Alzheimer’s Disease Pathology Outside of the Cerebrum Is Related to a Higher Odds of Dementia

Article type: Research Article

Authors: Buchman, Aron S.^{a; b; *} | Leurgans, Sue E.^{a; b} | Kim, Namhee^a | Agrawal, Sonal^{a; c} | Oveisgharan, Shahram ^{a; b} | Zammit, Andrea R.^{a; d} | VanderHorst, Veronique^e | Nag, Sukrit^a | Bennett, David A.^{a; b}

Affiliations: [a] Rush Alzheimer’s Disease Research Center, Rush University Medical Center, Chicago, IL, USA | [b] Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA | [c] Department of Pathology, Rush University Medical Center, Chicago, IL, USA | [d] Department of Behavioral Sciences, Rush University Medical Center, Chicago, IL, USA | [e] Department of Neurology, Harvard Medical School, Boston, MA, USA

Correspondence: [*] Correspondence to: Aron S. Buchman, MD, Rush Alzheimer’s Disease Center, 1750W. Harrison Street, Suite 1000, Chicago, IL 60612, USA. Tel.: +1 312 248 1951; Fax: +1 312 563 4604; E-mail: Aron_S_Buchman@rush.edu.

Abstract: Background:Assessments of Alzheimer’s disease pathology do not routinely include lower brainstem, olfactory bulb, and spinal cord. Objective:Test if amyloid-β (Aβ) and paired helical filament (PHF) tau-tangles outside the cerebrum are associated with the odds of dementia. Methods:Autopsies were obtained in decedents with cognitive testing (n = 300). Aβ plaques and PHF tau-tangles were assessed in 24 sites: cerebrum (n = 14), brainstem (n = 5), olfactory bulb, and four spinal cord levels. Since spinal Aβ were absent in the first 165 cases, it was not assessed in the remaining cases. Results:Age at death was 91 years old. About 90% had Aβ in cerebrum and of these, half had Aβ in the brainstem. Of the latter, 85% showed Aβ in the olfactory bulb. All but one participant had tau-tangles in the cerebrum and 86% had brainstem tau-tangles. Of the latter, 80% had tau-tangles in olfactory bulb and 36% tau-tangles in one or more spinal cord levels. About 90% of adults with tau-tangles also had Aβ in one or more regions. In a logistic model controlling for demographics, Aβ and tau-tangles within the cerebrum, the presence of Aβ in olfactory bulb [OR, 1.74(1.00, 3.05)]; tau-tangles in brainstem [OR, 4.00(1.1.57,10.21)]; and spinal cord [OR, 1.87 (1.21,3.11)] were independently associated with higher odds of dementia. Conclusion:Regional differences in Aβ and tau-tangle accumulation extend beyond cerebrum to spinal cord and their presence outside the cerebrum are associated with a higher odds of dementia. Further studies are needed to clarify the extent, burden, and consequences of AD pathology outside of cerebrum.

Keywords: Alzheimer’s disease dementia, amyloid-β, PHF tau-tangles

DOI: 10.3233/JAD-230223

Journal: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 563-578, 2023