Maternal Longevity is Associated With Reduced Risk but an Earlier Onset of Alzheimer’s Disease in Offspring

Introduction While human longevity has increased significantly over the last 2 centuries, the time spent in good physical and cognitive health has not risen proportionately. The incidence of Alzheimer’s disease (AD) increases with age, but parental longevity is often associated with better offspring health and lower AD risk. This study aimed to investigate the relationship between parental longevity and AD. Methods We included patients with AD and cognitively healthy subjects (over 75 years), collecting family history data, namely maternal and paternal age at death. We performed a logistic regression to evaluate the association of parental longevity and AD risk and linear regression models for the association with age of onset and CSF biomarkers, adjusting for confounders. Results We analyzed 3069 participants from a Portuguese cohort, including 893 AD patients and 2176 cognitively healthy controls. Maternal longevity was inversely associated with AD risk (OR: 0.989, 95%CI = 0.982, 0.997, P = 0.005). In AD patients, higher maternal age of death was associated with an earlier disease onset (β = −0.081, 95%CI = −0.148, −0.013, P = 0.019). No associations were found between parental longevity and CSF biomarkers. Discussion Maternal longevity appears protective against AD risk but is linked to an earlier onset in patients. This may indicate that protective factors for AD could become detrimental once AD is triggered. These findings highlight the complex interplay of genetic, environmental, and potentially epigenetic influences on AD.