The Spectrum of Alzheimer-Type Pathology in Cognitively Normal Individuals

Article type: Research Article

Authors: Walker, Jamie M.^{a; b; c; *} | Dehkordi, Shiva Kazempour^{c; d; 1} | Schaffert, Jeff^e | Goette, William^e | White III, Charles L.^f | Richardson, Timothy E.^a | Zare, Habil^{c; d}

Affiliations: [a] Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mt. Sinai, New York, NY, USA | [b] Nash Family Department of Neuroscience, Icahn School of Medicine at Mt. Sinai, New York, NY, USA | [c] Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health San Antonio, San Antonio, TX, USA | [d] Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, TX, USA | [e] Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA | [f] Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Correspondence: [*] Correspondence to: Jamie M. Walker, MD, PhD, Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, Annenberg Building, 15th Floor, 1468 Madison Avenue, New York, NY 10029, USA. E-mail: [email protected].

Note: [1] Co-first author.

Abstract: Background:The strongest risk factor for the development of Alzheimer’s disease (AD) is age. The progression of Braak stage and Thal phase with age has been demonstrated. However, prior studies did not include cognitive status. Objective:We set out to define normative values for Alzheimer-type pathologic changes in individuals without cognitive decline, and then define levels that would qualify them to be resistant to or resilient against these changes. Methods:Utilizing neuropathology data obtained from the National Alzheimer’s Coordinating Center (NACC), we demonstrate the age-related progression of Alzheimer-type pathologic changes in cognitively normal individuals (CDR = 0, n = 542). With plots generated from these data, we establish standard lines that may be utilized to measure the extent to which an individual’s Alzheimer-type pathology varies from the estimated normal range of pathology. Results:Although Braak stage and Thal phase progressively increase with age in cognitively normal individuals, the Consortium to Establish a Registry for Alzheimer’s Disease neuritic plaque score and Alzheimer’s disease neuropathologic change remain at low levels. Conclusion:These findings suggest that an increasing burden of neuritic plaques is a strong predictor of cognitive decline, whereas, neurofibrillary degeneration and amyloid-β (diffuse) plaque deposition, both to some degree, are normal pathologic changes of aging that occur in almost all individuals regardless of cognitive status. Furthermore, we have defined the amount of neuropathologic change in cognitively normal individuals that would qualify them to be “resilient” against the pathology (significantly above the normative values for age, but still cognitively normal) or “resistant” to the development of pathology (significantly below the normative values for age).

Keywords: Alzheimer’s disease, Braak stage, CERAD neuritic plaque score, cognitively normal, resilience, resistance, Thal phase

DOI: 10.3233/JAD-220898

Journal: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 683-695, 2023