Skip to main content
SpringerLink
Log in

Age, Sex, Hypertension and HDL-C Alter Serum BACE1 Activity in Cognitively Normal Subjects: Implications for Alzheimer’s Disease

  • Original Research
  • Published:
The Journal of Prevention of Alzheimer's Disease Aims and scope Submit manuscript

Abstract

Background

Increasing evidence indicates that β-secretase 1 (BACE1) activity and concentration in blood are candidate biomarkers for Alzheimer’s disease (AD). Investigating potential demographic, biological, and clinical determinants of BACE1 in the blood matrix is the critical step to validate and qualify BACE1 bio-indicators for different contexts-of-use (CoU), such as risk assessment, early detection, diagnosis, prognosis, management of AD, and outcome of amyloid pathway targeted drugs.

Objectives

To evaluate the influence of age, sex, HDL-cholesterol and comorbidities (cardiovascular diseases, hypertension, diabetes) on circulating BACE-1 activity.

Design

prospective analysis of serum samples, clinical, biological, and demographic variables.

Setting

Three cohorts: 1) Memory Clinic of the Department of Internal Medicine, S. Anna University Hospital, Ferrara (Italy); 2) outpatients attending the Menopause and Osteoporosis Centre (MOC) of the University of Ferrara (Ferrara, Italy); 3) Prevention Center of the University of Ferrara. Participants: 504 cognitively healthy individuals (median age: 62 years, interquartile range: 51–73) and 175 patients with AD (78 years, 74–82).

Measurements

serum BACE1 (sBACE1), age, sex, HDL-cholesterol, major comorbidities.

Results

Age was the strongest independent predictor of sBACE1 variance (β=0.425, p<0.0001), followed by sex (β=0.180, p<0.0001), high density lipoprotein-cholesterol (HDL-C) (β=−0.168, p<0.0001) and hypertension (β=0.111, p<0.05) (overall model, R2: 0.232). The probability of having elevated sBACE1 activity increased after 70 years of age, with women being more susceptible to higher sBACE1 activity than men.

Conclusions

We provide evidence about potential clinical and biological determinants of sBACE1 activity with a strong association among biomarker, female sex, and older age.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Hampel H, Cummings J, Blennow K, et al. Developing the ATX(N) classification for use across the Alzheimer disease continuum. Nat Rev Neurol 2021;17:580–589. https://doi.org/10.1038/s41582-021-00520-w

    Article  Google Scholar 

  2. Zetterberg H. Blood-based biomarkers for Alzheimer’s disease-An update. J Neurosci Methods 2019;319:2–6. https://doi.org/10.1016/j.jneumeth.2018.10.025

    Article  CAS  Google Scholar 

  3. Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement 2018;14:535–562. https://doi.org/10.1016/j.jalz.2018.02.018

    Article  Google Scholar 

  4. Cervellati C, Trentini A, Rosta V, et al. Serum beta-secretase 1 (BACE1) activity as candidate biomarker for late-onset Alzheimer’s disease. Geroscience 2020;42:159–167. https://doi.org/10.1007/s11357-019-00127-6

    Article  CAS  Google Scholar 

  5. Zuliani G, Trentini A, Rosta V, et al. Increased blood BACE1 activity as a potential common pathogenic factor of vascular dementia and late onset Alzheimer’s disease. Sci Rep 2020;10:14980. https://doi.org/10.1038/s41598-020-72168-3

    Article  Google Scholar 

  6. Zuliani G, Trentini A, Brombo G, et al. Serum beta-secretase 1 (BACE1) activity increases in patients with mild cognitive impairment. J Neurochem 2021;159:629–637. https://doi.org/10.1111/jnc.15513

    Article  CAS  Google Scholar 

  7. Shen Y, Wang H, Sun Q, et al. Increased Plasma Beta-Secretase 1 May Predict Conversion to Alzheimer’s Disease Dementia in Individuals With Mild Cognitive Impairment. Biol Psychiat 2018;83:447–455. https://doi.org/10.1016/j.biopsych.2017.02.007

    Article  CAS  Google Scholar 

  8. Mulder SD, Van Der Flier WM, Verheijen JH, et al. BACE1 activity in cerebrospinal fluid and its relation to markers of AD pathology. J Alzheimers Dis 2010;20(1):253–60. doi: https://doi.org/10.3233/JAD-2010-1367

    Article  CAS  Google Scholar 

  9. Ewers M, Cheng X, Zhong Z, et al. Increased CSF-BACE1 Activity Associated with Decreased Hippocampus Volume in Alzheimer’s Disease. J Alzheimers Dis 2011;25:373–381. https://doi.org/10.3233/JAD-2011-091153

    Article  CAS  Google Scholar 

  10. Wu G, Sankaranarayanan S, Wong J, et al. Characterization of plasma β-secretase (BACE1) activity and soluble amyloid precursor proteins as potential biomarkers for Alzheimer’s disease. J Neurosci Res 2012;90:2247–58. https://doi.org/10.1002/jnr.23122

    Article  CAS  Google Scholar 

  11. Fukumoto H. β-Secretase Protein and Activity Are Increased in the Neocortex in Alzheimer Disease. Arch Neurol 2002;59:1381. https://doi.org/10.1001/archneur.59.9.1381

    Article  Google Scholar 

  12. Stockley JH, O’Neill C. Understanding BACE1: essential protease for amyloid-β production in Alzheimer’s disease. Cell Mol Life Sci 2008;65:3265–3289. https://doi.org/10.1007/s00018-008-8271-3

    Article  CAS  Google Scholar 

  13. Hampel H, Vassar R, De Strooper B, et al. The β-Secretase BACE1 in Alzheimer’s Disease. Biol Psychiat 2020;S0006–3223:. https://doi.org/10.1016/j.biopsych.2020.02.001

  14. Hardy J. The amyloid hypothesis for Alzheimer’s disease: a critical reappraisal. J Neurochem 2009;110:1129–34. https://doi.org/10.1111/j.1471-4159.2009.06181.x

    Article  CAS  Google Scholar 

  15. Hampel H, Hardy J, Blennow K, et al. The Amyloid-β Pathway in Alzheimer’s Disease. Mol Psychiatr 2021;26:5481–5503. https://doi.org/10.1038/s41380-021-01249-0

    Article  CAS  Google Scholar 

  16. Vergallo A, Houot M, Cavedo E, et al. Brain Aβ load association and sexual dimorphism of plasma BACE1 concentrations in cognitively normal individuals at risk for AD. Alzheimers Dement 2019;15:1274–1285. https://doi.org/10.1016/j.jalz.2019.07.001

    Article  Google Scholar 

  17. Aisen PS, Cummings J, Jack CR, et al. On the path to 2025: understanding the Alzheimer’s disease continuum. Alzheimers Res Ther 2017;9:60. https://doi.org/10.1186/s13195-017-0283-5

    Article  Google Scholar 

  18. Zetterberg H, Andreasson U, Hansson O, et al. Elevated cerebrospinal fluid BACE1 activity in incipient Alzheimer disease. Arch Neurol 2008;65:1102–7. https://doi.org/10.1001/archneur.65.8.1102

    Article  Google Scholar 

  19. Vergallo A, Lemercier P, Cavedo E, et al. Plasma β-secretase1 concentrations correlate with basal forebrain atrophy and neurodegeneration in cognitively healthy individuals at risk for AD. Alzheimers Dement 2021;17:629–640. https://doi.org/10.1002/alz.12228

    Article  CAS  Google Scholar 

  20. Vergallo A, Houot M, Cavedo E, et al. Brain Aβ load association and sexual dimorphism of plasma BACE1 concentrations in cognitively normal individuals at risk for AD. Alzheimers Dement 2019;15:1274–1285. https://doi.org/10.1016/j.jalz.2019.07.001

    Article  Google Scholar 

  21. Chan AS, Choi M-K, Salmon DP. The Effects of Age, Education, and Gender on the Mattis Dementia Rating Scale Performance of Elderly Chinese and American Individuals. J Gerontol B Psychol Sci Soc Sci 2001;56:P356–P363. https://doi.org/10.1093/geronb/56.6.P356

    Article  CAS  Google Scholar 

  22. Riedel BC, Thompson PM, Brinton RD; Age, APOE and sex: Triad of risk of Alzheimer’s disease. J Steroid Biochem Mol Biol 2016;160:134–147. https://doi.org/10.1016/j.jsbmb.2016.03.012

    Article  CAS  Google Scholar 

  23. Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women’s Health Initiative Randomized Trials. JAMA 2017;318:927–938. https://doi.org/10.1001/jama.2017.11217

    Article  Google Scholar 

  24. Ferretti MT, Iulita MF, Cavedo E, et al. Sex differences in Alzheimer disease — the gateway to precision medicine. Nat Rev Neurol 2018;14:457–469. https://doi.org/10.1038/s41582-018-0032-9

    Article  Google Scholar 

  25. Ewers M, Zhong Z, Bürger K, et al. Increased CSF-BACE 1 activity is associated with ApoE-ε4 genotype in subjects with mild cognitive impairment and Alzheimer’s disease. Brain 2008;131:1252–1258. https://doi.org/10.1093/brain/awn034

    Article  Google Scholar 

  26. Nyarko JNK, Quartey MO, Pennington PR, et al. Profiles of β-Amyloid Peptides and Key Secretases in Brain Autopsy Samples Differ with Sex and APOE ε4 Status: Impact for Risk and Progression of Alzheimer Disease. Neuroscience 2018;373:20–36. https://doi.org/10.1016/j.neuroscience.2018.01.005

    Article  CAS  Google Scholar 

  27. Devi L, Alldred MJ, Ginsberg SD, Ohno M. Sex- and brain region-specific acceleration of β-amyloidogenesis following behavioral stress in a mouse model of Alzheimer’s disease. Mol Brain 2010;3:34. https://doi.org/10.1186/1756-6606-3-34

    Article  Google Scholar 

  28. Breteler MM, Claus JJ, Grobbee DE, Hofman A. Cardiovascular disease and distribution of cognitive function in elderly people: the Rotterdam Study. BMJ 1994;308:1604–8. https://doi.org/10.1136/bmj.308.6944.1604

    Article  CAS  Google Scholar 

  29. de la Torre JC. Alzheimer Disease as a Vascular Disorder. Stroke 2002;33:1152–1162. https://doi.org/10.1161/01.STR.0000014421.15948.67

    Article  CAS  Google Scholar 

  30. Tini G, Scagliola R, Monacelli F, et al. Alzheimer’s Disease and Cardiovascular Disease: A Particular Association. Cardiol Res Pract 2020:2617970. https://doi.org/10.1155/2020/2617970

  31. Kalaria RN. The pathology and pathophysiology of vascular dementia. Neuropharmacology 2018;134:226–239. https://doi.org/10.1016/j.neuropharm.2017.12.030

    Article  CAS  Google Scholar 

  32. Tamagno E, Bardini P, Obbili A, et al. Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol Dis 2002;10:279–88. https://doi.org/10.1006/nbdi.2002.0515

    Article  CAS  Google Scholar 

  33. Hampel H, Lista S, Neri C, Vergallo A. Time for the systems-level integration of aging: Resilience enhancing strategies to prevent Alzheimer’s disease. Prog Neurobiol. 2019;181:101662. doi: https://doi.org/10.1016/j.pneurobio.2019.101662

    Article  Google Scholar 

  34. Hara Y, McKeehan N, Fillit HM. Translating the biology of aging into novel therapeutics for Alzheimer disease. Neurology. 2019;92(2):84–93. doi: https://doi.org/10.1212/WNL.0000000000006745

    Article  Google Scholar 

  35. Hampel H, Lista S, Vanmechelen E, et al. β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualification. Alzheimers Res Ther 2020;12:130. https://doi.org/10.1186/s13195-020-00686-3

    Article  CAS  Google Scholar 

Download references

Funding

Funding: No specific funding was received for this research.

Author information

Authors and Affiliations

  1. Department of Translational Medicine and for Romagna, University of Ferrara, Ferrara, Italy

    C. Cervellati, G. Campo, F. Vieceli Dalla Sega, P. Rizzo, G. Bonaccorsi, V. Rosta, A. Passaro & G. Zuliani

  2. Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France

    A. Vergallo & H. Hampel

  3. Department of Environmental and Prevention Sciences, University of Ferrara, via Luigi Borsari 46, 44121, Ferrara, Italy

    Alessandro Trentini

  4. Associazione Sammarinese di Geriatria e Gerontologia (ASGG), Dogana, San Marino

    C. Renzini

  5. Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy

    S. Pacifico

  6. Azienda Ospedaliero-Universitaria S. Anna, Ferrara, Italy

    A. Passaro & G. Zuliani

Authors
  1. C. Cervellati
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Vergallo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alessandro Trentini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Campo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F. Vieceli Dalla Sega
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P. Rizzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G. Bonaccorsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. V. Rosta
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C. Renzini
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S. Pacifico
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. A. Passaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. H. Hampel
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. G. Zuliani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alessandro Trentini.

Ethics declarations

Conflict of interest Disclosure: All the authors declare no competing financial interests related to the present article.

Ethical standards: All studies were conducted in accordance with the Declaration of Helsinki, and local regulatory requirements. The study protocols were approved by an independent ethics committee. All patients, or next of keen, provided written consent before the start of the study.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cervellati, C., Vergallo, A., Trentini, A. et al. Age, Sex, Hypertension and HDL-C Alter Serum BACE1 Activity in Cognitively Normal Subjects: Implications for Alzheimer’s Disease. J Prev Alzheimers Dis 9, 708–714 (2022). https://doi.org/10.14283/jpad.2022.78

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.14283/jpad.2022.78

Key words

Search

Navigation