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.

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  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.

    References:

    Altmann A, Tian L, Henderson VW, Greicius MD, Alzheimer's Disease Neuroimaging Initiative Investigators. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol. 2014 Apr;75(4):563-73. Epub 2014 Apr 14 PubMed.

    Damoiseaux JS, Seeley WW, Zhou J, Shirer WR, Coppola G, Karydas A, Rosen HJ, Miller BL, Kramer JH, Greicius MD, . 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.

    Hua X, Hibar DP, Lee S, Toga AW, Jack CR, Weiner MW, Thompson PM, . Sex and age differences in atrophic rates: an ADNI study with n=1368 MRI scans. Neurobiol Aging. 2010 Aug;31(8):1463-80. PubMed.

    Koran ME, Wagener M, Hohman TJ, Alzheimer’s Neuroimaging Initiative. Sex differences in the association between AD biomarkers and cognitive decline. Brain Imaging Behav. 2017 Feb;11(1):205-213. PubMed.

    Maye JE, Betensky RA, Gidicsin CM, Locascio J, Becker JA, Pepin L, Carmasin J, Rentz DM, Marshall GA, Blacker D, Sperling RA, Johnson KA. 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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