People who carry a familial Alzheimer’s gene tend to develop symptoms at around the same age their parents did. This helps researchers predict their disease stage and select participants for clinical trials. Now, researchers led by Sylvia Villeneuve at McGill University in Montreal, Canada, suggest that the parental estimated year of onset (EYO) also has predictive value in late-onset Alzheimer’s disease. In the February 26 JAMA Neurology, they reported an association between higher amyloid burden and proximity to parental EYO in three separate cohorts of cognitively healthy older adults. Intriguingly, this relationship was seen only in women and ApoE4 carriers. Villeneuve suggested the data could help researchers screen participants for trials. “It might be a good strategy to select women within 10 years of their parent’s EYO,” Villeneuve told Alzforum.
- Women with family histories of late-onset AD have higher amyloid burdens the closer they are to parental age of onset.
- The effect appears strongest in ApoE4 carriers.
- Parental age of onset might be used to prescreen women for AD trials, reducing the number of screen failures.
Rachel Buckley of Massachusetts General Hospital, Boston, agreed. “While parental EYO will not replace other prescreening tools, it certainly could be used as a ‘boosted risk’ index,” she wrote to Alzforum (see comment below).
In dominantly inherited AD cohorts, researchers have found a strong link between amyloid accumulation and parental EYO. Aβ42 concentrations in cerebrospinal fluid drop about 25 years before EYO, while brain amyloid becomes detectable by PET scan about 15 years before (Jul 2012 news). Because late-onset AD is also believed to be largely an inherited disease, with about 70 percent of the risk due to genetic factors, Villeneuve and colleagues wondered if parental EYO could help predict the progression of LOAD, too (Gatz et al., 2006).
The authors selected 101 participants in the Presymptomatic Evaluation of Novel or Experimental Treatments for Alzheimer's Disease (PREVENT-AD) longitudinal study who had donated CSF. All had family histories of AD and were at least 55 years old and cognitively healthy. In cross-sectional data, the authors found that participants who were closest to their parental EYO had the lowest CSF Aβ42, regardless of the person’s age. When the researchers divided the cohort by gender, the association held true for women, but not men. Because people with an ApoE4 allele accumulate amyloid sooner than noncarriers, the authors also examined carrier status, and found most of the association in E4 carriers.
To see if the results would hold up in other populations, the authors analyzed data from two other cohorts. These comprised 128 cognitively healthy participants in the Adult Children Study (ACS) at the Knight ADRC at Washington University in St. Louis, and 135 participants in the Wisconsin Registry for Alzheimer Prevention (WRAP). In this latter group, about one-quarter had mild cognitive impairment, with the rest being cognitively healthy. In these two cohorts, most participants underwent amyloid scanning as well as lumbar punctures, with the majority having a follow-up scan.
In the ACS, women, but not men, had lower CSF Aβ42 and higher brain amyloid, and accumulated amyloid plaques faster, the closer they were to their parental EYO. In WRAP, the researchers did not see a relationship between amyloid burden and parental EYO, but the rate of plaque growth was higher in people closer to that age. A clear gender difference was not apparent in this cohort, although women trended in that direction. The ApoE effects partially replicated, as well. Genotype did not modify the effect of parental EYO in ACS, but ApoE4 carriers in WRAP did accumulate plaques faster the closer they were to parental EYO.
Villeneuve pointed out that the three cohorts were all recruited and assessed differently. “Even with all these confounds, we still replicate the main finding in the three cohorts,” she said. In ongoing work, she is following PREVENT-AD participants to see if they in fact develop symptoms at their parent’s EYO. She noted that parental EYO might have the most predictive value in younger cohorts, in which people have not accumulated much age-associated amyloid. The mean participant age across the three cohorts in this study was 62, with the parental EYO averaging 74.
Buckley said that the findings agree with other research on sex differences in AD. ApoE4 has been found to raise women’s risk of the disease more than men’s, particularly at younger ages (Jun 2012 news; Altmann et al., 2014; Sep 2017 news). Women also develop symptoms at a lower amyloid load than men do, and having a mother with AD exerts a greater effect on amyloid burden than having a father with the disease (Koran et al., 2017; Maye et al., 2016). “Accruing evidence suggests some level of susceptibility or sensitivity to amyloid load in younger females, and this may be passed down the maternal line,” Buckley wrote.
While a simple family history-based screening tool could help cut down on expensive PET scan screen failures, Prashanthi Vemuri at the Mayo Clinic in Rochester, Minnesota, sounded a note of caution. “The metric appears to have low specificity based on the data shown. Given that the associations only hold true in APOE4 carriers and women, additional longitudinal studies with greater numbers are needed to evaluate its utility as a prescreening measure,” she wrote to Alzforum.—Madolyn Bowman Rogers
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- Villeneuve S, Vogel JW, Gonneaud J, Pichet Binette A, Rosa-Neto P, Gauthier S, Bateman RJ, Fagan AM, Morris JC, Benzinger TL, Johnson SC, Breitner JC, Poirier J, Presymptomatic Evaluation of Novel or Experimental Treatments for Alzheimer Disease (PREVENT-AD) Research Group. Proximity to Parental Symptom Onset and Amyloid-β Burden in Sporadic Alzheimer Disease. JAMA Neurol. 2018 May 1;75(5):608-619. PubMed.