TY - JOUR
T1 - The presubiculumlinks incipient amyloid and tau pathology to memory function in older persons
AU - Jacobs, Heidi I. L.
AU - Augustinack, Jean C.
AU - Schultz, Aaron P.
AU - Hanseeuw, Bernard J.
AU - Locascio, Joseph
AU - Amariglio, Rebecca E.
AU - Papp, Kathryn
AU - Rentz, Dorene M.
AU - Sperling, Reisa A.
AU - Johnson, Keith A.
N1 - Funding Information:
This work was supported in part by the Athinoula A. Martinos Center for Biomedical Imaging P41 EEB015896 and shared instrumentation grants S10RR021110, S10OD010364, S10RR023401, S10RR023043, and 1S10RR019307. The research was supported in major part by the HABS (P01 AG036694). H. Jacobs received funding from Alzheimer Nederland (WE.15-2014-06). K. Papp is funded by National Institute on Aging grant K23 AG053422-01 and the Alzheimer's Association. K. Johnson received funding from NIH grants R01 EB014894, R21 AG038994, R01 AG026484, R01 AG034556, P50 AG00513421, U19 AG10483, P01 AG036694, R13 AG042201174210, R01 AG027435, and R01 AG037497; Alzheimer's Association grant ZEN-10-174210; the Harvard Neurodiscovery Center; and Fidelity Biosciences. R. Sperling receives research support from the following grants: P01 AG036694, U01 AG032438, U01 AG024904, R01 AG037497, R01 AG034556, K24 AG0350007, P50 AG005134, U19 AG010483, R01 AG027435, Fidelity Biosciences, Harvard NeuroDiscovery Center, and the Alzheimer's Association.
Publisher Copyright:
© American Academy of Neurology.
PY - 2020/5/5
Y1 - 2020/5/5
N2 - ObjectiveTo identify the hippocampal subregions linking initial amyloid and tau pathology to memory performance in clinically normal older individuals, reflecting preclinical Alzheimer disease (AD).MethodsA total of 127 individuals from the Harvard Aging Brain Study (mean age 76.22 +/- 6.42 years, 68 women [53.5%]) with a Clinical Dementia Rating score of 0, a flortaucipir tau-PET scan, a Pittsburgh compound B amyloid-PET scan, a structural MRI scan, and cognitive testing were included. From these images, we calculated neocortical, hippocampal, and entorhinal amyloid pathology; entorhinal and hippocampal tau pathology; and the volumes of 6 hippocampal subregions and total hippocampal volume. Memory was assessed with the selective reminding test. Mediation and moderation analyses modeled associations between regional markers and memory. Analyses included covariates for age, sex, and education.ResultsNeocortical amyloid, entorhinal tau, and presubiculum volume univariately associated with memory performance. The relationship between neocortical amyloid and memory was mediated by entorhinal tau and presubiculum volume, which was modified by hippocampal amyloid burden. With other biomarkers held constant, presubiculum volume was the only marker predicting memory performance in the total sample and in individuals with elevated hippocampal amyloid burden.ConclusionsThe presubiculum captures unique AD-related biological variation that is not reflected in total hippocampal volume. Presubiculum volume may be a promising marker of imminent memory problems and can contribute to understanding the interaction between incipient AD-related pathologies and memory performance. The modulation by hippocampal amyloid suggests that amyloid is a necessary, but not sufficient, process to drive neurodegeneration in memory-related regions.
AB - ObjectiveTo identify the hippocampal subregions linking initial amyloid and tau pathology to memory performance in clinically normal older individuals, reflecting preclinical Alzheimer disease (AD).MethodsA total of 127 individuals from the Harvard Aging Brain Study (mean age 76.22 +/- 6.42 years, 68 women [53.5%]) with a Clinical Dementia Rating score of 0, a flortaucipir tau-PET scan, a Pittsburgh compound B amyloid-PET scan, a structural MRI scan, and cognitive testing were included. From these images, we calculated neocortical, hippocampal, and entorhinal amyloid pathology; entorhinal and hippocampal tau pathology; and the volumes of 6 hippocampal subregions and total hippocampal volume. Memory was assessed with the selective reminding test. Mediation and moderation analyses modeled associations between regional markers and memory. Analyses included covariates for age, sex, and education.ResultsNeocortical amyloid, entorhinal tau, and presubiculum volume univariately associated with memory performance. The relationship between neocortical amyloid and memory was mediated by entorhinal tau and presubiculum volume, which was modified by hippocampal amyloid burden. With other biomarkers held constant, presubiculum volume was the only marker predicting memory performance in the total sample and in individuals with elevated hippocampal amyloid burden.ConclusionsThe presubiculum captures unique AD-related biological variation that is not reflected in total hippocampal volume. Presubiculum volume may be a promising marker of imminent memory problems and can contribute to understanding the interaction between incipient AD-related pathologies and memory performance. The modulation by hippocampal amyloid suggests that amyloid is a necessary, but not sufficient, process to drive neurodegeneration in memory-related regions.
KW - SURFACE-BASED ANALYSIS
KW - IN-VIVO
KW - HIPPOCAMPAL SUBFIELDS
KW - PERFORANT PATHWAY
KW - ENTORHINAL CORTEX
KW - BETA-PROTEIN
KW - PARAHIPPOCAMPAL SUBREGIONS
KW - ALZHEIMERS-DISEASE
KW - HUMAN BRAIN
KW - EX-VIVO
U2 - 10.1212/WNL.0000000000009362
DO - 10.1212/WNL.0000000000009362
M3 - Article
C2 - 32273431
SN - 0028-3878
VL - 94
SP - E1916-E1928
JO - Neurology
JF - Neurology
IS - 18
ER -