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Research Letters |

Dementia From Alzheimer Disease and Mixed Pathologies in the Oldest Old FREE

Bryan D. James, PhD; David A. Bennett, MD; Patricia A. Boyle, PhD; Sue Leurgans, PhD; Julie A. Schneider, MD
[+] Author Affiliations

Author Affiliations: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois (bryan_james@rush.edu).


Letters Section Editor: Jody W. Zylke, MD, Senior Editor.

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JAMA. 2012;307(17):1798-1800. doi:10.1001/jama.2012.3556.
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To the Editor: The oldest old (≥90 years of age) are the fastest growing segment of the US population and account for half of all persons with dementia. Alzheimer disease (AD) is the most common pathology underlying dementia in the old (ages 65-89 years). Recent community-based autopsy studies1,2 suggest the relationship between AD pathology and expression of dementia is attenuated in the oldest old.3 Studies may be complicated by the common coexistence of AD plus infarct and/or Lewy body (LB) pathology (mixed pathologies).4 Few data exist on mixed pathologies and dementia in the oldest old.5 We examined the relationship of AD and mixed pathologies to dementia in the oldest old compared with the old. We tested the hypothesis that the clinical expression of AD and mixed pathologies differs across age groups.

We included 804 persons from the Religious Orders Study (n = 456) and Rush Memory and Aging Project (n = 348), ongoing longitudinal clinical-pathological studies of aging started in 1994 and 1997, respectively.4 Both were convenience samples of community-dwelling older adults with high follow-up (>90%) and autopsy (87%) rates. All autopsied participants with complete data as of June 2, 2011 (93.7% of 858 autopsied) were included. Both studies were approved by the Rush University Medical Center institutional review board and all participants provided written consent.

Dementia was diagnosed using standard criteria (Table 1; last assessment: mean 7.1 months before death). Neuropathologic diagnoses were blinded to age and clinical diagnosis, using standard criteria (Table 1). Mixed pathologies included at least 2 of the following: a pathological diagnosis of AD, infarct (macroscopic or microscopic), or neocortical LB (identified on α-synuclein immunostaining) pathology. We report prevalence ratios from log-binomial regression models controlling for sex and education with interaction terms for pathology by age group. Analyses were performed using SAS version 9.2 (SAS Institute Inc). Testing was 2-sided with statistical significance threshold of α = .05.

Table Graphic Jump LocationTable 1. Clinical and Pathological Characteristics at or Proximate to Death for Persons Younger Than 90 Years of Age at Death Compared With Persons Aged 90 Years or Older

The oldest old (n = 301; mean age = 94.3 years) were more likely to be demented and to have pathological diagnoses of AD or infarct than the old (n = 503; mean age = 83.8 years) (Table 1). A pathological diagnosis of AD was associated with a higher prevalence of dementia in the old and the oldest old; however, the association was attenuated in the oldest old (model 1 in Table 2). In a model including pathological diagnoses of AD, infarct, and LB, all 3 pathologies were associated with dementia in the old and the oldest old, but only AD showed an interaction with age (model 2 in Table 2). Mixed but not single pathologies were more common in the oldest old, specifically AD plus infarct (Table 1). In both age groups, a pathological diagnosis of AD plus infarct and/or LB (mixed AD pathology) was associated with a higher prevalence ratio for dementia than a diagnosis of AD alone; however, the association of mixed AD pathologies with dementia was attenuated in the oldest old (model 3 in Table 2).

Table Graphic Jump LocationTable 2. Prevalence of Clinical Dementia Associated With Alzheimer Disease Pathology Alone and Mixed Pathologies

We found that a pathological diagnosis of AD was more common in the oldest old and strongly related to dementia. The increase in AD pathology in the oldest old was primarily in the form of mixed AD and infarct pathology, which was related to a higher probability of dementia than AD pathology alone. Thus, the proportional effect of AD pathology is high in the oldest old. Nonetheless, the relationship between a pathological diagnosis of AD and dementia was significantly attenuated in the oldest old compared with the old even after accounting for known mixed pathologies, suggesting additional factors in the pathogenesis of dementia in the oldest old.

Limitations include data from a volunteer cohort agreeable to autopsy and few minorities, which may limit generalizability. These data suggest that research on dementia in the oldest old should focus on AD, mixed pathologies, and exploration of additional factors in the pathogenesis of dementia in the oldest old.

Author Contributions: Dr James had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: James, Bennett, Schneider.

Acquisition of data: Bennett, Schneider.

Analysis and interpretation of data: James, Bennett, Boyle, Leurgans, Schneider.

Drafting of the manuscript: James, Schneider.

Critical revision of the manuscript for important intellectual content: James, Bennett, Boyle, Leurgans, Schneider.

Statistical analysis: James, Bennett, Leurgans, Schneider.

Obtained funding: Bennett, Boyle.

Administrative, technical, or material support: Bennett.

Study supervision: Bennett, Schneider.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr James reported serving as a consultant to the Alzheimer's Association and Partners. Dr Schneider reported being a consultant to AVID Radiopharmaceuticals Inc, GE Healthcare, and Eli Lilly. No other author reported disclosures.

Funding/Support: This research was supported by National Institute on Aging grants P30AG10161, R01AG15819, R01AG17917, R01AG34374, R01AG33678, RC2AG36547, P01AG14449, P01AG09466, and R01NS028127, and the Illinois Department of Public Health.

Role of the Sponsors: National Institute on Aging and the Illinois Department of Public Health had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

This article was corrected for errors on May 1, 2012.

Savva GM, Wharton SB, Ince PG, Forster G, Matthews FE, Brayne C.Medical Research Council Cognitive Function and Ageing Study.  Age, neuropathology, and dementia.  N Engl J Med. 2009;360(22):2302-2309
PubMed   |  Link to Article
Haroutunian V, Schnaider-Beeri M, Schmeidler J,  et al.  Role of the neuropathology of Alzheimer disease in dementia in the oldest-old.  Arch Neurol. 2008;65(9):1211-1217
PubMed   |  Link to Article
Imhof A, Kövari E, von Gunten A,  et al.  Morphological substrates of cognitive decline in nonagenarians and centenarians: a new paradigm?  J Neurol Sci. 2007;257(1-2):72-79
PubMed   |  Link to Article
Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons.  Neurology. 2007;69(24):2197-2204
PubMed   |  Link to Article
Middleton LE, Grinberg LT, Miller B, Kawas C, Yaffe K. Neuropathologic features associated with Alzheimer disease diagnosis: age matters.  Neurology. 2011;77(19):1737-1744
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Clinical and Pathological Characteristics at or Proximate to Death for Persons Younger Than 90 Years of Age at Death Compared With Persons Aged 90 Years or Older
Table Graphic Jump LocationTable 2. Prevalence of Clinical Dementia Associated With Alzheimer Disease Pathology Alone and Mixed Pathologies

References

Savva GM, Wharton SB, Ince PG, Forster G, Matthews FE, Brayne C.Medical Research Council Cognitive Function and Ageing Study.  Age, neuropathology, and dementia.  N Engl J Med. 2009;360(22):2302-2309
PubMed   |  Link to Article
Haroutunian V, Schnaider-Beeri M, Schmeidler J,  et al.  Role of the neuropathology of Alzheimer disease in dementia in the oldest-old.  Arch Neurol. 2008;65(9):1211-1217
PubMed   |  Link to Article
Imhof A, Kövari E, von Gunten A,  et al.  Morphological substrates of cognitive decline in nonagenarians and centenarians: a new paradigm?  J Neurol Sci. 2007;257(1-2):72-79
PubMed   |  Link to Article
Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons.  Neurology. 2007;69(24):2197-2204
PubMed   |  Link to Article
Middleton LE, Grinberg LT, Miller B, Kawas C, Yaffe K. Neuropathologic features associated with Alzheimer disease diagnosis: age matters.  Neurology. 2011;77(19):1737-1744
PubMed   |  Link to Article
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