Objective: To evaluate the hypothesis that proximity to parental age at onset (AAO) in sporadic Alzheimer’s disease (AD) is associated with greater AD and neural injury biomarker alterations during midlife and to assess the role of non-modifiable and modifiable factors.

Methods: This observational study included 290 cognitively unimpaired (CU) participants with family history (FH) of clinically-diagnosed sporadic AD (aged 49-73) from the ALFA study. [18F]Flutemetamol-PET SUVRs, CSF Aβ42/40 ratio and p-tau were used as AD biomarkers. Hippocampal volumes and CSF t-tau were used as neural injury biomarkers. Mental and vascular health proxies were calculated. In multiple regression models, we assessed the effect of proximity to parental AAO and its interaction with age on AD and neural injury biomarkers. Then, we evaluated the effects of FH load (number of parents affected), sex, APOE-Ɛ4, education, vascular and mental health.

Results: Proximity to parental AAO was associated with β-amyloid, but not with neural injury biomarkers, and interacted with sex and age, showing women and older participants increased β-amyloid. FH load and APOE-Ɛ4 showed independent contributions to β-amyloid load. Education, vascular and mental health proxies were not associated with AD biomarkers. However, lower mental health proxies were associated with decreased hippocampal volumes with age.

Conclusions: The identification of the earliest biomarker changes and modifiable factors to be targeted in early interventions is crucial for AD prevention. Proximity to parental AAO may offer a timeline for detection of incipient β-amyloid changes in women. In risk-enriched middle-aged cohorts, mental health may be a target for early interventions.

Classification of evidence: This study provides Class II evidence that in CU adults with FH of sporadic AD proximity to parental AAO was associated with β-amyloid but not with neural injury biomarkers.