MCI, but score ranges of these 2 groups overlapped. Therefore, a score <26 could indicate either MCI or AD, and the distinction depends on assessing the patient for functional impairment.

Neuropsychological testing can be more sensitive than office-based screening tools in defining MCI subtypes. In the Alzheimer’s Disease Cooperative Study (ADCS), the neuropsychological measures that most accurately predicted progression of patients with aMCI to AD within 36 months were the:

  • Symbol Digit Modalities Test
  • New York University Paragraph Recall Test (Delayed)
  • Delayed 10-Word List Recall
  • Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score.24

Laboratory tests, imaging. Use laboratory studies (Table 5) to rule out reversible causes of MCI symptoms.8 Reserve CSF studies for suspected CNS infection (such as meningitis, human immunodeficiency virus, or neurosyphilis) and brain imaging for suspected cerebral pathology (such as infarct, subdural hematoma, normal pressure hydrocephalus, or tumor).

Table 4

Alzheimer’s Disease Functional Assessment and Change Scale (ADFACS)

Basic ADL

Instrumental ADL (IADL)


Use of telephone


Household tasks


Using household appliances

Personal hygiene and grooming

Managing money




Food preparation


Ability to get around inside and outside home


Hobbies and leisure activities


Handling personal mail


Grasp of situations and explanations

The 16-item ADFACS total score ranges from 0 to 54 (best to worst):

  • Rate basic ADLs from 0 (no impairment) to 4 (very severe impairment), for a total score range of 0 to 24.
  • Rate IADLs from 0 (no impairment) to 3 (severe impairment), for a total score range of 0 to 30.

Use total scores to assess for functional decline from baseline. A decline from 0 to 1 on individual ADL and IADL items is not considered clinically significant.

ADL: activities of daily living

Source: Reprinted with permission from reference 21

Table 5

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