Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jul 11;101(2):e164-e177.
doi: 10.1212/WNL.0000000000207378. Epub 2023 May 18.

Longitudinal Relationships of White Matter Hyperintensities and Alzheimer Disease Biomarkers Across the Adult Life Span

Jingqin Luo  1 , Yinjiao Ma  1 , Folasade Jane Agboola  1 , Elizabeth Grant  1 , John C Morris  1 , Eric McDade  1 , Anne M Fagan  1 , Tammie L S Benzinger  1 , Jason Hassenstab  1 , Randall J Bateman  1 , Richard J Perrin  1 , Brian A Gordon  1 , Manu Goyal  1 , Jeremy F Strain  1 , Igor Yakushev  1 , Gregory S Day  1 , Chengjie Xiong  2 ; for Dominantly Inherited Alzheimer Network (DIAN)
Collaborators, Affiliations

Longitudinal Relationships of White Matter Hyperintensities and Alzheimer Disease Biomarkers Across the Adult Life Span

Jingqin Luo et al. Neurology. .

Abstract

Background and objectives: White matter hyperintensities (WMH) correlate with Alzheimer disease (AD) biomarkers cross-sectionally and modulate AD pathogenesis. Longitudinal changes have been reported for AD biomarkers, including concentrations of CSF β-amyloid (Aβ) 42, Aβ40, total tau and phosphorylated tau181, standardized uptake value ratio from the molecular imaging of cerebral fibrillar Aβ with PET using [11C] Pittsburgh Compound-B, MRI-based hippocampal volume, and cortical thickness. Correlations between established AD biomarkers and the longitudinal change for WMH have not been fully evaluated, especially among cognitively normal individuals across the adult life span.

Methods: We jointly analyzed the longitudinal data of WMH volume and each of the established AD biomarkers and cognition from 371 cognitively normal individuals whose baseline age spanned from 19.6 to 88.20 years from 4 longitudinal studies of aging and AD. A 2-stage algorithm was applied to identify the inflection point of baseline age whereby older participants had an accelerated longitudinal change in WMH volume, in comparison with the younger participants. The longitudinal correlations between WMH volume and AD biomarkers were estimated from the bivariate linear mixed-effects models.

Results: A longitudinal increase in WMH volume was associated with a longitudinal increase in PET amyloid uptake and a decrease in MRI hippocampal volume, cortical thickness, and cognition. The inflection point of baseline age in WMH volume was identified at 60.46 (95% CI 56.43-64.49) years, with the annual increase for the older participants (83.12 [SE = 10.19] mm3 per year) more than 13 times faster (p < 0.0001) than that for the younger participants (6.35 [SE = 5.63] mm3 per year). Accelerated rates of change among the older participants were similarly observed in almost all the AD biomarkers. Longitudinal correlations of WMH volume with MRI, PET amyloid biomarkers, and cognition seemed to be numerically stronger for the younger participants, but not significantly different from those for the older participants. Carrying APOE ε4 alleles did not alter the longitudinal correlations between WMH and AD biomarkers.

Discussion: Longitudinal increases in WMH volume started to accelerate around a baseline age of 60.46 years and correlated with the longitudinal change in PET amyloid uptake, MRI structural outcomes, and cognition.

PubMed Disclaimer

Conflict of interest statement

The authors report no disclosures relevant to the manuscript. The following disclosures should be noted. J.C. Morris consults for Barcelona Brain Research Center (BBRC) Int'l Advisory Board, TS Srinivasan-NIMHANS Knowledge Conclave (Chennai, India) International Advisory Board; Center for Brain Research (Bangalore, India) Native Alzheimer Disease-Related Resource Center in Minority Aging Research, Ext Adv Board, and Cure Alzheimer Fund, Research Strategy Council Diverse VCID Observational Study Monitoring Board LEADS Advisory Board, Indiana University, and received honoraria from Montefiore Grand Rounds, NY Tetra-Inst ADRC seminar series, Grand Rds, NY. A.M. Fagan has consulted for Biogen, Centene, Fujirebio, and Roche Diagnostics, is a member of the scientific advisory boards for Roche Diagnostics, Genentech, and AbbVie, and consults for Araclon/Grifols, Diadem, and DiamiR. T.L.S. Benzinger received research support from Avid Radiopharmaceuticals and participates in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly, and Hoffman-LaRoche and has received honoraria from Biogen, Eisai, and Genetech. R.J. Bateman has equity ownership interest in C2N Diagnostics and may receive income based on technology licensed or optioned by Washington University to C2N Diagnostics, receives income from C2N Diagnostics for serving on the scientific advisory board, received honoraria as a speaker/consultant/advisory board member from Amgen, Eisai, and Roche. B. Gordon participates in clinical trials sponsored by Avid Radio-pharmaceuticals (a wholly owned subsidiary of Eli Lilly), Eli Lilly, and Hoffman-LaRoche. G.S. Day is supported by the NIH/National Institute on Aging (K23AG064029), serves as a topic editor on dementia for DynaMed Plus (EBSCO Industries, Inc.), is a consultant for Parabon NanoLabs, is the clinical director for the Anti-NMDA Receptor Encephalitis Foundation (uncompensated), has provided record review and expert medical testimony on legal cases pertaining to the management of Wernicke encephalopathy, and holds stocks (>$10,000) in ANI Pharmaceuticals (a generic pharmaceutical company). C. Xiong consults for Diadem. There are no conflicts with this work. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. Study Flowchart
A total of 371 cognitively normal participants who had at least 2 longitudinal assessments of WMH volume were included for analyses, listing the number of participants with at least 2, 3, or 4 visits for each modality. Aβ = β-amyloid; ACS = Adult-Children Study; ADRC = Alzheimer Disease Research Center; CDR = Clinical Dementia Rating; DIAN = Dominantly Inherited Alzheimer Network; HASD = Healthy Aging and Senile Dementia; PiB = Pittsburgh compound B; pTau181 = tau phosphorylated at 181; t-Tau = total tau; WMH = white matter hyperintensities.
Figure 2
Figure 2. Longitudinal Trajectory and Inflection Point of WMH Volume
(A) Longitudinal spaghetti plot of WMH volume (in raw scale) as a function of age in the longitudinal follow-up. (B) Estimated participant-level annual rate of change (slope in raw scale) as a piecewise linear function of baseline age, indicating an inflection point of baseline age at 60.46 years. WMH = white matter hyperintensities.
See this image and copyright information in PMC

References

    1. Zlokovic BV, Gottesman RF, Bernstein KE, et al. . Vascular contributions to cognitive impairment and dementia (VCID): a report from the 2018 National Heart, Lung, and Blood Institute and National Institute of Neurological Disorders and Stroke Workshop. Alzheimers Dement. 2020;16(12):1714-1733. - PubMed
    1. Lee S, Viqar F, Zimmerman ME, et al. . White matter hyperintensities are a core feature of Alzheimer's disease: evidence from the dominantly inherited Alzheimer network. Ann Neurol. 2016;79(6):929-939. - PMC - PubMed
    1. Debette S, Markus HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ. 2010;341:c3666. - PMC - PubMed
    1. Prins ND, Scheltens P. White matter hyperintensities, cognitive impairment and dementia: an update. Nat Rev Neurol. 2015;11(3):157-165. - PubMed
    1. Brickman AM, Zahodne LB, Guzman VA, et al. . Reconsidering harbingers of dementia: progression of parietal lobe white matter hyperintensities predicts Alzheimer's disease incidence. Neurobiol Aging. 2015;36(1):27-32. - PMC - PubMed

Publication types