%0 Journal Article %J J Alzheimers Dis %D 2023 %T Alzheimer's Disease Pathology Outside of the Cerebrum Is Related to a Higher Odds of Dementia. %A Buchman, Aron S %A Leurgans, Sue E %A Kim, Namhee %A Agrawal, Sonal %A Oveisgharan, Shahram %A Zammit, Andrea R %A VanderHorst, Veronique %A Nag, Sukrit %A Bennett, David A %X

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.

%B J Alzheimers Dis %V 96 %P 563-578 %8 2023 Nov 07 %G eng %N 2 %R 10.3233/JAD-230223 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Latent Cognitive Class at Enrollment Predicts Future Cognitive Trajectories of Decline in a Community Sample of Older Adults. %A Zammit, Andrea R %A Yang, Jingyun %A Buchman, Aron S %A Leurgans, Sue E %A Muniz-Terrera, Graciela %A Lipton, Richard B %A Hall, Charles B %A Boyle, Patricia %A Bennett, David A %X

BACKGROUND: Methods that can identify subgroups with different trajectories of cognitive decline are crucial for isolating the biologic mechanisms which underlie these groupings.

OBJECTIVE: This study grouped older adults based on their baseline cognitive profiles using a latent variable approach and tested the hypothesis that these groups would differ in their subsequent trajectories of cognitive change.

METHODS: In this study we applied time-varying effects models (TVEMs) to examine the longitudinal trajectories of cognitive decline across different subgroups of older adults in the Rush Memory and Aging Project.

RESULTS: A total of 1,662 individuals (mean age = 79.6 years, SD = 7.4, 75.4%female) participated in the study; these were categorized into five previously identified classes of older adults differing in their baseline cognitive profiles: Superior Cognition (n = 328, 19.7%), Average Cognition (n = 767, 46.1%), Mixed-Domains Impairment (n = 71, 4.3%), Memory-Specific Impairment (n = 274, 16.5%), and Frontal Impairment (n = 222, 13.4%). Differences in the trajectories of cognition for these five classes persisted during 8 years of follow-up. Compared with the Average Cognition class, The Mixed-Domains and Memory-Specific Impairment classes showed steeper rates of decline, while other classes showed moderate declines.

CONCLUSION: Baseline cognitive classes of older adults derived through the use of latent variable methods were associated with distinct longitudinal trajectories of cognitive decline that did not converge during an average of 8 years of follow-up.

%B J Alzheimers Dis %V 83 %P 641-652 %8 2021 Sep 21 %G eng %N 2 %R 10.3233/JAD-210484 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Association of Low Systolic Blood Pressure with Postmortem Amyloid-β and Tau. %A Oveisgharan, Shahram %A Capuano, Ana W %A Kapasi, Alifiya %A Buchman, Aron S %A Schneider, Julie A %A Bennett, David A %A Arvanitakis, Zoe %X

BACKGROUND: Vascular mechanisms may contribute to the accumulation of AD pathology.

OBJECTIVE: We examined whether the burden of vascular risk factors proximate to death is associated with amyloid-β and tau levels or modified their known association.

METHODS: We examined the brains of 1, 585 participants from two longitudinal community-based studies of older adults. Amyloid-β and tau were quantified by postmortem examination. The burden of vascular risk factors was summarized by calculating the Framingham general cardiovascular risk score (FRS) proximate to death. Using linear regressions, we examined the association of the FRS with the amyloid-β and tau levels and examined if the FRS modified the association of the amyloid-β with tau.

RESULTS: On average, participants were nearly 90 years old and two-thirds were women. The FRS was not associated with amyloid-β (Spearman r  = -0.00, p  = 0.918) or tau (r = 0.01, p = 0.701). However, the FRS as a whole (estimate = -0.022, SE = 0.008, p = 0.009), and specifically the systolic blood pressure (SBP) component (estimate = -0.033, SE = 0.012, p = 0.009), modified the association of the amyloid-β with tau. Further analysis showed that the association between amyloid-β and tau was stronger at lower levels of SBP.

CONCLUSION: Late-life vascular risk scores were not related to postmortem levels of amyloid-β or tau. However, lower levels of vascular risk scores and SBP were associated with a stronger association between amyloid-β and tau. These data suggest that vascular risk factors may modify the relation of AD pathology markers to one another.

%B J Alzheimers Dis %V 78 %P 1755-1764 %8 2020 Dec 08 %G eng %N 4 %R 10.3233/JAD-200412 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Religious Orders Study and Rush Memory and Aging Project. %A Bennett, David A %A Buchman, Aron S %A Boyle, Patricia A %A Barnes, Lisa L %A Wilson, Robert S %A Schneider, Julie A %X

BACKGROUND: The Religious Orders Study and Rush Memory and Aging Project are both ongoing longitudinal clinical-pathologic cohort studies of aging and Alzheimer's disease (AD).

OBJECTIVES: To summarize progress over the past five years and its implications for understanding neurodegenerative diseases.

METHODS: Participants in both studies are older adults who enroll without dementia and agree to detailed longitudinal clinical evaluations and organ donation. The last review summarized findings through the end of 2011. Here we summarize progress and study findings over the past five years and discuss new directions for how these studies can inform on aging and AD in the future.

RESULTS: We summarize 1) findings on the relation of neurobiology to clinical AD; 2) neurobiologic pathways linking risk factors to clinical AD; 3) non-cognitive AD phenotypes including motor function and decision making; 4) the development of a novel drug discovery platform.

CONCLUSION: Complexity at multiple levels needs to be understood and overcome to develop effective treatments and preventions for cognitive decline and AD dementia.

%B J Alzheimers Dis %V 64 %P S161-S189 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865057?dopt=Abstract %R 10.3233/JAD-179939