Pulse pressure in relation to tau-mediated neurodegeneration, cerebral amyloidosis, and progression to dementia in very old adults.

IMPORTANCE Increased pulse pressure associated with age-related arterial stiffening increases risk for Alzheimer dementia but the mechanism responsible for this association remains unclear. OBJECTIVES 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. DESIGN, SETTING, AND PARTICIPANTS 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. MAIN OUTCOMES AND MEASURES 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 AND RELEVANCE 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.

[1]  David D. Shin,et al.  Elevated cerebrovascular resistance index is associated with cognitive dysfunction in the very-old , 2015, Alzheimer's Research & Therapy.

[2]  D. Knopman β-Amyloidosis and neurodegeneration in Alzheimer disease , 2014, Neurology.

[3]  D. Drachman The amyloid hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer's disease , 2014, Alzheimer's & Dementia.

[4]  C. Jack,et al.  Biomarker Modeling of Alzheimer’s Disease , 2013, Neuron.

[5]  D. Salmon,et al.  Pulse pressure is associated with Alzheimer biomarkers in cognitively normal older adults , 2013, Neurology.

[6]  L. Kuller,et al.  Pulse wave velocity is associated with β-amyloid deposition in the brains of very elderly adults , 2013, Neurology.

[7]  C. Bulpitt,et al.  Increased pulse pressure linked to dementia: further results from the Hypertension in the Very Elderly Trial – HYVET , 2013, Journal of hypertension.

[8]  J. Trojanowski,et al.  Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre. , 2013, Brain : a journal of neurology.

[9]  D. Salmon,et al.  Cortical and subcortical cerebrovascular resistance index in mild cognitive impairment and Alzheimer's disease. , 2013, Journal of Alzheimer's disease : JAD.

[10]  J. Weuve,et al.  Alzheimer disease in the United States (2010–2050) estimated using the 2010 census , 2013, Neurology.

[11]  Denise C. Park,et al.  Risk factors for β-amyloid deposition in healthy aging: vascular and genetic effects. , 2013, JAMA neurology.

[12]  C. Jack,et al.  Brain injury biomarkers are not dependent on β‐amyloid in normal elderly , 2013, Annals of neurology.

[13]  C. Jack,et al.  Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers , 2013, The Lancet Neurology.

[14]  E. Siegel,et al.  Interactive relations of blood pressure and age to subclinical cerebrovascular disease , 2012, Journal of hypertension.

[15]  H. Braak,et al.  Where, when, and in what form does sporadic Alzheimer's disease begin? , 2012, Current opinion in neurology.

[16]  David A Wolk,et al.  Cerebrovascular atherosclerosis correlates with Alzheimer pathology in neurodegenerative dementias. , 2012, Brain : a journal of neurology.

[17]  Sterling C. Johnson,et al.  CSF T-Tau/Aβ42 Predicts White Matter Microstructure in Healthy Adults at Risk for Alzheimer’s Disease , 2012, PloS one.

[18]  C. Jack,et al.  An operational approach to National Institute on Aging–Alzheimer's Association criteria for preclinical Alzheimer disease , 2012, Annals of neurology.

[19]  A. Fleisher,et al.  Blood pressure is associated with higher brain amyloid burden and lower glucose metabolism in healthy late middle-age persons , 2012, Neurobiology of Aging.

[20]  Wendy J Mack,et al.  Vascular risk factors and Alzheimer's disease: are these risk factors for plaques and tangles or for concomitant vascular pathology that increases the likelihood of dementia? An evidence-based review , 2011, Alzheimer's Research & Therapy.

[21]  B. Zlokovic Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders , 2011, Nature Reviews Neuroscience.

[22]  V. Gudnason,et al.  Arterial stiffness, pressure and flow pulsatility and brain structure and function: the Age, Gene/Environment Susceptibility--Reykjavik study. , 2011, Brain : a journal of neurology.

[23]  N. Wong,et al.  The significance of low DBP in US adults with isolated systolic hypertension , 2011, Journal of hypertension.

[24]  D. Knopman,et al.  Vascular risk factors: imaging and neuropathologic correlates. , 2010, Journal of Alzheimer's disease : JAD.

[25]  C. Jack,et al.  Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade , 2010, The Lancet Neurology.

[26]  S. Leurgans,et al.  The neuropathology of probable Alzheimer disease and mild cognitive impairment , 2009, Annals of neurology.

[27]  R. Petersen,et al.  Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects , 2009, Annals of neurology.

[28]  R. Weller,et al.  Microvasculature changes and cerebral amyloid angiopathy in Alzheimer’s disease and their potential impact on therapy , 2009, Acta Neuropathologica.

[29]  Julian F. Thayer,et al.  Pulse Pressure and Pulse Wave Velocity Are Related to Cognitive Decline in the Baltimore Longitudinal Study of Aging , 2008, Hypertension.

[30]  G. de Simone,et al.  High pulse pressure as a marker of preclinical cardiovascular disease. , 2006, Future cardiology.

[31]  R. Devereux,et al.  Is High Pulse Pressure a Marker of Preclinical Cardiovascular Disease? , 2005, Hypertension.

[32]  B. Lernfelt,et al.  15-year longitudinal study of blood pressure and dementia , 1996, The Lancet.

[33]  R B D'Agostino,et al.  Stroke risk profile: adjustment for antihypertensive medication. The Framingham Study. , 1994, Stroke.