Examination of the clinicopathologic continuum of Alzheimer disease in the autopsy cohort of the National Alzheimer Coordinating Center.
To test the hypothesis that Alzheimer disease (AD) is a clinical and pathologic continuum between normal aging and end-stage dementia, we selected a convenience sample of subjects from the National Alzheimer Coordinating Center 2005 to 2012 autopsy cohort (n = 2,083) with the last clinical evaluation within 2 years before autopsy and no other primary neuropathologic diagnosis. Demographic and neuropathologic characteristics were correlated with the Clinical Dementia Rating-Sum of Boxes in the 835 subjects meeting these criteria. Both neuritic plaques and neurofibrillary tangles independently predicted Clinical Dementia Rating-Sum of Boxes. Severe small-vessel disease, severe amyloid angiopathy, and hippocampal sclerosis were also independently associated with the degree of cognitive impairment. By contrast, education was a strong independent protective factor against cognitive deficits. The cause of mild to moderate dementia remained uncertain in 14% of the patients. Inverse probability weighting suggests the generalizability of these results to nonautopsied cohorts. These data indicate that plaques and tangles independently contribute to cognitive impairment, that concurrent vascular disease strongly correlates with cognitive dysfunction even in a sample selected to represent the AD pathologic continuum, and that education further modifies clinical expression. Thus, multiple concomitant etiologies of brain damage and premorbid characteristics contribute to the uncertainty of AD clinicopathologic correlations based only on tangles and plaques.
From the Massachusetts Alzheimer Disease Research Center, Massachusetts General Hospital (AS-P, MPF, BTH); and Department of Biostatistics, Harvard School of Public Health (JQ, RAB), Boston; and Division of Biostatistics and Epidemiology, University of Massachusetts, Amherst (JQ), Massachusetts; and National Alzheimer Coordinating Center and Department of Epidemiology, University of Washington, Seattle, Washington (SEM).
Alberto
A
Serrano-Pozo
Jing
J
Qian
Sarah E
SE
Monsell
Matthew P
MP
Frosch
Rebecca A
RA
Betensky
Bradley T
BT
Hyman
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications* / Q000473:pathology*; D001344:Autopsy; D001921:Brain / Q000473:pathology*; D003072:Cognition Disorders / Q000175:diagnosis / Q000209:etiology* / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D011569:Psychiatric Status Rating Scales; D012189:Retrospective Studies