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. 2025 Aug;32(8):e70322.
doi: 10.1111/ene.70322.

Neurodevelopmental Vulnerability in Alzheimer's Disease and Frontotemporal Dementia

Perrine Laury Marie Siguier  1   2 , Mélanie Planton  1   3   4 , Bérengère Pages  3 , Fleur Gérard  3 , Marie Rafiq  1   3 , Marie Wolfrum  3 , Ombeline Archambault  2 , Anise Damour  2 , Valentine Guidolin  1 , Pauline Pefferkorn  2 , Lola Danet  1   3 , Laurine Virchien  3 , Eloi Magnin  4   5   6 , Aurélie Richard-Mornas  4   7   8 , Mathilde Sauvée  4   9   10 , Catherine Thomas-Antérion  4   11 , Servane Mouton  4   12 , Mélanie Jucla  2 , Jérémie Pariente  1   3   4
Affiliations

Neurodevelopmental Vulnerability in Alzheimer's Disease and Frontotemporal Dementia

Perrine Laury Marie Siguier et al. Eur J Neurol. 2025 Aug.

Abstract

Background: Neurodevelopmental disorders (NDDs) may influence the course of Alzheimer's disease (AD) and frontotemporal dementia (FTD). However, prior studies have focused on specific pairs of NDDs and variants of AD/FTD. Adopting a dimensional approach to NDDs and considering the heterogeneity of AD/FTD, we investigated the association between a neurodevelopmental vulnerability (DV) and the clinical presentation and age at onset of AD/FTD.

Methods: We prospectively and consecutively recruited 84 AD/FTD participants and 41 matched controls. AD/FTD participants were classified into typical (amnestic AD, behavioral FTD) and atypical (primary progressive aphasia, frontal and posterior variants of AD, right temporal variant of FTD, amnestic FTD) presentations. Participants underwent a neuropsychological assessment and answered a novel questionnaire on NDDs symptoms. Using k-means clustering based on the questionnaire, participants were assigned to a DV+ (with neurodevelopmental vulnerability) or a DV- (without) cluster. This data-driven approach enabled an unbiased classification of individuals with a DV, beyond traditional diagnostic labels.

Results: DV frequencies did not differ between the AD/FTD (18%) and control (15%) χ2 = 0.205; p = 0.651); and between typical (21%) and atypical (11%) subgroups (Fisher's test, p = 0.184). However, in DV+ patients, symptom onset occurred 8.0 years earlier than in DV- patients (95% CI [-14, -3.0]; p = 0.005), with a median onset age of 58 years (IQR: 15).

Conclusions: A DV could favor early-onset AD/FTD, but may not affect susceptibility to typical and atypical variants of AD/FTD. The underlying neurophysiological processes involved require future investigation, with implications for precision medicine and individualized treatment strategies.

Study registration numbers: RnIPH 2023-71 and Research Ethics Committee file No. 2023_765.

Keywords: dimensional approach; early‐onset dementia; lifespan approach; neurocognitive disorders; neurodevelopmental disorders.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Flowchart of AD/FTD participants. The 21 patients who refused to participate did not statistically differ from included patients on any of the following variables: age, level of education, MMSE, sex ratio, proportions of AD/FTD, proportions of Typical/Atypical variants, proportions of genetic cases, age at onset, age at diagnosis, time between first symptoms and diagnosis, time since diagnosis (cf. Table S2).
FIGURE 2
FIGURE 2
Participants with AD/FTD and a developmental vulnerability showed earlier onset of disease. The letter “Δ” refers to the mean difference between the median in the DV+ cluster and the median in the DV‐ cluster. The “95CI” is the 95% confidence interval of the mean difference.
See this image and copyright information in PMC

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