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Glymphatic system dysfunction predicts amyloid deposition, neurodegeneration, and clinical progression in Alzheimer's disease
Huang SY, Zhang YR, Guo Y, Du J, Ren P, Wu BS, Feng JF, Alzheimer's Disease Neuroimaging Initiative, Cheng W, Yu JT. Alzheimer's & Dementia, 2024-03-19
Topic: Brain proteins, microglia and lab models
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.
Key findings
- 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.
Why it matters
In participants with Alzheimer's disease dementia, mild cognitive impairment and normal controls, a lower ALPS index was associated with faster amyloid PET burden change, higher risk of amyloid-positive transition and clinical progression, and faster cognitive decline, with the associations fully mediated by amyloid PET and brain atrophy. The findings suggest glymphatic failure may precede amyloid pathology and predict progression, but no treatment, cure or prevention is tested.
Study details
- Study designcohort
- Participants419
- Evidence strengthModerate
Limitations
The authors caution that the ALPS index has not been rigorously validated against pathophysiological measures of human glymphatic function and should be interpreted with caution, and that it assesses global rather than regional glymphatic activity.
How this study scored 71/100
Published in a leading specialty journal, and it is a cohort study following people over time. Scored zero for effect reported and randomised / blinded because the record does not state it. We have no data on free to read, so that was left out: it earned 70 of the 98 points we could judge it on, which is 71 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Alzheimer's & Dementia) |
| Journal's citation record | 2 / 4 | Alzheimer s & Dementia: journal h-index 228 (OpenAlex, 2026-10-29) |
| Study design | 7 / 12 | A cohort study following people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2024 — within 3 year(s) of the newest study here |
| Sample size | 2 / 4 | 419 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 283 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 70.8 citations a year over 4 year(s) since 2024 |
| Impact for its field and year | 6 / 6 | Cited 77.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 7 other studies in this library |
| Still being cited | 4 / 4 | Cited 283 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Jin‐Tai Yu: h-index 94 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | UNSW Sydney: institution h-index 1,101 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 9 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 38501315) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 70 / 98 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 70 of the 98 points we could judge it on is 71 out of 100. |
| Total | 71 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record names 10 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Huang, S. Y., Zhang, Y. R., Guo, Y., Du, J., Ren, P., Wu, B. S., et al. (2024). Glymphatic system dysfunction predicts amyloid deposition, neurodegeneration, and clinical progression in Alzheimer's disease. Alzheimer's & Dementia. https://doi.org/10.1002/alz.13789
Vancouver
Huang SY, Zhang YR, Guo Y, Du J, Ren P, Wu BS, et al. Glymphatic system dysfunction predicts amyloid deposition, neurodegeneration, and clinical progression in Alzheimer's disease. Alzheimer's & Dementia. 2024. doi:10.1002/alz.13789. PMID: 38501315.
BibTeX
@article{huang2024-38501315,
author = {Huang, S. Y. and Zhang, Y. R. and Guo, Y. and Du, J. and Ren, P. and Wu, B. S. and Feng, J. F. and {Alzheimer's Disease Neuroimaging Initiative} and Cheng, W. and Yu, J. T.},
title = {{Glymphatic system dysfunction predicts amyloid deposition, neurodegeneration, and clinical progression in Alzheimer's disease}},
journal = {Alzheimer's \& Dementia},
year = {2024},
doi = {10.1002/alz.13789},
pmid = {38501315},
url = {https://doi.org/10.1002/alz.13789}
}
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