Onset of Preclinical Alzheimer Disease in Monozygotic Twins

Ann Neurol. 2021 May;89(5):987-1000. doi: 10.1002/ana.26048. Epub 2021 Mar 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Twin Study

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / cerebrospinal fluid*
  • Alzheimer Disease / diagnostic imaging
  • Alzheimer Disease / genetics*
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Apolipoproteins E / genetics
  • Biomarkers / cerebrospinal fluid
  • Depression / psychology
  • Environment
  • Female
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Neuropsychological Tests
  • Peptide Fragments / cerebrospinal fluid
  • Positron-Emission Tomography
  • Twins, Monozygotic
  • tau Proteins / cerebrospinal fluid


  • Amyloid beta-Peptides
  • Apolipoproteins E
  • Biomarkers
  • MAPT protein, human
  • Peptide Fragments
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • tau Proteins