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Hypercortisolemia and glucocorticoid receptor-signaling insufficiency in Alzheimer's disease initiation and development
Notarianni E.. Current Alzheimer research, 2013-09-01
Topic: Amyloid, tau and blood-test diagnosis
The cause and mechanism of development of Alzheimer' s disease (AD) remain unexplained. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, denoted by adrenal cortisol hypersecretion, is a recognised feature of the condition but generally disregarded as causative, due to lack of association between AD and other hypercortisolemic states. However, a meta-analysis of published studies suggests a need for reappraisal. A specific circadian rhythm of cortisol hypersecretion pertains at mild-to-moderate AD stages, entailing increased levels at the circadian peak from a low nadir. This is in contrast to the continuously elevated levels that are characteristic of other hypercortisolemic states, e.g. Cushing' s disease or major depression. This previously overlooked detail provides a starting premise here: that equating the form of hypercortisolism in AD with that in other states is inappropriate, as phasic and chronic elevation elicit different neuroendocrine effects. Theoretical implications are discussed in this review. Given the capacity of glucocorticoids and corticotropin-releasing hormone to induce AD-associated pathologies, I suggest a role for circadian cortisol hypersecretion in the initiation of sporadic AD; and propose a temporal mechanism for AD development featuring neuroinflammation- mediated suppression of central glucocorticoid receptor (GR) signaling. This latter may represent a critical phase in AD development, where the density of functional GR is proposed to underlie the "cognitive reserve". Supporting evidence for this mechanism is drawn from the brain regional locations of AD neuropathologies, and from risk factors for AD development (aging, ApoE-4 genotype, and hypertension). Thus, it is argued that basal hypercortisolemia merits further scrutiny regarding AD causation and development.
Key findings
- Theoretical implications are discussed in this review.
- Given the capacity of glucocorticoids and corticotropin-releasing hormone to induce AD-associated pathologies, I suggest a role for circadian cortisol hypersecretion in the initiation of sporadic AD; and propose a temporal mechanism for AD development featuring neuroinflammation- mediated suppression of central glucocorticoid receptor (GR) signaling.
- This latter may represent a critical phase in AD development, where the density of functional GR is proposed to underlie the "cognitive reserve".
- Supporting evidence for this mechanism is drawn from the brain regional locations of AD neuropathologies, and from risk factors for AD development (aging, ApoE-4 genotype, and hypertension).
- Thus, it is argued that basal hypercortisolemia merits further scrutiny regarding AD causation and development.
Why it matters
Drawing on a meta-analysis of published studies, this review argues that the raised cortisol (a stress hormone) seen at mild-to-moderate Alzheimer's stages follows a specific daily rhythm, unlike the constantly high levels in Cushing's disease or major depression. The author proposes that this pattern may help start sporadic Alzheimer's and that neuroinflammation later suppresses glucocorticoid receptor signalling. These are theoretical proposals that the author says merit further scrutiny, not tested findings.
Study details
- Study designmeta-analysis
- Evidence strengthHigh
How this study scored 50/100
Published in a peer-reviewed journal, and it is a meta-analysis pooling many studies. Scored zero for sample size, effect reported and studied in people because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Current Alzheimer research) |
| Journal's citation record | 1 / 4 | Current Alzheimer Research: journal h-index 119 (OpenAlex, 2026-10-29) |
| Study design | 12 / 12 | A meta-analysis pooling many studies |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2013 — within 20 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 | A review of other studies — randomisation is not credited here |
| Times cited | 4 / 7 | Cited 48 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 3.2 citations a year over 15 year(s) since 2013 |
| Impact for its field and year | 2 / 6 | Cited 2.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 2 other studies in this library |
| Still being cited | 1 / 4 | Cited 6 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Elena L. Notarianni: h-index 15 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Durham University: institution h-index 718 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 23906001) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 50 / 100 | — |
What each of these 20 components measures, and what this score is not →
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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. Check the citation against the original before you use it.
APA 7th
Notarianni, E. (2013). Hypercortisolemia and glucocorticoid receptor-signaling insufficiency in Alzheimer's disease initiation and development. Current Alzheimer research. https://doi.org/10.2174/15672050113109990137
Vancouver
Notarianni E. Hypercortisolemia and glucocorticoid receptor-signaling insufficiency in Alzheimer's disease initiation and development. Current Alzheimer research. 2013. doi:10.2174/15672050113109990137. PMID: 23906001.
BibTeX
@article{notarianni2013-23906001,
author = {Notarianni, E.},
title = {{Hypercortisolemia and glucocorticoid receptor-signaling insufficiency in Alzheimer's disease initiation and development}},
journal = {Current Alzheimer research},
year = {2013},
doi = {10.2174/15672050113109990137},
pmid = {23906001},
url = {https://doi.org/10.2174/15672050113109990137}
}
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