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

Abstract

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.

Figure 1. Pulse Pressure by Alzheimer Disease Biomarker Profile in Young Old vs Very Old Participants

Bar graphs display pulse pressure values (estimated marginal means) corresponding to different cerebrospinal fluid biomarker profiles in the young old and very old age groups. Aβ−Ptau+ indicates negative biomarkers for β-amyloid 1–42 and positive biomarkers for phosphorylated tau and Aβ+Ptau+, positive biomarkers for both Aβ1-42 and P-tau. ^aP < .05 vs positive β-amyloid 1–42 only (Aβ+Ptau−). ^bP < .05 vs Aβ+Ptau− and P = .07 vs negative β-amyloid 1–42 and phosphorylated tau (Aβ−Ptau−). ^c P < .001 vs Aβ−Ptau− and P = .06 vs Aβ+Ptau−.

Figure 2. Pulse Pressure Predicts More Rapid Progression to Dementia in Very Old Participants

Cox regression indicating that higher pulse pressure was associated with more rapid progression to dementia in very old participants. For visual comparison, the survival plot displays results for high pulse pressure (>63 mmHg) in comparison with low pulse pressure (≤63mmHg).

Figure 3. Systolic, Diastolic, and Mean Arterial Blood Pressure by Alzheimer Disease Biomarker Profile in Young Old vs Very Old Groups

Bar graphs display systolic, diastolic, and mean arterial pressure values (estimated marginal means) corresponding to different cerebrospinal fluid biomarker profiles in the young old and very old age groups. Aβ−Ptau+ indicates negative biomarkers for β-amyloid 1–42 and positive biomarkers for phosphorylated tau. ^aP < .001 vs negative β-amyloid 1–42 and phosphorylated tau (Aβ−Ptau−) and P < .05 vs positive β-amyloid 1–42 only (Aβ+Ptau−). ^bP < .05 vs Aβ+Ptau− and positive β-amyloid 1–42 and phosphorylated tau (Aβ+Ptau+) and P < .01 vs Aβ−Ptau−.