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. 2025 Mar:113:105585.
doi: 10.1016/j.ebiom.2025.105585. Epub 2025 Feb 5.

Ten years preceding a diagnosis of neurodegenerative disease in Europe and Australia: medication use, health conditions, and biomarkers associated with Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis

Dang Wei  1 , Anna Freydenzon  2 , Octave Guinebretiere  3 , Karim Zaidi  3 , Fen Yang  4 , Weimin Ye  5 , Niklas Hammar  4 , Karin Modig  4 , Naomi R Wray  6 , Maria Feychting  4 , Nadine Hamieh  3 , Bruno Ventelou  7 , Beranger Lekens  8 , Laurene Gantzer  8 , Stanley Durrleman  3 , Allan McRae  2 , Baptiste Couvy-Duchesne  9 , Fang Fang  4 , Thomas Nedelec  3 ; LeMeReND consortium
Collaborators, Affiliations

Ten years preceding a diagnosis of neurodegenerative disease in Europe and Australia: medication use, health conditions, and biomarkers associated with Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis

Dang Wei et al. EBioMedicine. 2025 Mar.

Abstract

Background: Many studies have investigated early predictors for Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). However, evidence is sparse regarding specific and common predictors for these diseases. We aimed to identify medication use, health conditions, and blood biomarkers that might be associated with the risk of AD, PD, and ALS ten years later.

Methods: We conducted population-based nested case-control studies of AD, PD, and ALS using electronic medical records in Europe (France, the UK, and Sweden) and Australia. We retrieved data on medication use, diagnosed health conditions, and measured blood biomarkers from electronic medical records or biomedical cohorts. Conditional logistic regression models and meta-analysis were applied to assess the associations between these factors and the risk of receiving a diagnosis of AD, PD, or ALS.

Findings: We included a total of 149,642 AD cases (mean age: 79.1-81.2 years), 252,696 PD cases (73.2-75.9 years), and 27,533 ALS cases (64.4-69.6 years). The prescription of psychoanaleptics and nasal preparations was consistently associated with an increased risk of AD, PD, and ALS 5-10 years later. Constipation and use of related medications were associated with an increased risk of AD and PD, while diabetes and use of antidiabetics were associated with a reduced risk of ALS. A higher level of triglycerides was associated with a lower risk of AD, whereas a higher level of Apolipoprotein B was associated with a lower risk of PD, 5-10 years later.

Interpretation: Psychoanaleptics and nasal preparations may serve as common predictors for diagnosis of AD, PD, and ALS 5-10 years later. Conversely, the increased prevalence of constipation is specific to AD and PD, while the decreased prevalence of diabetes and use of antidiabetics is specific to ALS.

Funding: EU Joint Programme-Neurodegenerative Disease Research.

Keywords: Alzheimer's disease; Amyotrophic lateral sclerosis; Biomarkers; Health conditions; Medications; Neurodegenerative disease; Parkinson's disease.

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Conflict of interest statement

Declaration of interests The LeMeReND consortium was established to build a predictive algorithm for neurodegenerative diseases, designed for implementation in primary care settings. This initiative is supported by financial backing from the EU Joint Programme–Neurodegenerative Disease Research and involves researchers from Australia, France, and Sweden. NK has received consulting fee from Sobi and holds shares in AstraZeneca. KM received support from the Swedish Research Council for Health, Working Life and Welfare for research projects. KM also serves as a board member on the board for national screening of diseases at the Swedish National Board of Health and is the Vice chair in the Swedish Epidemiology Association. MF chairs the steering group for the AMORIS cohort. BV received support from the French government under the “France 2030” investment plan managed by the French National Research Agency (reference: ANR-17-EURE-0020) and from Excellence Initiative of Aix-Marseille University - A∗MIDEX. BV is also a panel member of the advisory board for the Ministry of Health in France and a member of the Haut Conseil de la Santé Publique in Paris, France. SD received support from Sanofi and Biogen for research projects. SD was compensated by the Union régionale des professionnels de santé (URPS) de Paris for lectures, holds a patent (“A method for determining the temporal progression of a biological phenomenon and associated methods and devices”; PCT/IB2017/052722), and is a shareholder of Qairnel SAS. BCD was compensated by the International Statistical Genetics Workshop for lectures and received support from AFRAN—Australia + French embassy to attend a conference. All other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Summary of study design and results for investigating the associations of prescribed medications, health conditions, and blood biomarkers with the subsequent diagnosis of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis in Australia, France, the UK, and Sweden. ∗No meta-analysis was performed since the analysis of blood biomarkes was only available in Sweden. As blood biomarkers were measure at midlife (mean: 43 years), we reported the results of biomarkers measured >10 years before diagnosis.
Fig. 2
Fig. 2
Prescribed medications associated with the subsequent diagnosis of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis during 5–10 years before the diagnosis, meta-analyses from Australia, France, the UK, and Sweden. AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; PD, Parkinson's disease. Panel a: nine out of 43 medications were associated with amyotrophic lateral sclerosis 5–10 years later based on meta-analysis (n = 261,228; P < 0.05 from Wald test); panel b: twenty out of 45 medications were associated with Parkinson's disease 5–10 years later based on meta-analysis (n = 591,449; P < 0.05 from Wald test); panel c: seven out of 49 medications were associated with Alzheimer's disease 5–10 years later based on meta-analysis (n = 510,743; P < 0.05 from Wald test). Only classes of medications with an incidence rate ratio from the meta-analysis above 1.2 or below 0.8 and P-value<0.05 in at least one of three diseases are shown in panel d. The size of the dot is the average prevalence of prescribed medications in cases across countries. Bars correspond to 95% confidence intervals in the meta-analysis after correction for multiple testing.
Fig. 3
Fig. 3
Health conditions associated with the subsequent diagnosis of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis during 5–10 years before the diagnosis, meta-analyses from France, the UK, and Sweden. Health conditions presented in this figure are related to the prescribed medications that were associated with the neurodegenerative diseases shown in Fig. 2 (n = 1,286,683 for Alzheimer's disease, 1,019,481 for Parkinson's disease, and 148,148 for amyotrophic lateral sclerosis; P < 0.05 from Wald test). The size of the dot is the average prevalence of prescribed medications in cases across countries. Bars correspond to 95% confidence intervals in the meta-analysis after correction for multiple testing.
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