Subjective cognitive concerns and neuropsychiatric predictors of progression to the early clinical stages of Alzheimer disease.
OBJECTIVE
To examine neuropsychiatric and neuropsychological predictors of progression from normal to early clinical stages of Alzheimer disease (AD).


METHODS
From a total sample of 559 older adults from the Massachusetts Alzheimer's Disease Research Center longitudinal cohort, 454 were included in the primary analysis: 283 with clinically normal cognition (CN), 115 with mild cognitive impairment (MCI), and 56 with subjective cognitive concerns (SCC) but no objective impairment, a proposed transitional group between CN and MCI. Two latent cognitive factors (memory-semantic, attention-executive) and two neuropsychiatric factors (affective, psychotic) were derived from the Alzheimer's Disease Centers' Uniform Data Set neuropsychological battery and Neuropsychiatric Inventory brief questionnaire. Factors were analyzed as predictors of time to progression to a worse diagnosis using a Cox proportional hazards regression model with backward elimination. Covariates included baseline diagnosis, gender, age, education, prior depression, antidepressant medication, symptom duration, and interaction terms.


RESULTS
Higher/better memory-semantic factor score predicted lower hazard of progression (hazard ratio [HR] = 0.4 for 1 standard deviation [SD] increase, p <0.0001), and higher/worse affective factor score predicted higher hazard (HR = 1.3 for one SD increase, p = 0.01). No other predictors were significant in adjusted analyses. Using diagnosis as a sole predictor of transition to MCI, the SCC diagnosis carried a fourfold risk of progression compared with CN (HR = 4.1, p <0.0001).


CONCLUSIONS
These results identify affective and memory-semantic factors as significant predictors of more rapid progression from normal to early stages of cognitive decline and highlight the subgroup of cognitively normal elderly with SCC as those with elevated risk of progression to MCI.
Center for Alzheimer Research and Treatment and Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. Electronic address: njdonovan@partners.org.
Nancy J
NJ
Donovan
Center for Alzheimer Research and Treatment and Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Rebecca E
RE
Amariglio
Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Amy S
AS
Zoller
Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Rebecca K
RK
Rudel
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Teresa
T
Gomez-Isla
Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Deborah
D
Blacker
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Bradley T
BT
Hyman
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Joseph J
JJ
Locascio
Center for Alzheimer Research and Treatment and Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Keith A
KA
Johnson
Center for Alzheimer Research and Treatment and Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Reisa A
RA
Sperling
Center for Alzheimer Research and Treatment and Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Gad A
GA
Marshall
Center for Alzheimer Research and Treatment and Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Dorene M
DM
Rentz
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000503:physiopathology* / Q000523:psychology; D060825:Cognitive Dysfunction / Q000175:diagnosis / Q000503:physiopathology* / Q000523:psychology; D059026:Diagnostic Self Evaluation; D018450:Disease Progression; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008404:Massachusetts; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D012306:Risk
Alzheimer disease; Neuropsychiatric and neuropsychological factors; mild cognitive impairment; subjective cognitive concerns