The influence of a neurodevelopmental vulnerability on Alzheimer′s disease and frontotemporal dementia

Abstract

BACKGROUND AND OBJECTIVES: 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, limiting generalizability. Adopting a dimensional approach to NDDs and considering the heterogeneity of AD/FTD, we investigated whether a neurodevelopmental vulnerability (DV) is associated with clinical presentation and age at onset in AD and FTD. METHODS: We prospectively and consecutively recruited 84 AD/FTD participants and selected 41 matched controls. AD/FTD participants were classified into typical (amnestic AD, behavioral FTD) and focal (primary progressive aphasia, frontal and posterior variants of AD, right temporal variant of FTD, amnestic FTD) presentations. All participants underwent a neuropsychological assessment and answered a novel questionnaire on NDDs symptoms. Using k-means clustering, participants were assigned to a DV+ (with neurodevelopmental vulnerability) or a DV− (without) cluster, based on their responses on the questionnaire. 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%) groups (χ 2 =.205; p=.651); and between the typical (21%) and focal (11%) subgroups (Fisher′s test, p=.184). However, in DV+ patients, symptom onset occurred 8.0 years earlier than in DV− patients (95% CI [ −14, − 3.0]; p = .005), with a median onset age of 58 years (IQR: 15). DISCUSSION: Our findings do not support an increased risk of dementia in DV+ individuals, including in focal presentations. However, a DV would significantly hasten symptom onset. Thus, DV may act as a disease modifier and should be considered in clinical trial design, particularly for early-onset dementia. Further research is needed to elucidate the neurophysiological mechanisms linking DV to early-onset AD/FTD, with implications for precision medicine and individualized treatment strategies