Glymphatic system dysfunction predicts amyloid deposition, neurodegeneration, and clinical progression in Alzheimer's disease

Abstract

Introduction: Although glymphatic function is involved in Alzheimer's disease (AD), its potential for predicting the pathological and clinical progression of AD and its sequential association with core AD biomarkers is poorly understood.

Methods: Whole-brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS) in participants with AD dementia (n = 47), mild cognitive impairment (MCI; n = 137), and normal controls (n = 235) from the Alzheimer's Disease Neuroimaging Initiative.

Results: ALPS index was significantly lower in AD dementia than in MCI or controls. Lower ALPS index was significantly associated with faster changes in amyloid positron emission tomography (PET) burden and AD signature region of interest volume, higher risk of amyloid-positive transition and clinical progression, and faster rates of amyloid- and neurodegeneration-related cognitive decline. Furthermore, the associations of the ALPS index with cognitive decline were fully mediated by amyloid PET and brain atrophy.

Discussion: Glymphatic failure may precede amyloid pathology, and predicts amyloid deposition, neurodegeneration, and clinical progression in AD.

Highlights: The analysis along the perivascular space (ALPS) index is reduced in patients with Alzheimer's disease (AD) dementia, prodromal AD, and preclinical AD. Lower ALPS index predicted accelerated amyloid beta (Aβ) positron emission tomography (PET) burden and Aβ-positive transition. The decrease in the ALPS index occurs before cerebrospinal fluid Aβ42 reaches the positive threshold. ALPS index predicted brain atrophy, clinical progression, and cognitive decline. Aβ PET and brain atrophy mediated the link of ALPS index with cognitive decline.

Keywords: Alzheimer's disease; amyloid; analysis along the perivascular space; cognitive decline; glymphatic; neurodegeneration; progression.

FIGURE 1

Overview of the study. A, amyloid; Aβ, amyloid beta; AD, Alzheimer's disease; ADNI, Alzheimer's Disease Neuroimaging Initiative; ALPS, analysis along the perivascular space; AV45, florbetapir; AV1451, flortaucipir; CN, cognitively normal; CSF, cerebrospinal fluid; FBB, florbetaben; FDG, fluorodeoxyglucose; MCI, mild cognitive impairment; MRI, magnetic resonance imaging; PACC, Preclinical Alzheimer's Cognitive Composite; PET, positron emission tomography; p‐tau181, phosphorylated tau 181; ROI, region of interest; SUVR, standard uptake value ratio; t‐tau, total tau.

FIGURE 2

ALPS indexes by diagnosis and biological stages. The graphs display the 95% CIs around the median of raw values of each plasma biomarker. ALPS indexes were Box–Cox transformed for normalization prior to the analysis. Statistical analyses were conducted using analyses of covariance controlling for age, sex, education, and APOE ε4 carrier status (A–C). Comparing ALPS indexes in different biological groups, covariates include age, sex, education, APOE ε4 carrier status, and baseline diagnoses (D–F). A status was defined by CSF Aβ42 and amyloid PET (AV45 and FBB PET) (D). T status was defined by CSF p‐tau181 and AV1451 PET (E). N status was defined by CSF t‐tau and FDG PET (F). Significant P values after FDR corrected post hoc pairwise comparisons are marked with ***P < 0.001, *P<0.05, **P<0.01, ***P<0.001. “–” indicates negative; “+” indicates positive. A, amyloid; Aβ, amyloid beta; AD, Alzheimer's disease; ALPS, analysis along the perivascular space; APOE, apolipoprotein E; AV45, florbetapir; AV1451, flortaucipir; CI, confidence interval; CN, cognitively normal; CSF, cerebrospinal fluid; FBB, florbetaben; FDG, fluorodeoxyglucose; FDR, false discovery rate; MCI, mild cognitive impairment; N, neurodegeneration; PET, positron emission tomography; p‐tau181, phosphorylated tau 181; T, tau pathology; t‐tau, total tau.

FIGURE 3

Association of ALPS indexes with core AD biomarkers. A, Cross‐sectional association between ALPS index and core AD variables. B, Prediction of longitudinal changes of core AD variables by baseline ALPS index. C, Association between baseline core AD variables and longitudinal slope of ALPS index. The points (red, CN; blue, MCI; yellow, AD dementia) and solid lines represent the individuals and regression lines, respectively. The regression coefficients (β) and P values were computed using a linear model across all participants, adjusting for age, sex, education, APOE ε4 carrier status. Association of baseline ALPS index with baseline and slope of regional Aβ PET SUVR (D–E) and cortical volume (F–G). The strength of associations with neuroimaging measures is shown in color scales representing the t value. Aβ, amyloid beta; AD, Alzheimer's disease; ALPS, analysis along the perivascular space; APOE, apolipoprotein E; CN, cognitively normal; FDG, fluorodeoxyglucose; MCI, mild cognitive impairment; p‐tau181, phosphorylated tau 181; PET, positron emission tomography; ROI, region of interest; SUVR, standard uptake value ratio; t‐tau, total tau.

FIGURE 4

ALPS index reduction may occur prior to amyloid and predict amyloid‐positive transition. Trajectories of ALPS index, CSF Aβ42, Aβ PET (AV45 PET), and PACC score were modeled using CSF Aβ42 (A) or PACC score (B) as proxy of disease progression. The values of Aβ PET (AV45 PET) and PACC score were scaled to 0% to 100%, with 0% representing the minimal value and 100% representing the maximal value. The original ALPS index and CSF Aβ42 were reversed, with 100% representing the minimal value and 0% representing the maximal value. This normalization procedure made the higher values of abnormalities in ALPS index, CSF Aβ42, Aβ PET (AV45 PET), and PACC score represent the more severe disease state. C–D, The Kaplan–Meier curves showing cumulative probability of amyloid status progression. Results of multivariable Cox regression treating the ALPS index as a continuous variable after adjustment for age, sex, education, and APOE ε4 genotype are shown in the lower left. The table under the curve illustrates number at risk (%) at 2‐year intervals, to facilitate interpretation of the curves. A, amyloid; Aβ, amyloid beta; AD, Alzheimer's disease; APOE, apolipoprotein E; ALPS, analysis along the perivascular space; AV45, florbetapir; CN, cognitively normal; CSF, cerebrospinal fluid; CI, confidence interval; MCI, mild cognitive impairment; HR, hazard ratio; PACC, Preclinical Alzheimer's Cognitive Composite; PET, positron emission tomography.

FIGURE 5

Associations of ALPS indexes with risk of clinical progression. The Kaplan–Meier curves of clinical progression to MCI/AD dementia in non‐demented participants (A), progression to MCI/AD dementia in CN participants (B), or progression to AD in UKB participants (C). Results of multivariable Cox regression treating the ALPS index as a continuous variable after adjustment for age, sex, education, and APOE ε4 carrier status are shown in the lower left. The table under the curve illustrates number at risk (%) at 2‐year intervals, to facilitate interpretation of the curves. AD, Alzheimer's disease; ALPS, analysis along the perivascular space; APOE, apolipoprotein E; CN, cognitively normal; CI, confidence interval; MCI, mild cognitive impairment; HR, hazard ratio; UKB, UK Biobank.

FIGURE 6

Associations of ALPS indexes with cognitive performance. A, Cross‐sectional association between ALPS and cognitive performance. B, Association between baseline ALPS and longitudinal slope of cognitive performance. C, Association between baseline cognitive performance and longitudinal slope of ALPS. The points (red, CN; blue, MCI; yellow, AD dementia) and solid lines represent the individuals and regression lines, respectively. The regression coefficients (β) and P values were computed using a linear model across all participants, adjusting for age, sex, education, APOE ε4 carrier status. AD, Alzheimer's disease; ALPS, analysis along the perivascular space; APOE, apolipoprotein E; CN, cognitively normal; EF, executive function composite score; PACC, Preclinical Alzheimer's Cognitive Composite; MCI, mild cognitive impairment; MEM, memory composite score.

FIGURE 7

ALPS index predicts cognition change through amyloid and neurodegeneration. A, A model integrating the findings in the present study, together with previous studies, depicts an approximative order of ALPS and AD core biomarkers in the AD continuum. B, Mediation analysis based on structural equation modeling. We computed the standardized coefficients (β) of each association. P values are visualized with *P<0.05, **P<0.01, ***P<0.001. The horizontal gray line in lollipop chart represents the absolute value of β, and the color of the circle represents the positive (orange) or negative (blue) direction of β. Aβ, amyloid beta; AD, Alzheimer's disease; ALPS, analysis along the perivascular space; AV45, florbetapir; CSF, cerebrospinal fluid; PACC, preclinical Alzheimer cognitive composite; IE, indirect effect; PET, positron emission tomography; ROI, region of interest.