Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comment
. 2019 Oct 1;76(10):1174-1183.
doi: 10.1001/jamaneurol.2019.1971.

Prevalence of Biologically vs Clinically Defined Alzheimer Spectrum Entities Using the National Institute on Aging-Alzheimer's Association Research Framework

Clifford R Jack Jr  1 , Terry M Therneau  2 , Stephen D Weigand  2 , Heather J Wiste  2 , David S Knopman  3 , Prashanthi Vemuri  1 , Val J Lowe  4 , Michelle M Mielke  2 , Rosebud O Roberts  3 , Mary M Machulda  5 , Jonathan Graff-Radford  3 , David T Jones  1   3 , Christopher G Schwarz  1 , Jeffrey L Gunter  1 , Matthew L Senjem  1 , Walter A Rocca  2   3 , Ronald C Petersen  2   3
Affiliations
Comment

Prevalence of Biologically vs Clinically Defined Alzheimer Spectrum Entities Using the National Institute on Aging-Alzheimer's Association Research Framework

Clifford R Jack Jr et al. JAMA Neurol. .

Abstract

Importance: A National Institute on Aging-Alzheimer's Association (NIA-AA) workgroup recently published a research framework in which Alzheimer disease is defined by neuropathologic or biomarker evidence of β-amyloid plaques and tau tangles and not by clinical symptoms.

Objectives: To estimate the sex- and age-specific prevalence of 3 imaging biomarker-based definitions of the Alzheimer disease spectrum from the NIA-AA research framework and to compare these entities with clinically defined diagnostic entities commonly linked with Alzheimer disease.

Design, setting, and participants: The Mayo Clinic Study of Aging (MCSA) is a population-based cohort study of cognitive aging in Olmsted County, Minnesota. The MCSA in-person participants (n = 4660) and passively ascertained (ie, through the medical record rather than in-person) individuals with dementia (n = 553) aged 60 to 89 years were included. Subsets underwent amyloid positron emission tomography (PET) (n = 1524) or both amyloid and tau PET (n = 576). Therefore, this study included 3 nested cohorts examined between November 29, 2004, and June 5, 2018. Data were analyzed between February 19, 2018, and March 26, 2019.

Main outcomes and measures: The sex- and age-specific prevalence of the following 3 biologically defined diagnostic entities was estimated: Alzheimer continuum (abnormal amyloid regardless of tau status), Alzheimer pathologic change (abnormal amyloid but normal tau), and Alzheimer disease (abnormal amyloid and tau). These were compared with the prevalence of 3 clinically defined diagnostic groups (mild cognitive impairment or dementia, dementia, and clinically defined probable Alzheimer disease).

Results: The median (interquartile range) age was 77 (72-83) years in the clinical cohort (n = 5213 participants), 77 (70-83) years in the amyloid PET cohort (n = 1524 participants), and 77 (69-83) years in the tau PET cohort (n = 576 participants). There were roughly equal numbers of women and men. The prevalence of all diagnostic entities (biological and clinical) increased rapidly with age, with the exception of Alzheimer pathologic change. The prevalence of biological Alzheimer disease was greater than clinically defined probable Alzheimer disease for women and men. Among women, these values were 10% (95% CI, 6%-14%) vs 1% (95% CI, 1%-1%) at age 70 years and 33% (95% CI, 25%-41%) vs 10% (95% CI, 9%-12%) at age 85 years (P < .001). Among men, these values were 9% (95% CI, 5%-12%) vs 1% (95% CI, 0%-1%) at age 70 years and 31% (95% CI, 24%-38%) vs 9% (95% CI, 8%-11%) at age 85 years (P < .001). The only notable difference by sex was a greater prevalence of the mild cognitive impairment or dementia clinical category among men than women.

Conclusions and relevance: Results of this study suggest that biologically defined Alzheimer disease is more prevalent than clinically defined probable Alzheimer disease at any age and is 3 times more prevalent at age 85 years among both women and men. This difference is mostly driven by asymptomatic individuals with biological Alzheimer disease. These findings illustrate the magnitude of the consequences on public health that potentially exist by intervening with disease-specific treatments to prevent symptom onset.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Jack reported serving as a consultant for Eli Lilly and Company and on an independent data monitoring board for Roche (no personal compensation is received from any commercial entity) and reported receiving funding from the National Institutes of Health (NIH) and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. Dr Knopman reported receiving research support from the NIH and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program of the Mayo Foundation, reported serving on a data safety monitoring board for Lundbeck Pharmaceuticals and for the Dominantly Inherited Alzheimer Network (DIAN) study, and reported being an investigator for clinical trials sponsored by Biogen, TauRx Pharmaceuticals, Lilly Pharmaceuticals, and the Alzheimer’s Disease Treatment and Research Institute, University of Southern California. Dr Vemuri reported receiving funding from the NIH. Dr Lowe reported consulting for Bayer Schering Pharma, Piramal Life Sciences, and Merck Research and reported receiving research support from GE Healthcare, Siemens Molecular Imaging, Avid Radiopharmaceuticals, and the NIH (National Institute on Aging and National Cancer Institute). Dr Schwarz reported receiving funding from the NIH. Dr Petersen reported serving on data monitoring committees for Pfizer Inc and Janssen Alzheimer Immunotherapy; reported working as a consultant for Merck Inc, Roche Inc, Biogen Inc, Eli Lilly and Company, and Genentech Inc; reported receiving publishing royalties for Mild Cognitive Impairment (Oxford University Press, 2003); and reported receiving research support from the NIH and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program of the Mayo Foundation. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flowchart Detailing the Study Design of the Mayo Clinic Study of Aging (MCSA) Among Individuals Aged 60 to 89 Years
After enumeration of the Olmsted County, Minnesota, population, individuals’ medical records were screened for eligibility before being contacted to participate in the MCSA. Among the 770 administrative exclusions, 626 were unable to be contacted, 100 were terminally ill, and 44 were excluded for other reasons. Among the 5643 nonparticipants, 40 died after contact, 1847 participated by telephone only, and 3756 refused to participate. In-person participants were classified by cognitive status using a consensus diagnosis. The beige boxes represent the individuals included in the clinical cohort for this study, including cognitively unimpaired, MCI, and dementia groups from the MCSA plus individuals with dementia excluded from the MCSA. Twelve MCSA participants who could not be categorized as cognitively unimpaired, MCI, or dementia were excluded. MCI indicates mild cognitive impairment.
Figure 2.
Figure 2.. Prevalence of Clinically Defined Diagnoses
A-D, Shown is the estimated prevalence of clinically defined diagnoses by sex and age with 95% CIs based on jackknife methods. Inverse probability weights were used to account for potential enrollment bias related to sex, age, and education. MCI indicates mild cognitive impairment.
Figure 3.
Figure 3.. Prevalence of Biologically and Clinically Defined Diagnostic Entities
A and B, Shown is the estimated prevalence of various entities by sex and age with 95% CIs based on jackknife methods. Inverse probability weights were used to account for potential enrollment bias related to sex, age, and education. Biologically defined Alzheimer disease spectrum entities are Alzheimer continuum (A+), Alzheimer pathologic change (A+T−), and Alzheimer disease (A+T+). Clinically defined syndromes are MCI or dementia, dementia, and clinically defined probable Alzheimer disease. MCI indicates mild cognitive impairment.
Figure 4.
Figure 4.. Sex Differences in the Prevalence of Biologically and Clinically Defined Diagnostic Entities
The estimates shown in the graph are differences in the prevalence for men and women. Positive values indicate higher prevalence for men than women, negative values would indicate higher prevalence for women than men. Inverse probability weights were used to account for potential enrollment bias related to sex, age, and education. A-C, Biologically defined Alzheimer disease spectrum entities are Alzheimer continuum (A+), Alzheimer pathologic change (A+T−), and Alzheimer disease (A+T+). D-F, Clinically defined syndromes are MCI or dementia, dementia, and clinically defined probable Alzheimer disease. MCI indicates mild cognitive impairment.
See this image and copyright information in PMC

Comment in

Comment on

References

    1. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;34(7):939-944. doi:10.1212/WNL.34.7.939 - DOI - PubMed
    1. Khachaturian ZS. Diagnosis of Alzheimer’s disease. Arch Neurol. 1985;42(11):1097-1105. doi:10.1001/archneur.1985.04060100083029 - DOI - PubMed
    1. McKhann GM, Knopman DS, Chertkow H, et al. . The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging and the Alzheimer’s Association Workgroup. Alzheimers Dement. 2011;7(3):263-269. doi:10.1016/j.jalz.2011.03.005 - DOI - PMC - PubMed
    1. Beach TG, Monsell SE, Phillips LE, Kukull W. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. J Neuropathol Exp Neurol. 2012;71(4):266-273. doi:10.1097/NEN.0b013e31824b211b - DOI - PMC - PubMed
    1. Dubois B, Feldman HH, Jacova C, et al. . Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol. 2010;9(11):1118-1127. doi:10.1016/S1474-4422(10)70223-4 - DOI - PubMed