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 for both men and women

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. Published online July 15, 2019. doi:10.1001/jamaneurol.2019.1971

Key Points
Question  How does the prevalence of 3 imaging biomarker–based definitions of the Alzheimer disease spectrum from the National Institute on Aging–Alzheimer’s Association research framework compare with clinically defined diagnostic entities commonly linked with Alzheimer disease?

Findings  Among a sample of 5213 individuals from Olmsted County, Minnesota, in this population-based cohort study, biologically defined Alzheimer disease is more prevalent than clinically diagnosed probable Alzheimer disease at any age and is 3 times more prevalent at age 85 years among both women and men.

Meaning  Most patients with biologically defined Alzheimer disease are not symptomatic, which creates potential confusion around the definition of Alzheimer disease.

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.


Introduction

Since 1984, a diagnosis of probable Alzheimer disease has been based on clinical findings of a progressive amnestic multidomain cognitive impairment culminating in dementia after other potential causes were excluded.1-3 Neuropathologic identification of β-amyloid plaques and tau tangles has always been required for a definite diagnosis of Alzheimer disease. Numerous studies have identified discrepancies between the clinical syndrome and the neuropathologic diagnosis of Alzheimer disease.4 Many individuals who meet neuropathologic criteria either do not have symptoms or have symptoms that differ from the classic amnestic presentation. National Institute on Aging–Alzheimer’s Association (NIA-AA) committees in 2011 and the International Work Group addressed this conundrum by adding biomarkers to clinical criteria to improve the specificity of the clinical diagnosis.3,5-8 These modified clinical diagnostic criteria cast Alzheimer disease as a clinical biomarker entity, but the diagnosis was not divorced from clinical impairment.3,5-8 The NIA-AA 2011 preclinical Alzheimer disease recommendations were an exception,9 as were the 2012 NIA-AA neuropathologic guidelines, which separated the neuropathologic definition of Alzheimer disease from the clinical syndrome.10,11

Building on the work above, a workgroup commissioned by the NIA-AA recently published a research framework12 defining Alzheimer disease biologically throughout its entire course. Alzheimer disease was defined either by neuropathologic examination or, in living persons, by positron emission tomography (PET) or biofluid biomarkers of the 2 hallmark diagnostic proteinopathies, namely, β-amyloid plaques and tau neurofibrillary tangles. The NIA-AA research framework harmonized the in vivo with the previously established neuropathologic10,11 definition of Alzheimer disease.

Epidemiologic studies estimating the prevalence of Alzheimer disease have typically used the clinical criteria by McKhann et al1,3 to define the condition. The new NIA-AA research framework12 leads to the following question: what is the prevalence of Alzheimer disease defined biologically using biomarkers compared with the prevalence using conventional definitions based on clinical symptoms? To address this question in the Mayo Clinic Study of Aging (MCSA) population, we estimated the sex- and age-specific prevalence of 3 imaging biomarker–based definitions of the Alzheimer disease spectrum from the NIA-AA research framework and compared these estimates with the prevalence of clinically defined diagnostic entities commonly linked with Alzheimer disease. Although biomarkers are now commonly used in aging and dementia research, most cohorts deeply phenotyped by biomarkers are clinic based and not population based. However, the MCSA is a population-based sample (ie, a random sample from a defined geographic area) with deep biomarker phenotyping.


In Discussion:

A biological definition leads to an increase in the apparent prevalence of Alzheimer disease compared with a syndromal definition. This is not surprising; the same is true for any other disease (eg, cancer, diabetes, etc) in which tests can detect disease in both symptomatic and asymptomatic individuals. Even though there are no therapies proven to alter clinical outcomes, our data illustrate that a significant opportunity exists to influence public health by intervention in the preclinical phase of the disease if that proves to be efficacious.^56-58 As other late-life diseases become better controlled, there is an imperative to delay or prevent symptoms due to Alzheimer disease; otherwise, those gains in life expectancy will be transformed into longer life with dementia. Intervention to prevent symptom onset was explicitly identified as a major public health objective in the National Plan to Address Alzheimer’s Disease.³⁶