Longitudinal cognitive performance of Alzheimer's disease neuropathological subtypes

Madeline Uretsky, Laura E. Gibbons, Shubhabrata Mukherjee, Emily H. Trittschuh, David W. Fardo, Patricia A. Boyle, C. Dirk Keene, Andrew J. Saykin, Paul K. Crane, Julie A. Schneider, Jesse Mez

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Introduction: Alzheimer's disease (AD) neuropathological subtypes (limbic predominant [lpAD], hippocampal sparing [HpSpAD], and typical [tAD]), defined by relative neurofibrillary tangle (NFT) burden in limbic and cortical regions, have not been studied in prospectively characterized epidemiological cohorts with robust cognitive assessments. Methods: Two hundred ninety-two participants with neuropathologically confirmed AD from the Religious Orders Study and Memory and Aging Project were categorized by neuropathological subtype based on previously specified diagnostic criteria using quantitative regional NFT counts. Rates of cognitive decline were compared across subtypes using linear mixed-effects models that included subtype, time, and a subtype–time interaction as predictors and four cognitive domain factor scores (memory, executive function, language, visuospatial) and a global score as outcomes. To assess if memory was relatively preserved in HpSpAD, non-memory factor scores were included as covariates in the mixed-effects model with memory as the outcome. Results: There were 57 (20%) with lpAD, 22 (8%) with HpSpAD and 213 (73%) with tAD. LpAD died significantly later than the participants with tAD (2.4 years, P =.01) and with HpSpAD (3.8 years, P =.03). Compared to tAD, HpSpAD, but not lpAD, performed significantly worse in all cognitive domains at the time of initial impairment and declined significantly faster in memory, language, and globally. HpSpAD did not have relatively preserved memory performance at any time point. Conclusion: The relative frequencies of AD neuropathological subtypes in an epidemiological sample were consistent with a previous report in a convenience sample. People with HpSpAD decline rapidly, but may not have a memory-sparing clinical syndrome. Cohort-specific differences in regional tau burden and comorbid neuropathology may explain the lack of clinicopathological correlation.

Original languageEnglish
Article numbere12201
JournalAlzheimer's and Dementia: Translational Research and Clinical Interventions
Issue number1
StatePublished - 2021

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health (Advanced Psychometrics Methods in Cognitive Aging Research [R13AG030995], P50AG05136, K23AG046377, P30AG13846, P30AG10161, R01AG061028, R01AG042437); Alzheimer's Disease Neuroimaging Initiative U01AG024904, Indiana Alzheimer's Disease Research Center P30AG010133, R01AG019771 (A.J.S.), and the Nancy and Buster Alvord Endowment (C.D.K.).

Publisher Copyright:
© 2021 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.

ASJC Scopus subject areas

  • Clinical Neurology
  • Psychiatry and Mental health


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