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. 2022 Dec 19;145(12):4489-4505.
doi: 10.1093/brain/awac229.

Amyloid, tau and metabolic PET correlates of cognition in early and late-onset Alzheimer's disease

Jeremy A Tanner  1 , Leonardo Iaccarino  1 , Lauren Edwards  1 , Breton M Asken  1 , Maria L Gorno-Tempini  1 , Joel H Kramer  1 , Julie Pham  1 , David C Perry  1 , Katherine Possin  1 , Maura Malpetti  1   2 , Taylor Mellinger  1 , Bruce L Miller  1 , Zachary Miller  1 , Nidhi S Mundada  1 , Howard J Rosen  1 , David N Soleimani-Meigooni  1 , Amelia Strom  1 , Renaud La Joie  1 , Gil D Rabinovici  1   3   4
Affiliations

Amyloid, tau and metabolic PET correlates of cognition in early and late-onset Alzheimer's disease

Jeremy A Tanner et al. Brain. .

Abstract

Early-onset (age < 65) Alzheimer's disease is associated with greater non-amnestic cognitive symptoms and neuropathological burden than late-onset disease. It is not fully understood whether these groups also differ in the associations between molecular pathology, neurodegeneration and cognitive performance. We studied amyloid-positive patients with early-onset (n = 60, mean age 58 ± 4, MMSE 21 ± 6, 58% female) and late-onset (n = 53, mean age 74 ± 6, MMSE 23 ± 5, 45% female) Alzheimer's disease who underwent neurological evaluation, neuropsychological testing, 11C-Pittsburgh compound B PET (amyloid-PET) and 18F-flortaucipir PET (tau-PET). 18F-fluorodeoxyglucose PET (brain glucose metabolism PET) was also available in 74% (n = 84) of participants. Composite scores for episodic memory, semantic memory, language, executive function and visuospatial domains were calculated based on cognitively unimpaired controls. Voxel-wise regressions evaluated correlations between PET biomarkers and cognitive scores and early-onset versus late-onset differences were tested with a PET × Age group interaction. Mediation analyses estimated direct and indirect (18F-fluorodeoxyglucose mediated) local associations between 18F-flortaucipir binding and cognitive scores in domain-specific regions of interest. We found that early-onset patients had higher 18F-flortaucipir binding in parietal, lateral temporal and lateral frontal cortex; more severe 18F-fluorodeoxyglucose hypometabolism in the precuneus and angular gyrus; and greater 11C-Pittsburgh compound B binding in occipital regions compared to late-onset patients. In our primary analyses, PET-cognition correlations did not meaningfully differ between age groups.18F-flortaucipir and 18F-fluorodeoxyglucose, but not 11C-Pittsburgh compound B, were significantly associated with cognition in expected domain-specific patterns in both age groups (e.g. left perisylvian/language, frontal/executive, occipital/visuospatial). 18F-fluorodeoxyglucose mediated the relationship between 18F-flortaucipir and cognition in both age groups across all domains except episodic memory in late-onset patients. Additional direct effects of 18F-flortaucipir were observed for executive function in all age groups, language in early-onset Alzheimer's disease and in the total sample and visuospatial function in the total sample. In conclusion, tau and neurodegeneration, but not amyloid, were similarly associated with cognition in both early and late-onset Alzheimer's disease. Tau had an association with cognition independent of neurodegeneration in language, executive and visuospatial functions in the total sample. Our findings support tau PET as a biomarker that captures both the clinical severity and molecular pathology specific to Alzheimer's disease across the broad spectrum of ages and clinical phenotypes in Alzheimer's disease.

Keywords: Alzheimer’s disease; PET; cognition; early-onset; tau.

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Conflict of interest statement

B.L.M. receives research support from the NIH/NIA and the Centers for Medicare & Medicaid Services (CMS) as grants for the Memory and Aging Center. As an additional disclosure, B.L.M. serves as Medical Director for the John Douglas French Foundation; Scientific Director for the Tau Consortium; Director/Medical Advisory Board of the Larry L. Hillblom Foundation; Scientific Advisory Board Member for the National Institute for Health Research Cambridge Biomedical Research Centre and its subunit, the Biomedical Research Unit in Dementia (UK); and Board Member for the American Brain Foundation (ABF). R.L.J. serves as an Associate Editor for Alzheimer’s Research & Therapy. G.D.R. has research support from Avid Radiopharmaceuticals, GE Healthcare, Life Molecular Imaging, Genentech; has served as a consultant for Eisai, Eli Lilly, Genentech, GE Healthcare, Johnson & Johnson, Roche; and serves as an Associate Editor for JAMA Neurology. All other authors report no competing interests.

Figures

Figure 1
Figure 1
Mean images and group comparisons of biomarkers. (A) Mean interpolated surface projections of average SUVR maps are displayed for EOAD and LOAD subgroups for PIB-PET, FTP-PET and FDG-PET. (B) Voxel-wise comparisons between groups, with significant differences presented at a peak-level threshold of P < 0.001 uncorrected, cluster-level family-wise error corrected P < 0.05.
Figure 2
Figure 2
Voxel-wise correlation between episodic memory and PET neuroimaging. Voxel-wise regression analyses showing correlation between episodic memory W-scores and each imaging modality for the total sample and for each age group. Pearson correlation coefficients (left) are shown for voxels significant at a peak-level threshold of P < 0.001 uncorrected, cluster-level family-wise error corrected P < 0.05. Scatterplots (right) were obtained by extracting average SUVR values from significant clusters for the total sample and plotted separately by age group. Higher W-scores indicate more severe impairment. NS = not significant.
Figure 3
Figure 3
Voxel-wise correlation between semantic memory and PET neuroimaging. Voxel-wise regression analyses showing correlation between semantic memory W-scores and each imaging modality for the total sample and for each age group. Pearson correlation coefficients (left) are shown for voxels significant at a peak-level threshold of P < 0.001 uncorrected, cluster-level family-wise error corrected P < 0.05. Scatterplots (right) were obtained by extracting average SUVR values from significant clusters for the total sample, and plotted separately by age group. Higher W-scores indicate more severe impairment.
Figure 4
Figure 4
Voxel-wise correlation between language and PET neuroimaging. Voxel-wise regression analyses showing correlation between language W-scores and each imaging modality for the total sample and for each age group. Pearson correlation coefficients (left) are shown for voxels significant at a peak-level threshold of P < 0.001 uncorrected, cluster-level family-wise error corrected P < 0.05. Scatterplots (right) were obtained by extracting average SUVR values from significant clusters for the total sample and plotted separately by age group. Higher W-scores indicate more severe impairment.
Figure 5
Figure 5
Voxel-wise correlation between executive function and PET neuroimaging. Voxel-wise regression analyses showing correlation between executive function W-scores and each imaging modality for the total sample and for each age group. Pearson correlation coefficients (left) are shown for voxels significant at a peak-level threshold of P < 0.001 uncorrected, cluster-level family-wise error corrected P < 0.05. Scatterplots (right) were obtained by extracting average SUVR values from significant clusters for the total sample, and plotted separately by age group. Higher W-scores indicate more severe impairment.
Figure 6
Figure 6
Voxel-wise correlation between visuospatial function and PET neuroimaging. Voxel-wise regression analyses showing correlation between visuospatial function W-scores and each imaging modality for the total sample and for each age group. Pearson correlation coefficients (left) are shown for voxels significant at a peak-level threshold of P < 0.001 uncorrected, cluster-level family-wise error corrected P < 0.05. Scatterplots (right) were obtained by extracting average SUVR values from significant clusters for the total sample, and plotted separately by age group. Higher W-scores indicate more severe impairment.
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