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. 2023 Dec 12;101(24):e2533-e2544.
doi: 10.1212/WNL.0000000000207962. Epub 2023 Nov 8.

Association of Pathologic and Volumetric Biomarker Changes With Cognitive Decline in Clinically Normal Adults

Bernard J Hanseeuw  1 , Heidi I L Jacobs  1 , Aaron P Schultz  1 , Rachel F Buckley  1 , Michelle E Farrell  1 , Nicolas J Guehl  1 , John A Becker  1 , Michael Properzi  1 , Justin S Sanchez  1 , Yakeel T Quiroz  1 , Patrizia Vannini  1 , Jorge Sepulcre  1 , Hyun-Sik Yang  1 , Jasmeer P Chhatwal  1 , Jennifer Gatchel  1 , Gad A Marshall  1 , Rebecca Amariglio  1 , Kathryn Papp  1 , Dorene M Rentz  1 , Marc Normandin  1 , Julie C Price  1 , Brian C Healy  1 , Georges El Fakhri  1 , Reisa A Sperling  1 , Keith A Johnson  1
Affiliations

Association of Pathologic and Volumetric Biomarker Changes With Cognitive Decline in Clinically Normal Adults

Bernard J Hanseeuw et al. Neurology. .

Abstract

Background and objectives: Hippocampal volume (HV) atrophy is a well-known biomarker of memory impairment. However, compared with β-amyloid (Aβ) and tau imaging, it is less specific for Alzheimer disease (AD) pathology. This lack of specificity could provide indirect information about potential copathologies that cannot be observed in vivo. In this prospective cohort study, we aimed to assess the associations among Aβ, tau, HV, and cognition, measured over a 10-year follow-up period with a special focus on the contributions of HV atrophy to cognition after adjusting for Aβ and tau.

Methods: We enrolled 283 older adults without dementia or overt cognitive impairment in the Harvard Aging Brain Study. In this report, we only analyzed data from individuals with available longitudinal imaging and cognition data. Serial MRI (follow-up duration 1.3-7.0 years), neocortical Aβ imaging on Pittsburgh Compound B PET scans (1.9-8.5 years), entorhinal and inferior temporal tau on flortaucipir PET scans (0.8-6.0 years), and the Preclinical Alzheimer Cognitive Composite (3.0-9.8 years) were prospectively collected. We evaluated the longitudinal associations between Aβ, tau, volume, and cognition data and investigated sequential models to test the contribution of each biomarker to cognitive decline.

Results: We analyzed data from 128 clinically normal older adults, including 72 (56%) women and 56 (44%) men; median age at inclusion was 73 years (range 63-87). Thirty-four participants (27%) exhibited an initial high-Aβ burden on PET imaging. Faster HV atrophy was correlated with faster cognitive decline (R2 = 0.28, p < 0.0001). When comparing all biomarkers, HV slope was associated with cognitive decline independently of Aβ and tau measures, uniquely accounting for 10% of the variance. Altogether, 45% of the variance in cognitive decline was explained by combining the change measures in the different imaging biomarkers.

Discussion: In older adults, longitudinal hippocampal atrophy is associated with cognitive decline, independently of Aβ or tau, suggesting that non-AD pathologies (e.g., TDP-43, vascular) may contribute to hippocampal-mediated cognitive decline. Serial HV measures, in addition to AD-specific biomarkers, may help evaluate the contribution of non-AD pathologies that cannot be measured otherwise in vivo.

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Conflict of interest statement

B.J. Hanseeuw reports funding from the Belgian Fund for Scientific Research (FNRS #CCL40010417, Welbio #40010035). H.I.L. Jacobs reports funding from the NIH (R01 AG062559, R01 AG068062, R21 AG074220) and the Alzheimer's Association (AARG-22-920434). She serves as chair on the Neuromodulatory Subcortical Systems Professional Interest Area, as advisory council member of ISTAART, and as associate editor for the Journal of Alzheimer's Disease. Y.T. Quiroz serves as consultant for Biogen. H.S. Yang reports funding from the NIH (K23 AG062750). J.P. Chhatwal reports funding from the NIH (R01 AG062667, R01AG071865). He has served on advisory boards for Humana Healthcare, Leerink Partners, and Expert connect. G.A. Marshall reports funding from the NIH (R01 AG067021, R01 AG053184, R01 AG071074, R42 AG069629, and R21 AG070877) and research salary support unrelated to the current study from Eisai Inc., Eli Lilly and Company, and Genentech. J.C. Price reports funding from the NIH (R01 AG050436, R01 AG052414). B.C. Healy has received research support from Analysis Group, Celgene (Bristol-Myers Squibb), Verily Life Sciences, Merck-Serono, Novartis, and Genzyme. R.A. Sperling reports funding from the NIH (P01 AG036694). K.A. Johnson reports funding from the NIH (P01 AG036694, R01 AG046396). All other authors report no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.

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References

    1. Hyman BT, Phelps CH, Beach TG, et al. . National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement. 2012;8(1):1-13. doi:10.1016/j.jalz.2011.10.007 - DOI - PMC - PubMed
    1. McKhann GM, Knopman DS, Chertkow H, et al. . The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):263-269. doi:10.1016/j.jalz.2011.03.005 - DOI - PMC - PubMed
    1. Apostolova L, Zarow C, Biado K, et al. . Relationship between hippocampal atrophy and neuropathology markers: a 7T MRI validation study of the EADC-ADNI Harmonized Hippocampal Segmentation Protocol. Alzheimers Dement. 2015;11(2):139-150. doi:10.1016/j.jalz.2015.01.001 - DOI - PMC - PubMed
    1. Nelson PT, Alafuzoff I, Bigio EH, et al. . Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012;71(5):362-381. doi:10.1097/NEN.0b013e31825018f7 - DOI - PMC - PubMed
    1. Johnson KA, Schultz A, Betensky RA, et al. . Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol. 2016;79(1):110-119. doi:10.1002/ana.24546 - DOI - PMC - PubMed