Association of Factors With Elevated Amyloid Burden in Clinically Normal Older Individuals

Abstract

The Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) Study is an ongoing prevention trial in clinically normal older individuals with evidence of elevated brain amyloid. The large number of participants screened with amyloid positron emission tomography (PET) and standardized assessments provides an unprecedented opportunity to evaluate factors associated with elevated brain amyloid. OBJECTIVE To investigate the association of elevated amyloid with demographic and lifestyle factors, apolipoprotein E (APOE), neuropsychological testing, and self-and study partner reports of cognitive function. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study included screening data in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study collected from April 2014 to December 2017 and classified by amyloid status. Data were was analyzed from 2018 to 2019 across 67 sites in the US, Canada, Australia, and Japan and included 4486 older individuals (age 65-85 years) who were eligible for amyloid PET (clinically normal [Clinical Dementia Rating = 0] and cognitively unimpaired [Mini-Mental State Examination score, Ն25; logical memory IIa 6-18]). MAIN OUTCOMES AND MEASURES Screening demographics, lifestyle variables, APOE genotyping, and cognitive testing (Preclinical Alzheimer Cognitive Composite), self-and study partner reports of high-level daily cognitive function (Cognitive Function Index). Florbetapir amyloid PET imaging was used to classify participants as having elevated amyloid (Aβ+) or not having elevated amyloid (Aβ−). RESULTS Amyloid PET results were acquired for 4486 participants (mean [SD] age, 71.29 [4.67] years; 2647 women [59%]), with 1323 (29.5%) classified as Aβ+. Aβ+ participants were slightly older than Aβ−, with no observed differences in sex, education, marital or retirement status, or any self-reported lifestyle factors. Aβ+ participants were more likely to have a family history of dementia (3320 Aβ+ [74%] vs 3050 Aβ− [68%]) and at least 1 APOE ε4 allele (2602 Aβ+ [58%] vs 1122 Aβ− [25%]). Aβ+ participants demonstrated worse performance on screening Preclinical Alzheimer Cognitive Composite results and reported higher change scores on the Cognitive Function Index.CONCLUSIONS AND RELEVANCE Among a large group of older individuals screening for an Alzheimer disease (AD) prevention trial, elevated brain amyloid was associated with family history and APOE ε4 allele but not with multiple other previously reported risk factors for AD. Elevated amyloid was associated with lower test performance results and increased reports of subtle recent declines in daily cognitive function. These results support the hypothesis that elevated amyloid represents an early stage in the Alzheimer continuum and demonstrate the feasibility of enrolling these high-risk participants in secondary prevention trials aimed at slowing cognitive decline during the preclinical stages of AD.

The A4 study: β‐amyloid and cognition in 4432 cognitively unimpaired adults

“…Participants who were screened for inclusion in the A4 study 9,10 (https://clinicaltrials.gov/ct2/show/NCT02008357) were included in this study if they completed an 18F‐florbetapir PET scan, had APOE genotype information, completed a battery of neuropsychological testing, scored between 25 and 30 on the Mini‐Mental State Examination (MMSE), had a Clinical Dementia Rating of 0, and were between the ages of 65 and 85. Participants were excluded from the A4 study if they were (1) taking a prescription Alzheimer’s medication (acetylcholinesterase inhibitor and/or memantine); (2) had a current serious or unstable illness, including cardiovascular, hepatic, renal, gastroenterologic, respiratory, endocrinologic, neurologic, psychiatric, immunologic, or hematologic disease or other conditions that could interfere with the study; (3) had a history within the last 5 years of a serious infectious disease affecting the brain (including neurosyphilis, meningitis, or encephalitis) or head trauma resulting in protracted loss of consciousness; (4) had a history within the last 5 years of a primary or recurrent malignant disease, with the exception of resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with normal prostate‐specific antigen posttreatment; (5) had a known history of human immunodeficiency virus (HIV), clinically significant multiple or severe drug allergies, or severe posttreatment hypersensitivity reactions, including but not limited to erythema multiforme major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, or exfoliative dermatitis; (6) were at serious risk for suicide or had a history within the past 2 years of major depression or bipolar disorder; (7) had a history within the past 5 years of chronic alcohol or drug abuse/dependence; or (8) were residing in a skilled nursing facility or nursing home.…”

Parallels between retinal and brain pathology and response to immunotherapy in old, late‐stage Alzheimer's disease mouse models

“…AD is a fatal neurodegenerative disorder and the most common form of dementia clinically diagnosed by the progressive loss of memory and cognitive function (Alzheimer's Association, 2018). Neuropathologically, AD is typified by progressive, age‐dependent accumulation of amyloid β‐protein (Aβ; Sperling et al, 2020) in both soluble and insoluble plaque conformations, as well as neurofibrillary tangles mostly comprised of hyperphosphorylated tau, leading to vast synaptic and neuronal degeneration (De Strooper & Karran, 2016; Hardy et al, 1998; Li et al, 2020). In particular, Aβ 42 and Aβ 40 alloforms have been strongly implicated in AD pathogenesis and cognitive decline (Benilova et al, 2012; Chiti & Dobson, 2017; Kayed et al, 2003; Lambert et al, 1998; McLean et al, 1999; Shankar et al, 2008).…”

“…While these promising effects were reported in pre‐ and early‐symptomatic (5‐ to 12‐month‐old) ADtg mice, they have never been investigated in old, late‐stage mouse models of AD. Given that aging is a fundamental factor in AD development (Sperling et al, 2020), mice allowed to progress into old age may better represent the clinical manifestations of human AD. Such old mice could offer greater insights into the potential translation of effective therapies.…”

Cognitive Practice Effects Delay Diagnosis; Implications for Clinical Trials

“…Obtaining the cognitively normal, amyloid positive A4 sample of 1323 required the recruitment of 5.11 times as many people for initial screening (n=6763) and 3.39 times as many people to undergo amyloid PET imaging (4486). 33 Our calculations showed that this sample size of 1323 would be powered to detect a 27.4% drug effect on incident MCI outcomes. Due to the higher base rates of incident MCI at follow-up after PE adjustment, calculations from the R powerMediation package showed that only 1045 participants would be required.…”