Onset of Preclinical Alzheimer Disease in Monozygotic Twins

OBJECTIVE: The present work was undertaken to study the genetic contribution to the start of Alzheimer's disease (AD) with amyloid and tau biomarkers in cognitively intact older identical twins. METHODS: We studied in 96 monozygotic twin‐pairs relationships between amyloid‐beta (Aβ) aggregation as measured by the Aβ1–42/1–40 ratio in cerebrospinal fluid (CSF; n = 126) and positron emission tomography (PET, n = 194), and CSF markers for Aβ production (beta‐secretase 1, Aβ1–40, and Aβ1–38) and CSF tau. Associations among markers were tested with generalized estimating equations including a random effect for twin status, adjusted for age, gender, and apolipoprotein E ε4 genotype. We used twin analyses to determine relative contributions of genetic and/or environmental factors to AD pathophysiological processes. RESULTS: Twenty‐seven individuals (14%) had an abnormal amyloid PET, and 14 twin‐pairs (15%) showed discordant amyloid PET scans. Within twin‐pairs, Aβ production markers and total‐tau (t‐tau) levels strongly correlated (r range = 0.73–0.86, all p < 0.0001), and Aβ aggregation markers and 181‐phosphorylated‐tau (p‐tau) levels correlated moderately strongly (r range = 0.50–0.64, all p < 0.0001). Cross‐twin cross‐trait analysis showed that Aβ1–38 in one twin correlated with Aβ1–42/1–40 ratios, and t‐tau and p‐tau levels in their cotwins (r range = −0.28 to 0.58, all p < .007). Within‐pair differences in Aβ production markers related to differences in tau levels (r range = 0.49–0.61, all p < 0.0001). Twin discordance analyses suggest that Aβ production and tau levels show coordinated increases in very early AD. INTERPRETATION: Our results suggest a substantial genetic/shared environmental background contributes to both Aβ and tau increases, suggesting that modulation of environmental risk factors may aid in delaying the onset of AD pathophysiological processes. ANN NEUROL 2021;89:987–1000