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Distinct regional patterns of synaptic vulnerability across hippocampal and parahippocampal subregions in Alzheimer's disease
Maud M. A. Bouwman, Irene Frigerio, Yvon Galis-de Graaf, Wilma D. J. van de Berg, Laura E. Jonkman. Brain Pathology, 2026-02-09
Topic: Amyloid, tau and blood-test diagnosis
Synaptic loss in the (para)hippocampus is a major contributor to cognitive decline in Alzheimer's disease (AD), yet its regional specificity and pathological correlates remain poorly understood. Here, we quantified synaptophysin-positive puncta across hippocampal subregions (CA4, CA2, CA1, and subiculum) and parahippocampal cortex (entorhinal cortex, parahippocampal and fusiform gyrus) in postmortem tissue from 28 AD and 17 controls, and assessed relationships to neuropathological severity and cognitive decline. Amyloid-β, phosphorylated tau (p-tau) load and neurofilament light (NfL) immunoreactivity were quantified, and Clinical Dementia Rating scores were collected as a cognitive measure. Group differences were analyzed with linear mixed models; correlations between synaptic puncta, pathology and cognitive scores with linear regressions, corrected for age, sex and multiple comparisons. We found selective synaptic loss in the entorhinal cortex (-14%, p = 0.017) and parahippocampal gyrus (-14%, p = 0.021) in AD versus controls. Hippocampal synaptic density negatively correlated with amyloid-β in controls (r = -0.52, p < 0.001) and positively in AD (r = 0.25, p = 0.007), suggesting a disease-dependent shift. In AD, hippocampal, but not parahippocampal, subregions with higher p-tau burden showed greater synaptic density (r = 0.21, p = 0.003), raising questions about the role of p-tau in synaptic loss at late stages. Axonal damage (i.e., higher NfL load) in the parahippocampal cortex associated with synaptic loss locally and in interconnected subregions. Worse cognitive performance was strongly associated with synaptic loss in the CA1 (r = -0.64, p = 0.003), subiculum (r = -0.62, p = 0.012), entorhinal cortex (r = -0.60, p = 0.008), parahippocampal (r = -0.48, p = 0.041) and fusiform gyrus (r = -0.67, p = 0.002). These findings highlight the vulnerability of the entorhinal cortex and parahippocampal gyrus to synaptic loss in AD. Our results suggest that amyloid-β and p-tau pathology may play a limited role in synaptic loss at end-stage disease, and the strong link between synaptic loss in (para)hippocampal subregions and cognitive decline underscores the need for monitoring synaptic change in light of disease progression and evaluating therapeutic interventions.
Key findings
- We found selective synaptic loss in the entorhinal cortex (-14%, p = 0.017) and parahippocampal gyrus (-14%, p = 0.021) in AD versus controls.
- Axonal damage (i.e., higher NfL load) in the parahippocampal cortex associated with synaptic loss locally and in interconnected subregions.
- Worse cognitive performance was strongly associated with synaptic loss in the CA1 (r = -0.64, p = 0.003), subiculum (r = -0.62, p = 0.012), entorhinal cortex (r = -0.60, p = 0.008), parahippocampal (r = -0.48, p = 0.041) and fusiform gyrus (r = -0.67, p = 0.002).
- These findings highlight the vulnerability of the entorhinal cortex and parahippocampal gyrus to synaptic loss in AD.
- Our results suggest that amyloid-β and p-tau pathology may play a limited role in synaptic loss at end-stage disease, and the strong link between synaptic loss in (para)hippocampal subregions and cognitive decline underscores the need for monitoring synaptic change in light of disease progression and evaluating therapeutic interventions.
Why it matters
In postmortem brain tissue from 28 people with Alzheimer's disease and 17 controls, synaptic loss was found in the entorhinal cortex and parahippocampal gyrus, and worse cognitive performance was strongly associated with synaptic loss in several regions. This describes patterns of brain changes and does not test a treatment.
Study details
- Evidence strengthLow
How this study scored 39/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Brain Pathology) |
| Journal's citation record | 2 / 4 | Brain Pathology: journal h-index 183 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 1 / 7 | Cited 2 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.0 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | 4 / 6 | Cited 8.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 2 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Laura E. Jonkman: h-index 25 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Vrije Universiteit Amsterdam: institution h-index 1,014 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41664510) |
| Free to read | 2 / 2 | Free to read |
| Total | 39 / 100 | — |
What each of these 20 components measures, and what this score is not →
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APA 7th
Bouwman, M. M. A., Frigerio, I., Graaf, Y. G.-d., van de Berg, W. D. J., & Jonkman, L. E. (2026). Distinct regional patterns of synaptic vulnerability across hippocampal and parahippocampal subregions in Alzheimer's disease. Brain Pathology. https://doi.org/10.1111/bpa.70081
Vancouver
Bouwman MMA, Frigerio I, Graaf YG.-d, van de Berg WDJ, Jonkman LE. Distinct regional patterns of synaptic vulnerability across hippocampal and parahippocampal subregions in Alzheimer's disease. Brain Pathology. 2026. doi:10.1111/bpa.70081. PMID: 41664510.
BibTeX
@article{bouwman2026-41664510,
author = {Bouwman, Maud M. A. and Frigerio, Irene and Graaf, Yvon Galis-de and van de Berg, Wilma D. J. and Jonkman, Laura E.},
title = {{Distinct regional patterns of synaptic vulnerability across hippocampal and parahippocampal subregions in Alzheimer's disease}},
journal = {Brain Pathology},
year = {2026},
doi = {10.1111/bpa.70081},
pmid = {41664510},
url = {https://doi.org/10.1111/bpa.70081}
}
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