Mild cognitive impairment — diagnostic criteria, progression and treatment modalities

The MCI construct originated with Ronald Petersen and the Mayo Clinic group, and has been repeatedly revised as biomarker science advanced, chiefly to locate MCI within the prodromal phase of Alzheimer’s disease.

MCI is defined by (i) a subjective disorder of memory and/or other cognitive domains, (ii) objective impairment of memory and/or other cognitive domains, and (iii) no significant impact on activities of daily living. Patients therefore do not meet accepted diagnostic criteria for dementia.

Old age alone does not cause cognitive impairment severe enough to render a person dysfunctional. Slowed thinking, slowed reaction time, mild recent memory loss and impaired executive function may occur with age and may or may not progress to dementia — labelled MCI or cognitive impairment, not dementia (CIND).

MCI is heterogeneous: it may be due to AD (prodromal AD), other neurodegenerative disease, depression, vascular lesions or traumatic brain injury.

Concern regarding a change in cognition — obtained from the patient, an informant, or a clinician observing the patient.

Impairment in one or more cognitive domains — performance lower than expected for the patient’s age and education.

Preservation of independence in functional abilities — mild difficulty with complex tasks is common, but independence is maintained with minimal aids or assistance.

Not demented — changes are mild enough that there is no significant impairment of social or occupational functioning. Note that no defined thresholds are specified for the degree of cognitive impairment; the syndrome is almost identical to Petersen’s original description.

NIA-AA biomarkers fall into three classes: (i) markers directly reflecting AD pathology — CSF low Aβ42, amyloid PET, CSF raised total tau or p-tau; (ii) non-specific markers of neuronal injury — atrophy on MRI, hypometabolism or hypoperfusion on FDG-PET/SPECT; (iii) markers of cell death, synaptic damage, oxidative stress or inflammation.

Levels of diagnostic certainty: MCI due to AD “high likelihood” = positive Aβ and positive neuronal-injury biomarker; “intermediate likelihood” = one positive with the other untested; “unlikely due to AD” = both negative. Results may also be uninformative if ambiguous or conflicting.

The International Working Group (Dubois) criteria for prodromal AD run in parallel: IWG-1 requires abnormal amyloid, tau, FDG-PET or hippocampal atrophy; IWG-2 requires abnormal CSF Aβ1-42 and tau, or abnormal amyloid PET. They also separate typical AD (amnestic syndrome of hippocampal type) from atypical AD (posterior cortical atrophy, logopenic variant, frontal variant).

The NIA-AA 2018 Research Framework introduced the AT(N) classification: A = aggregated Aβ (CSF Aβ42 or Aβ42/40, amyloid PET); T = aggregated tau (CSF p-tau, tau PET); (N) = neurodegeneration, non-specific and hence bracketed (MRI, FDG-PET, CSF total tau). It uses the label “Alzheimer’s disease with MCI” rather than “MCI due to AD”.

DSM-5 replaced dementia with major neurocognitive disorder and introduced mild neurocognitive disorder (mNCD), which parallels MCI — cognitive complaint, psychometric impairment and relative preservation of ADLs.

Just over 20% of people aged 71 and older in the United States have cognitive impairment without dementia.

Progression: up to 15–20% of those diagnosed with MCI or CIND convert to dementia over the course of a year. Progression is not inevitable — a proportion remain stable and some revert to normal, especially where depression or drugs were contributory.

Subjective cognitive decline (SCD) precedes MCI; cross-sectional studies show SCD does not necessarily correlate with objective impairment, but longitudinal studies link SCD to future AD or dementia. A cognitively unimpaired subject with a positive AD biomarker is regarded as at risk of AD or in a preclinical stage.

No intervention has been shown to prevent progression to dementia in classical practice; the therapeutic implications of MCI remain an area of intensive research. Cholinesterase inhibitors are not licensed for MCI, and European practice prescribes them less often than American practice.

Identify and treat contributory conditions: depression (SSRI such as citalopram or sertraline, or mirtazapine, all with minimal cognitive side effects), hypothyroidism, vitamin B12 deficiency, drug side effects, obstructive sleep apnoea and alcohol excess; and withdraw anticholinergic drugs.

Vascular risk factor control, especially hypertension, may favourably influence the clinical course of both degenerative and vascular cognitive impairment. Physical activity and multicomponent exercise carry the most promising evidence, supported by the FINGER trial of multidomain intervention; the MAPT trial of omega-3 with or without multidomain intervention was largely negative except in amyloid-positive subgroups.

Practical management includes an informed discussion of diagnosis and prognosis, arrangements for ongoing review and support, cognitive training and stimulation, driving and safety assessment, and advance planning. Most countries, including India, lack national guidelines on biomarker use in early AD, which limits harmonisation of practice.