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., 2014Sep 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


  1. Dr. Villeneuve and colleagues provide an interesting take to assessment of APOE and sex effects on amyloid levels in clinically normal adults. Similar to findings presented in ADAD participants, the authors calculated an “estimated year of onset” for all participants in the PREVENT-AD, WRAP, and ACS cohorts who had a parental history of dementia. While it is understood that this EYO is dissimilar to that calculated in ADAD as sporadic AD is not 100 percent heritable, it provides an interesting insight into the explanatory power of parental age of onset on level of amyloid burden.

    Specifically, Dr. Villeneuve found that women showed a stronger association between EYO and amyloid load, measured both via CSF and PET. Some evidence was found for APOE4 status, however, this was not reliably replicated across studies. This finding is interesting on multiple fronts:

    1. This study provides some level of replicability across multiple convenience-sample cohorts, which is persuasive given idiosyncratic recruitment and eligibility differences between the studies;
    2. Sex differences were found to be evident in levels of amyloid load related to EYO in younger-age older adults (~60 years) given that many studies in cohorts of older clinically normal individuals (~73 years) do not find a sex effect on amyloid load (HABS, AIBL, ADNI, Mayo—although none of these have tested a relationship with EYO);
    3. Findings are reported for both CSF and PET measures, and both cross-sectionally and longitudinally, which show a degree of consistency in their findings. 

    In particular, I am fascinated by the sex effect on the relationship between amyloid and EYO. It suggests a level of susceptibility that younger women may exhibit to EYO with regard to encroaching pathology. It is unclear whether this is a biological effect, from the findings presented here, but considering menopause is a salient transitional period around this time, it is hard not to immediately wonder what hormonal effect might be at play here.

    A slightly divergent thought I have is in relation to a recent paper by our lab showing that maternal family history influences greater brain amyloid load (PiB-PET) (Maye et al., 2016). Further, mothers have an earlier age of onset than fathers for a given level of PiB retention for the subject. Although Villeneuve and colleagues did not find an effect of maternal or paternal family history here, it is hard to shake the feeling that accruing evidence is suggesting some level of susceptibility or sensitivity to amyloid load in younger women, and that this may be passed down the maternal line. Further research needs to be conducted in this space, but what really needs to be focused on more are the underlying biological, and potential sociological, mechanisms that are driving sex-related differences in AD biomarkers.

    One cannot forget that amyloid is not the only sex-related difference in AD biomarkers that have been reported. Studies are also suggesting sex effects on tau (CSF: Koran et al., 2017; Altmann et al., 2014), and brain function (Damoiseaux et al., 2012) and structure (Hua et al., 2010). So as the evidence gathers, we may need to start thinking hard about how these influences may have an impact on sex-related treatment responses in clinical trials.

    It’s certainly the case that family history is of great import when considering an individual’s likelihood of AD risk. While not a requirement in many clinical trials, family history is certainly of note, and studies do show that family history increases likelihood for APOE4 carriage and greater level of amyloid burden. These data presented by Villeneuve and colleagues add further evidence by suggesting that the age of onset of the individual with family history is also of value, which implies that even in sporadic AD, family history can provide important information about when offspring might start to accrue AD pathology.

    While parental EYO may not replace other prescreening tools (that is, individuals without known family history can also progress to AD dementia), it certainly could be used as a “boosted risk” index. And for those with family history, EYO may be harnessed to give an indication of where along the AD pathological spectrum an individual is potentially likely to be. Although these findings were replicated to some extent across three cohorts, there was still some disagreement, and so further evidence needs to be gathered.


    . Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol. 2014 Apr;75(4):563-73. Epub 2014 Apr 14 PubMed.

    . Gender modulates the APOE ε4 effect in healthy older adults: convergent evidence from functional brain connectivity and spinal fluid tau levels. J Neurosci. 2012 Jun 13;32(24):8254-62. PubMed.

    . Sex and age differences in atrophic rates: an ADNI study with n=1368 MRI scans. Neurobiol Aging. 2010 Aug;31(8):1463-80. PubMed.

    . Sex differences in the association between AD biomarkers and cognitive decline. Brain Imaging Behav. 2017 Feb;11(1):205-213. PubMed.

    . Maternal dementia age at onset in relation to amyloid burden in non-demented elderly offspring. Neurobiol Aging. 2016 Apr;40:61-7. Epub 2015 Dec 28 PubMed.

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News Citations

  1. Paper Alert: DIAN Biomarker Data Show Changes Decades Before AD
  2. What’s Sex Got to Do With It? Differences in Connectivity, Synapses
  3. New Look at Sex and ApoE4 Puts Women at Risk Earlier than Men

Paper Citations

  1. . Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006 Feb;63(2):168-74. PubMed.
  2. . Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol. 2014 Apr;75(4):563-73. Epub 2014 Apr 14 PubMed.
  3. . Sex differences in the association between AD biomarkers and cognitive decline. Brain Imaging Behav. 2017 Feb;11(1):205-213. PubMed.
  4. . Maternal dementia age at onset in relation to amyloid burden in non-demented elderly offspring. Neurobiol Aging. 2016 Apr;40:61-7. Epub 2015 Dec 28 PubMed.

Further Reading

Primary Papers

  1. . Proximity to Parental Symptom Onset and Amyloid-β Burden in Sporadic Alzheimer Disease. JAMA Neurol. 2018 May 1;75(5):608-619. PubMed.