title: Pulse pressure in relation to tau-mediated neurodegeneration, cerebral amyloidosis, and progression to dementia in very old adults.
abstract: OBJECTIVE
  Increased pulse pressure associated with age-related arterial stiffening increases risk for Alzheimer dementia but the mechanism responsible for this association remains unclear.
  
  
  OBJECTIVE
  To determine the relationship between pulse pressure and cerebral spinal fluid biomarker profiles of preclinical Alzheimer disease, investigate whether observed relationships are stronger in adults with more advanced arterial age (≥80 years of age), and examine the relationship between pulse pressure and progression to dementia.
  
  
  METHODS
  In this retrospective cohort study, 877 participants without dementia (55-91 years of age) from the Alzheimer's Disease Neuroimaging Initiative underwent baseline health assessment, including blood pressure assessment and lumbar puncture for determination of cerebral spinal fluid phosphorylated tau (P-tau) and β-amyloid 1-42. Participants have been followed up longitudinally since 2005. The last date of examination was October 15, 2013. Clinical follow-up between 6 and 96 months tracked progression to dementia.
  
  
  METHODS
  Regression and analysis of covariance analyses investigated relationships between pulse pressure and distinct cerebral spinal fluid biomarker profiles. Very old participants (80 years or older) were compared with younger participants (55-79 years of age) on clinical measures and pulse pressure × age group interactions were investigated. Survival analysis examined the effect of baseline pulse pressure on progression to dementia. Covariates were age, sex, apolipoprotein E genotype, body mass index, vascular risk factors, and antihypertensive medication use.
  
  
  RESULTS
  Individuals with a P-tau-positive biomarker profile exhibited mean (SD) elevated pulse pressure regardless of age (62.0 [15.6] mm Hg for a P-tau-positive biomarker vs 57.4 [14.0] mm Hg for P-tau-negative biomarker; P = .04). In very old participants, a further increase in pulse pressure was observed in those exhibiting both P-tau elevation and β-amyloid 1-42 reduction vs either biomarkers alone (69.7 [16.0] mm Hg for both positive biomarkers vs 63.18 [13.0] mm Hg for P-tau alone vs 60.1 [16.4] mm Hg for β-amyloid 1-42 alone vs 56.6 [14.5] mm Hg for negative biomarkers; P = .003). Those with higher baseline pulse pressure progressed to dementia more rapidly (95% CI, 1.000-1.048; P = .05; hazard ratio = 1.024). Systolic pressure exhibited similar relationships with Alzheimer disease biomarkers and progression to dementia in the very old subgroup (P < .05) but showed no associations in the young old subgroup (P > .10). Diastolic pressure was reduced in young old participants with isolated phosphorylated tau elevation (P = .04).
  
  
  CONCLUSIONS
  Pulse pressure, an index of vascular aging, was associated with neurodegenerative change prior to the onset of dementia across a broad age range. Among those with more advanced age, higher pulse pressure was also associated with cerebral amyloidosis in the presence of neurodegeneration and more rapid progression to dementia. Diastolic contributions to these biomarker associations were limited to young old participants whereas systolic contributions were found only in very old participants.
authors.affiliation: Department of Psychology, University of Southern California, Los Angeles.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Nation
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Edmonds
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla3Veterans Affairs San Diego Healthcare System, San Diego, California.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Bangen
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla3Veterans Affairs San Diego Healthcare System, San Diego, California.
authors.forename: Lisa
authors.initials: L
authors.lastname: Delano-Wood
authors.affiliation: Sierra-Pacific Mental Illness Research, Education, and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, California5Stanford/Veterans Affairs Alzheimer's Research Center, Palo Alto, California.
authors.forename: Blake K
authors.initials: BK
authors.lastname: Scanlon
authors.affiliation: Veterans Affairs Long Beach Healthcare System, Long Beach, California7Department of Behavioral Sciences, Rush University, Chicago, Illinois.
authors.forename: S Duke
authors.initials: SD
authors.lastname: Han
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Edland
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla.
authors.forename: David P
authors.initials: DP
authors.lastname: Salmon
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego, California8Department of Neurosciences, University of California, San Diego, La Jolla.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Galasko
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla3Veterans Affairs San Diego Healthcare System, San Diego, California.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Bondi
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000134:cerebrospinal fluid / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001794:Blood Pressure / Q000502:physiology*; D016657:Cerebral Amyloid Angiopathy / Q000134:cerebrospinal fluid / Q000503:physiopathology; D003704:Dementia / Q000134:cerebrospinal fluid / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000134:cerebrospinal fluid / Q000503:physiopathology; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
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