Neurodevelopmental Vulnerability in Alzheimer's Disease and Frontotemporal Dementia

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.

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.

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).

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.

RnIPH 2023-71 and Research Ethics Committee file No. 2023_765.