. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. 2015 May 19;313(19):1924-38. PubMed.


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  1. My overall comment about both papers is that these are outstanding meta-analyses, which pull together all of the published data concerning the prevalence of amyloid positivity in various dementias, in normal and MCI subjects, and the effects of age and APOE genotype. The paper by Jansen et al. concerning the prevalence of amyloid positivity in the cognitively normal and MCI cases concluded in the abstract that “[t]hese findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.” This conclusion is likely to draw notice in both the scientific community and in the public press.

    In their discussion sections, the authors review several caveats about making such conclusions, including that this is a cross-sectional study, self-selection bias, and the possibility that “cognitive reserve” may allow some subjects to resist the downstream effects of amyloid pathology. Other investigators using data from other sources have estimated that there might be only a 15-year window between development of significant amyloid pathology and onset of dementia. The final answer will come from large longitudinal studies of normal subjects, MCI, and patients with AD that use amyloid phenotyping and cognitive follow-up. The Alzheimer’s Disease Neuroimaging Initiative is one example of this approach.  

    We can all agree that many years elapse between the development of significant amyloid pathology, which is detected by amyloid PET scans or CSF measurements of amyloid beta, and the onset of cognitive decline leading to dementia.

    Furthermore, our field has reached consensus that AD is an “amyloid- facilitated tauopathy,” in which the accumulation of tau tangles is more closely correlated with synapse loss, neurodegeneration, and the development of cognitive decline than the accumulation of amyloid beta. Therefore, there is a substantial window for “prevention trials” using lifestyle modifications or pharmaceutical treatments to prevent the symptoms and disability due to AD.

    View all comments by Michael Weiner
  2. Regarding Jansen et al., this paper estimates the percentage of people who are amyloid positive from a cross-sectional meta-analysis of published studies in cognitively normal people, people with subjective cognitive impairment, and people with mild cognitive impairment. The findings are similar to what has been suggested from many previous studies, i.e., that amyloid deposition begins in some people starting after age 40 and that the percentage of amyloid-positive people is greatly dependent on ApoE genotype.

    Other studies have estimated that amyloid deposition begins about 10-20 years prior to the onset of symptomatic Alzheimer’s disease or very mild dementia due to AD. The authors here argue that amyloid deposition may begin 20-30 years prior to the onset of cognitive decline due to AD. I think longitudinal studies that are ongoing will be required to determine the timeframe following amyloid deposition in which cognitive decline begins to occur.

    Ossenkoppele et al. looked at the percentage of people who are amyloid positive with a clinical diagnosis of AD as a function of age as well as the percentage of people who have different neurodegenerative diseases such as FTD, corticobasal syndrome, and vascular dementia (as well as cognitively normal people) as a function of age. They found that for individuals diagnosed with AD in their 50s, more than 90 percent were amyloid positive whereas by around age 90, a little less than 80 percent were amyloid positive. This is consistent with the fact that as people get older, a number of additional age-related diseases can mimic or phenocopy AD (hippocampal sclerosis, tangle predominant dementia, vascular dementia). 

    They also found that in FTD, vascular dementia, and dementia with Lewy bodies, the percentage of amyloid-positive people with these disorders increased with age (only studied until about age 80). Amyloid deposition gets more common the older one is after age 50 in cognitively normal people, so is not surprising it gets more common in the setting of these other diseases with aging. In some cases, in particular corticobasal syndrome, the individuals may have their corticobasal syndrome from AD. In the case of FTD and vascular dementia, it may be that many of these people are developing preclinical AD, which gets more common the older people are.

    View all comments by David Holtzman
  3. The meta-analysis presented in these two papers should be very useful for AD researchers to test their favorite hypotheses of AD pathogenesis. Although most of the observations reported here are not surprising, one finding that stands out is the awareness that amyloid deposition begins even earlier—20-30 years prior to the onset of clinical symptoms—than the 10-15 year period previously thought. However, this finding should be not be surprising either, because Braak and colleagues (Braak et al., 2011), based on 2,332 brain autopsies from individuals 0 to 100 years old on, had previously found that amyloid deposits begin as early as 40 years of age and are found in 75-80 percent of all brains after the age of 80 years. (They also found that tau pathology begins in a different region of the brain and at least a decade before amyloid deposition occurs, but this finding does not receive much attention.)

    There are many interesting findings in this study. I would like to comment only on the real but poor correlation between amyloid deposits and AD and the “illusion of causality” (Yarritu and Matute, 2015) that it confers. This study shows that amyloid positivity increases with age in different populations examined (cognitively normal, SCI, MCI, or patients with dementia syndromes) and the rate is remarkably similar (the curves are approximately parallel). By contrast, the rate actually drops with age in the AD population. They also reported increased amyloid positivity with higher education levels, which paradoxically protect from developing AD. (The concept of “cognitive reserve” has been proposed to explain this paradox, but it is a circular argument. Plus, it is difficult to imagine Nobel laureate scientists and writers with AD as having low cognitive reserve.)

    The findings from these two papers can be interpreted as supporting the amyloid hypothesis because of the higher prevalence of amyloid positivity in MCI/AD. However, one would essentially find a similar picture even if AD and amyloid positivity were independent of each other, and were caused by aging—a scenario similar to yellow teeth and lung cancer being independent but correlated with and caused by smoking. The causality of amyloid in AD can only be proven by a robustly successful anti-amyloid clinical trial. Should the currently ongoing secondary prevention trials also fail, then the question will remain open as to whether they failed because the amyloid pathology starts even earlier than we thought (and even the presymptomatic intervention came too late) or because the amyloid hypothesis is flawed, as many of us have argued.


    . Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011 Nov;70(11):960-9. PubMed.

    . Previous knowledge can induce an illusion of causality through actively biasing behavior. Front Psychol. 2015;6:389. Epub 2015 Apr 8 PubMed.

    View all comments by Sanjay Pimplikar

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