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

J Alzheimers Dis. 2023;96(2):563-578. doi: 10.3233/JAD-230223.


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; PHF tau-tangles; amyloid-β.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged, 80 and over
  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides / metabolism
  • Cerebrum* / metabolism
  • Humans
  • Neurofibrillary Tangles / pathology
  • Neuropsychological Tests
  • Olfactory Bulb / metabolism
  • tau Proteins / metabolism


  • tau Proteins
  • Amyloid beta-Peptides