Assessing Parental Symptom Onset Proximity in Alzheimer Disease

In asymptomatic women and carriers of apolipoprotein E ε4 (APOE ε4) who have a parental history of Alzheimer disease (AD) dementia, the proximity to parental age at symptom onset may identify amyloid-β (Aβ) biomarker advancement and assist in early prediction of disease occurrence, according to study findings published in JAMA Neurology.

Using patient data from the Presymptomatic Evaluation of Novel or Experimental Treatments for Alzheimer Disease (PREVENT-AD) cohort, investigators evaluated cerebrospinal fluid (CSF) Aβ1-42 levels obtained from individuals who presented no signs of cognitive dysfunction at enrollment (n = 101). The researchers estimated the proximity of participants’ age to their parents’ age at AD symptom onset. In addition, the investigators used APOE ε4 status and sex as interactive terms to identify the relationship between each participant’s proximity to parental symptom onset and Aβ levels. Findings were validated in an additional 2 independent study cohorts: Adult Children Study (ACS, n = 128) and Wisconsin Registry for Alzheimer Prevention (WRAP, n = 135).

Participants in the PREVENT-AD cohort who were close to approaching their parents’ age at symptom onset demonstrated significantly lower CSF Aβ1-42 levels than those who were not in proximity to their parental onset age range (range, 402, 1597; B = −9.09; P =.04). The relationship between proximity to parental age of onset and lower CSF Aβ1-42 was found to be significantly stronger among women (B = −19.8; P =.02) and those who carried APOE ε4 (B = −17.9; P =.03).

In the ACS cohort, participants who underwent Pittsburgh compound B carbon 11–labeled positron emission tomography demonstrated an association between sporadic parental estimated years to symptom onset score and Aβ burden. Additionally, the investigators found an increase in brain Aβ deposition among participants who approached parental age of AD dementia symptom onset, with women showing faster accumulation of brain Aβ than men as they reached their parental symptom onset age. Similarly, participants in the WRAP cohort who approached their parents’ age at symptom onset showed quicker brain Aβ accumulation. The relationship was particularly strong in APOE ε4 carriers vs APOE ε4 noncarriers.

Many participants in the ACS cohort had passed their parental age of onset while demonstrating abnormal biomarkers, which may mean this study was limited to only evaluating relationships between delayed age of onset and brain biomarker levels.

The investigators suggest that the sporadic parental estimated years to symptom onset score, while not a replacement for in vivo Aβ assessment, may “be applied as an inexpensive prescreening method that could enrich trial candidate populations for Aβ positivity” in asymptomatic individuals.