Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer's pathology.
There is considerable debate whether Alzheimer's disease (AD) originates in basal forebrain or entorhinal cortex. Here we examined whether longitudinal decreases in basal forebrain and entorhinal cortex grey matter volume were interdependent and sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, we demonstrate that basal forebrain volume predicts longitudinal entorhinal degeneration. Models of parallel degeneration or entorhinal origin received negligible support. We then integrated volumetric measures with an amyloid biomarker sensitive to pre-symptomatic AD pathology. Comparison between cognitively matched normal adult subgroups, delineated according to the amyloid biomarker, revealed abnormal degeneration in basal forebrain, but not entorhinal cortex. Abnormal degeneration in both basal forebrain and entorhinal cortex was only observed among prodromal (mildly amnestic) individuals. We provide evidence that basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin.
Medical Research Council, Cognition and Brain Sciences Unit, 15 Chaucer Road, Cambridge CB2 7EF, UK.|Wolfson College, University of Cambridge, Barton Road, Cambridge CB3 9BB, UK.
Taylor W
0000-0003-0585-7524
TW
Schmitz
Laboratory of Brain and Cognition, Department of Human Development, Human Neuroscience Institute, Cornell University, Martha Van Rensselaer Hall G62C, Ithaca, New York 14853, USA.
R
0000-0003-1530-8916
R
Nathan Spreng
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D000682:Amyloid / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D066187:Basal Forebrain / Q000000981:diagnostic imaging* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D015331:Cohort Studies; D018728:Entorhinal Cortex / Q000000981:diagnostic imaging* / Q000473:pathology; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D011379:Prognosis
D000682:Amyloid; D016229:Amyloid beta-Peptides; D015415:Biomarkers