Early CA2 Tau Inclusions Do Not Distinguish an Age-Related Tauopathy from Early Alzheimer’s Disease

Article type: Research Article

Authors: Del Tredici, Kelly^{a; *} | Schön, Michael^b | Feldengut, Simone^a | Ghebremedhin, Estifanos^c | Kaufman, Sarah K.^d | Wiesner, Diana^{e; f} | Roselli, Francesco^{e; f} | Mayer, Benjamin^g | Amunts, Katrin^{h; i} | Braak, Heiko^a

Affiliations: [a] Clinical Neuroanatomy/Department of Neurology, Center for Biomedical Research, University of Ulm, Ulm, Germany | [b] Institute for Anatomy and Cell Biology, University of Ulm, Ulm, Germany | [c] Institute of Clinical Neuroanatomy, Goethe University Frankfurt, Frankfurt am Main, Germany | [d] Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA | [e] Department of Neurology, Ulm University, Ulm, Germany | [f] German Center for Neurodegenerative Diseases (DZNE), Ulm, Germany | [g] Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany | [h] Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany | [i] Cécile and Oskar Vogt Institute for Brain Research, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Correspondence: [*] Correspondence to: Kelly Del Tredici, MD, PhD, Department of Neurology, Clinical Neuroanatomy, Center for Biomedical Research, University of Ulm, Helmholtzstrasse 8/1, 89081 Ulm, Germany. E-mail: [email protected]; ORCID: https://orcid.org/0000-0002-9130-7838.

Abstract: Background:Neuropathologic studies of brains from autopsy series show tau inclusions (pretangles, neuropils threads, neurofibrillary tangles) are detectable more than a decade before amyloid-β (Aβ) deposition in Alzheimer’s disease (AD) and develop in a characteristic manner that forms the basis for AD staging. An alternative position views pathological tau without Aβ deposition as a ‘primary age-related tauopathy’ (PART) rather than prodromal AD. Recently, an early focus of tau inclusions in the Ammon’s horn second sector (CA2) with relative sparing of CA1 that occurs before tau inclusions develop in the entorhinal cortex (EC) was proposed as an additional feature of PART. Objective:To test the ‘definite PART’ hypothesis. Methods:We used AT8-immunohistochemistry in 100μm sections to examine the EC, transentorhinal cortex (TRE), and Ammon’s horn in 325 brains with tau inclusions lacking Aβ deposits (average age at death 66.7 years for females, 66.4 years for males). Results:100% of cases displayed tau inclusions in the TRE. In 89% of cases, the CA1 tau rating was greater than or equal to that in CA2. In 25%, CA2 was devoid of tau inclusions. Only 4% displayed a higher tau score in CA2 than in the TRE, EC, and CA1. The perforant path also displayed early tau changes. APOE genotyping was available for 199/325 individuals. Of these, 44% had an ɛ4 allele that placed them at greater risk for developing later NFT stages and, therefore, clinical AD. Conclusions:Our new findings call into question the PART hypothesis and are consistent with the idea that our cases represent prodromal AD.

Keywords: Alzheimer’s disease, Ammon’s horn, APOE, CA2, entorhinal cortex, neurofibrillary tangles, PART hypothesis, pretangles, tau seeding, tractus perforans

DOI: 10.3233/JAD-240483

Journal: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1333-1353, 2024