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.
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• The pre-mild cognitive impairment stage of Alzheimer disease 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.
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• 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.
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• 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.
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• 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, and cognitive interventions.
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) (46). This scale included 2 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 2 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 (04). 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 3 groups: (1) amnestic pre-mild cognitive impairment-NP patients who had impairment at 1.5 SD or more on 1 of 3 memory measures; (2) amnestic pre-mild cognitive impairment NP+ patients who had impairment at 1.5 SD or more on 2 or 3 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 (29).
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 (09). 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 (24). 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 2019, 1425 cognitively healthy controls from 3 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 6 years to meet clinical criteria for mild cognitive impairment (19).
Pre-mild cognitive impairment with subjective cognitive decline. In 2014, the working group of the Subjective Cognitive Decline Initiative developed a conceptual framework that subdivided the course of Alzheimer disease into 3 stages: pre-mild cognitive impairment with subjective cognitive decline (self-experienced decline in cognitive capacity but no objective cognitive deficits), mild cognitive impairment (episodic memory deficits present but no functional problems), and Alzheimer dementia (Alzheimer biomarkers present, memory deficits present, as well as functional decline) (23). These authors pointed out that to make a diagnosis of pre-mild cognitive impairment, the symptoms could not be explained by medication, substance abuse, medical disease, or another psychiatric or neurologic disease.