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  • Updated 10.30.2023
  • Released 11.12.2019
  • Expires For CME 10.30.2026

Pre-mild cognitive impairment



In this article, the authors provide an overview of the diagnostic concept of pre-mild cognitive impairment, or subjective cognitive decline, which is a self-reported state of cognitive decline that is a transition state between normal aging and mild cognitive impairment. The authors also discuss the differential diagnosis for pre-Alzheimer mild cognitive impairment; memory complaints can also be caused by other neurodegenerative diseases, as well as medications, psychiatric conditions, sleep disorders, and medical illnesses. They review the various clinical, behavioral, radiologic, and genetic factors that are useful in predicting which cognitively normal older individuals will eventually go on to develop pre-mild cognitive impairment and dementia and discuss prevention and management techniques to slow this progression.

Key points

• The pre-mild cognitive impairment stage of Alzheimer disease (subjective cognitive decline) is present when there are subtle symptoms of cognitive decline, but when the patient’s clinical signs of cognitive impairment are still insufficient to meet criteria for mild cognitive impairment. Mild behavioral impairment (affective dysregulation, poor impulse control, or decreased motivation) is more prevalent among those with mild cognitive impairment than among those with subjective cognitive decline.

• The presence of subjective cognitive decline is not always sufficient to diagnose pre-Alzheimer mild cognitive impairment because other types of dementia and dementia mimics (medications, sleep disorders, psychiatric and medical conditions) can produce memory loss and other cognitive symptoms.

• The imaging biomarker that best predicts transition from pre-mild cognitive impairment to mild cognitive impairment is abnormal amyloid PET, and the one that predicts transition from mild cognitive impairment to Alzheimer disease is abnormal tau PET. MRI features that best predict the transition to mild cognitive impairment are reduced hippocampal volume and any microhemorrhages, regardless of location. In a cognitively unimpaired older adult, the plasma biomarkers that best predict Alzheimer disease dementia within the first six years are p-tau 181 and the APOE-4 allelic carrier status.

• Longitudinal studies have shown that patients who have subjective cognitive decline or pre-mild cognitive impairment progress cognitively and functionally to mild cognitive impairment or dementia at a rate of about 7% per year. The rate of progression can be slowed with diet, exercise, as well as social, medical, and cognitive interventions.

• Patients with pre-mild cognitive impairment progress faster to mild cognitive impairment than those who have no cognitive impairment at all, yet the rate of progression is slower than that seen when mild cognitive impairment progresses to dementia. Having more years of education and living in a more advantaged neighborhood increases cognitive reserve (slower decline in cognitive scores over time) and brain reserve (less cortical thinning).

Historical note and terminology

Subjective cognitive decline. This is the term used to describe subjective symptoms of memory loss or other cognitive changes that precede mild cognitive impairment or dementia. In 1982, Reisberg and others developed the 7-point global deterioration scale (GDS) for the description of progression from normal old age (GDS=0) to end-stage Alzheimer disease (GDS=7) (84). This scale included two stages (GDS=1 and GDS=2) that preceded mild cognitive impairment (GDS=3). Subjects with GDS stage 1 had subjective cognitive symptoms but no objective signs of cognitive decline whereas those with stage two had symptoms and subtle signs of cognitive decline.

Amnestic pre-mild cognitive impairment. In 2008, Caselli and colleagues were performing a longitudinal study on a group of healthy apolipoprotein E epsilon 4 (APOE-e4) carriers when they noticed an accelerated cognitive decline among those who appeared to be in a transitional state between normal aging and mild cognitive impairment (13). They identified these patients as having amnestic pre-mild cognitive impairment because their cognition declined more rapidly than normal controls but more slowly than those with mild cognitive impairment. In 2012, Loewenstein and others divided pre-mild cognitive impairment patients into three groups: (1) amnestic pre-mild cognitive impairment-NP patients who had impairment at 1.5 SD or more on one of three memory measures; (2) amnestic pre-mild cognitive impairment NP+ patients who had impairment at 1.5 SD or more on two or three memory measures; and (3) pre-mild cognitive impairment-clinical patients who had normal cognitive results on all memory and nonmemory cognitive measures, even though they had subjective complaints (54).

Predementia Alzheimer disease. In 2013, data from the Einstein Aging Study were used to prospectively evaluate the free recall score from the free and cued selective reminding test and the logical memory immediate recall subtest of the Wechsler memory scale-revised for prediction of incident Alzheimer disease dementia among a community-based cohort of 854 older individuals (> 70 years) who had memory complaints but no dementia (20). After 2 to 4 years, they found that the free recall score had better operating characteristics than the logical memory score in predicting which of the predementia patients would develop Alzheimer disease. APOE-e4 status improved positive predictive value but it did not affect the choice of optimal cut points.

Preclinical Alzheimer disease. In 2013, 145 cognitively normal individuals over 45 years of age were recruited from a longitudinal study of adult children of Alzheimer disease patients or normal elderly adults (45). Amyloid status was assessed with CSF measurement of amyloid-beta 42 levels (22.5% of the participants were amyloid positive). The amyloid positive group showed worse sleep quality than the amyloid negative group. In 2009, 183 Pittsburgh participants older than 80 years from the Ginkgo biloba Memory Study (145 normal; 38 MCI) were tested with amyloid PET and MRI at baseline. When they were re-examined five years later, 33% had developed dementia, and the best predictors were low hippocampal volume, high white matter hyperintensity volume, and the deposition of amyloid-beta on PET (55). In 2019, 1425 cognitively healthy controls from three large prospective studies were tested at baseline with amyloid PET or CSF amyloid-beta 42 levels. Those with preclinical Alzheimer disease (positive amyloid PET or CSF beta-amyloid) progressed cognitively over an average of six years to meet clinical criteria for mild cognitive impairment (39). In 2022, results from 461 cognitively unimpaired controls were reported from the BioFINDER study (77). Those who developed Alzheimer disease dementia within six years were more likely to have had elevated plasma levels of p-tau 181 at baseline. In 2023, 91 cognitively normal adults were followed in the Harvard Aging Brain Study (81). Those who developed Alzheimer disease after 4.6 years were more likely to have lower novelty-related locus coeruleus function with entorhinal tau deposition on tau-PET and elevated amyloid levels on amyloid-PET.

Resistance and resilience in Alzheimer disease. About 30% of people remain cognitively normal throughout their lifetime, even though at autopsy they have signs of Alzheimer disease (03). “Resilience” is the term used when cognitive symptoms are less severe than would be expected, given the pathology that is present (this “cognitive reserve” can often be explained by a patient’s higher level of education, their consumption of a healthy diet, their participation in regular exercise, or avoidance of cardiovascular risk factors, etc.). Higher cognitive reserve has been shown to attenuate the genetic risk of Alzheimer disease dementia (80). “Resistance” is the term used when amyloid or tau levels are less than would be expected, given the patient’s family history, etc. For example, there is an Icelandic sequence variation in the APP gene that confers protection against the onset and progression of Alzheimer disease (32).

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