Cognitive and Neuropsychological Profiles in Alzheimer’s Disease and Primary Age-Related Tauopathy and the Influence of Comorbid Neuropathologies

Article type: Research Article

Authors: Walker, Jamie M.^{a; b; c} | Gonzales, Mitzi M.^{c; d} | Goette, William^e | Farrell, Kurt^{a; b; f; g; h} | White III, Charles L.ⁱ | Crary, John F.^{a; b; f; g; h} | Richardson, Timothy E.^{a; *}

Affiliations: [a] Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA | [b] Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA | [c] Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA | [d] Department of Neurology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA | [e] Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA | [f] Department of Artificial Intelligence & Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA | [g] Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA | [h] Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, NY, USA | [i] Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Correspondence: [*] Correspondence to: Timothy E. Richardson, DO, PhD, Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, Annenberg Building, 15.58, 1468 Madison Avenue, New York, NY 10029, USA. E-mail: [email protected].

Abstract: Background:Alzheimer’s disease neuropathologic change (ADNC) is defined by the progression of both hyperphosphorylated-tau (p-tau) and amyloid-β (Aβ) and is the most common underlying cause of dementia worldwide. Primary age-related tauopathy (PART), an Aβ-negative tauopathy largely confined to the medial temporal lobe, is increasingly being recognized as an entity separate from ADNC with diverging clinical, genetic, neuroanatomic, and radiologic profiles. Objective:The specific clinical correlates of PART are largely unknown; we aimed to identify cognitive and neuropsychological differences between PART, ADNC, and subjects with no tauopathy (NT). Methods:We compared 2,884 subjects with autopsy-confirmed intermediate-high stage ADNC to 208 subjects with definite PART (Braak stage I–IV, Thal phase 0, CERAD NP score “absent”) and 178 NT subjects from the National Alzheimer’s Coordinating Center dataset. Results:PART subjects were older than either ADNC or NT patients. The ADNC cohort had more frequent neuropathological comorbidities as well as APOE ɛ4 alleles than the PART or NT cohort, and less frequent APOE ɛ2 alleles than either group. Clinically, ADNC patients performed significantly worse than NT or PART subjects across cognitive measures, but PART subjects had selective deficits in measures of processing speed, executive function, and visuospatial function, although additional cognitive measures were further impaired in the presence of neuropathologic comorbidities. In isolated cases of PART with Braak stage III-IV, there are additional deficits in measures of language. Conclusion:Overall, these findings demonstrate underlying cognitive features specifically associated with PART, and reinforce the concept that PART is a distinct entity from ADNC.

Keywords: Alzheimer’s disease, cerebrovascular disease, Clinical Dementia Rating, Lewy body dementia, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), Mini-Mental State Examination, primary age-related tauopathy

DOI: 10.3233/JAD-230022

Journal: Journal of Alzheimer's Disease, vol. 92, no. 3, pp. 1037-1049, 2023