Association of Amyloid Pathology With Myelin Alteration in Preclinical Alzheimer Disease

Abstract

Importance: The accumulation of aggregated β-amyloid and tau proteins into plaques and tangles is a central feature of Alzheimer disease (AD). While plaque and tangle accumulation likely contributes to neuron and synapse loss, disease-related changes to oligodendrocytes and myelin are also suspected of playing a role in development of AD dementia. Still, to our knowledge, little is known about AD-related myelin changes, and even when present, they are often regarded as secondary to concomitant arteriosclerosis or related to aging.

Objective: To assess associations between hallmark AD pathology and novel quantitative neuroimaging markers while being sensitive to white matter myelin content.

Design, setting, and participants: Magnetic resonance imaging was performed at an academic research neuroimaging center on a cohort of 71 cognitively asymptomatic adults enriched for AD risk. Lumbar punctures were performed and assayed for cerebrospinal fluid (CSF) biomarkers of AD pathology, including β-amyloid 42, total tau protein, phosphorylated tau 181, and soluble amyloid precursor protein. We measured whole-brain longitudinal and transverse relaxation rates as well as the myelin water fraction from each of these individuals.

Main outcomes and measures: Automated brain mapping algorithms and statistical models were used to evaluate the relationships between age, CSF biomarkers of AD pathology, and quantitative magnetic resonance imaging relaxometry measures, including the longitudinal and transverse relaxation rates and the myelin water fraction.

Results: The mean (SD) age for the 19 male participants and 52 female participants in the study was 61.6 (6.4) years. Widespread age-related changes to myelin were observed across the brain, particularly in late myelinating brain regions such as frontal white matter and the genu of the corpus callosum. Quantitative relaxometry measures were negatively associated with levels of CSF biomarkers across brain white matter and in areas preferentially affected in AD. Furthermore, significant age-by-biomarker interactions were observed between myelin water fraction and phosphorylated tau 181/β-amyloid 42, suggesting that phosphorylated tau 181/β-amyloid 42 levels modulate age-related changes in myelin water fraction.

Conclusions and relevance: These findings suggest amyloid pathologies significantly influence white matter and that these abnormalities may signify an early feature of the disease process. We expect that clarifying the nature of myelin damage in preclinical AD may be informative on the disease's course and lead to new markers of efficacy for prevention and treatment trials.

Figure 1. Associations Between Age and Quantitative Relaxometry Measures

A, Significant (P < .05, false discovery rate [FDR] corrected) age-related relationships with myelin water fraction (MWF) (top row), R₁ (middle row), and R₂ (bottom row) overlaid on the group mean MWF map. Negative relationships were observed across widespread white matter, with late myelinating areas, including frontal and temporal white matter, having the strongest age-related declines. B, representative scatter plot depicts the mean MWF, R₁, and R₂ calculated from areas of significant age decline plotted against the age of each participant. Scatter points represent individual mean parameter (MWF, R₁, and R₂) values and the solid trend line represents the line of best fit with age.

Figure 2. Regional White Matter Myelin Content, as Measured by Myelin Water Fraction (MWF), Associated With Soluble Amyloid Precursor Protein/β-Amyloid 42 (sAPPβ/Aβ42)

Representative axial slices depicting areas of significant relationship between MWF and sAPPβ/Aβ42 overlaid on the group mean MWF map. Widespread white matter was observed to be negatively related to levels of sAPPβ/Aβ42. Results are false discovery rate (FDR) corrected for multiple comparisons (P < .05).

Figure 3. Associations Between Soluble Amyloid Precursor Protein (sAPPβ)/β-Amyloid 42 (Aβ42) and Myelin Water Fraction (MWF)

Clusters of 50 voxels or greater were determined from false discovery rate–corrected associations between MWF and sAPPβ/Aβ42. Mean MWF from the indicated significant clusters were calculated and plotted against sAPPβ/Aβ42. Each point in the scatter represents mean MWF and corresponding sAPPβ/Aβ42 from 1 participant (n = 71).

Figure 4. Levels of Phosphorylated Tau (Ptau181)/β-Amyloid 42 (Aβ42) Moderate Age-Related Changes of Myelin Water Fraction (MWF)

A, Representative illustration of significant interactions of age and Ptau181/Aβ42 with MWF. Myelin water fraction from the peak voxel (as indicated by the cross-hair) was extracted and participants were subsequently split into 2 groups by the Ptau181/Aβ42 ratio median. B, Myelin water fraction was plotted and fit against participant age for each group. These plots demonstrate the changing age relationship with dissimilar Ptau181/Aβ42 ratio.