Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease

Neurology. 2018 Oct 2;91(14):e1295-e1306. doi: 10.1212/WNL.0000000000006277. Epub 2018 Sep 14.


Objective: To assess the onset, sequence, and rate of progression of comprehensive biomarker and clinical measures across the spectrum of Alzheimer disease (AD) using the Dominantly Inherited Alzheimer Network (DIAN) study and compare these to cross-sectional estimates.

Methods: We conducted longitudinal clinical, cognitive, CSF, and neuroimaging assessments (mean of 2.7 [±1.1] visits) in 217 DIAN participants. Linear mixed effects models were used to assess changes in each measure relative to individuals' estimated years to symptom onset and to compare mutation carriers and noncarriers.

Results: Longitudinal β-amyloid measures changed first (starting 25 years before estimated symptom onset), followed by declines in measures of cortical metabolism (approximately 7-10 years later), then cognition and hippocampal atrophy (approximately 20 years later). There were significant differences in the estimates of CSF p-tau181 and tau, with elevations from cross-sectional estimates preceding longitudinal estimates by over 10 years; further, longitudinal estimates identified a significant decline in CSF p-tau181 near symptom onset as opposed to continued elevations.

Conclusion: These longitudinal estimates clarify the sequence and temporal dynamics of presymptomatic pathologic changes in autosomal dominant AD, information critical to a better understanding of the disease. The pattern of biomarker changes identified here also suggests that once β-amyloidosis begins, additional pathologies may begin to develop less than 10 years later, but more than 15 years before symptom onset, an important consideration for interventions meant to alter the disease course.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alzheimer Disease / cerebrospinal fluid*
  • Alzheimer Disease / diagnostic imaging
  • Alzheimer Disease / genetics
  • Alzheimer Disease / psychology*
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Amyloid beta-Protein Precursor / genetics
  • Biomarkers / cerebrospinal fluid
  • Brain / diagnostic imaging
  • Cognition*
  • Cross-Sectional Studies
  • Female
  • Follow-Up Studies
  • Genes, Dominant
  • Heterozygote
  • Humans
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Mutation
  • Peptide Fragments / cerebrospinal fluid
  • Phosphorylation
  • Presenilin-1 / genetics
  • Presenilin-2 / genetics
  • tau Proteins / cerebrospinal fluid


  • APP protein, human
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Biomarkers
  • MAPT protein, human
  • PSEN1 protein, human
  • PSEN2 protein, human
  • Peptide Fragments
  • Presenilin-1
  • Presenilin-2
  • amyloid beta-protein (1-42)
  • tau Proteins