1. Preclinical amyloid-β was associated with significant cognitive decline in clinically normal adults across screening and comprehensive measures.
2. Amyloid-β-positive individuals were more likely to carry at least one APOE ε4 allele and have a family history of dementia.
Evidence Rating Level: 3 (Average)
Amyloid-β (Aβ) pathology is known as the preclinical phase of Alzheimer’s disease (AD) continuum, which can begin at least one decade prior to AD dementia. This cross-sectional analysis of the Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) Study sought to investigate whether or not Aβ burden is associated with genetic, demographic, and lifestyle factors as well as cognitive functioning in older, clinically-normal individuals. This study utilized positron emission tomography (PET) and standardized assessments to evaluate factors associated with amyloid deposition. Data from total of 4,486 individuals were collected from April 2014 to December 2017 and were eligible if between the ages of 65 and 85 years and cognitively normal in terms of the Mini-Mental Status Examination (MMSE; ≥25), Wechsler Memory Scale Logical Memory II (LM; 6-18) and amyloid PET. Across the entire sample (M [SD] age = 71.29 [4.67] years), 85% were enrolled in the US, 10% in Australia, 4% in Canada, and 2% in Japan. Approximately 29.5% were categorized as Aβ+ and 70.5% were Aβ-. The mean (SD) cortical standardized uptake value ratio (SUVr) for the Aβ+ group was 1.33 (0.18). Aβ+ individuals were slightly older than Aβ- individual (p<0.001) and had lower mean PET SUVr (p<0.001). Reports of family history of dementia in Aβ+ participants and 58% of the Aβ+ group carried one or more APOE ε4 alleles (25% of Aβ-), with the former group showing higher amyloid burden (mean [SD] SUVr = 1.36 [0.176]) compared to noncarriers (p<0.001). Neuropsychological measures suggested significantly lower scores in Aβ+ participants on each measure, including MMSE (p<0.01), Free and Cued Selective Reminding Test’s free and total scores (p<0.001), LM delay (p<0.001), and digit symbol (p<0.001). Marginal evidence was found to suggest that factors such as lower education, decreased physical activity, female sex, body mass index, or lifestyle were associated with elevated amyloid. The main limitation of this study is the limited diversity of the PET sample, such that participants of color were underrepresented. However, this study highlights the significant cognitive impact of preclinical AD and the associations with APOE ε4 and family history of dementia.
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