"ApoE4 does not influence brain function at young age"

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NF52
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"ApoE4 does not influence brain function at young age"

Post by NF52 »

Here is some good news for young carriers of ApoE4 from a poster session by Lara Mentink of the Netherlands at the Alzheimer's Association International Conference today. Study size matters--especially when drawing conclusions about all young people with ApoE4 from a decade-old study of a few dozen.
Background: Filippini et al. [2009] reported an increased default mode network (DMN) co-activation during rest in young APOE ε4-carriers... However, this study only assessed a small sample.

Here, we aimed to replicate their finding in a substantially larger sample from the Human Connectome Project (HCP).
Method: We included participants from the HCP S1200 dataset...we assessed gray matter volume with FreeSurfer. To test for differences in [default mode network]DMN co-activation and gray matter volume between APOE ε4-carriers and non-carriers, we used Permutation Analysis of Linear Models (PALM). PALM controls for biases induced by the family structure of the HCP sample. Results were family-wise error rate corrected at p < 0.05.

Result: We included 167 APOE ε4-carriers and 419 non-carriers for the DMN analysis. In contrast to [Filippini], we did not find significant differences in DMN co-activation between carriers and non-carriers. For the morphometric analyses, 243 carriers and 544 non-carriers were included. No differences in brain volume were found between carriers and non-carriers. For both analyses...different combinations of age, sex, education level, head motion, did not alter the results.

Conclusion: We could not replicate the early findings of [1] in a large sample. Our results suggest that solely APOE ε4-carriership does not influence brain function at a young age. Future work will focus on the use of polygenic risk scores to study whether any genetic predisposition for AD influences brain function in young adults. Still, genetic predisposition for AD might not have any measurable effect decades before clinical expression of AD. Therefore, repeating the analysis in a healthy, middle-aged cohort could inform us whether the influence of genetic predisposition for AD increases over time.
Patterns of default mode network co-activation in young APOE ε4-carriers: an HCP replication study
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Re: "ApoE4 does not influence brain function at young age"

Post by Tincup »

NF52 wrote: Our results suggest that solely APOE ε4-carriership does not influence brain function at a young age.
My personal experience and observation of known ε4 carriers early in life would agree with this statement.

One anecdote, my mother was a very bright woman. She died with dementia at 87. I have no idea if she is the parent I got my ε4 from. She got a degree in theoretical physics in 1948. Went on soon after graduation to supervise the military's early use of computers to track missiles (she wryly would comment - they gave the job to a woman because they expected it to fail and they could pay her half as much). When she was around 60, she went back to school and picked up a degree in computer science. She was always setting the curve, competing with students in their teens and early 20's. She would comment to me that her brain worked so much slower than when she was 19. I wasn't very sympathetic, saying, "but mom, you are setting the curve, how slow can you be?" Knowing what I know now about ε4's and glucose metabolism would validate her statement. Her ability to set the curve came not just from IQ (which may have been diminished), but her organization, focus, motivation, grit and so on.
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Re: "ApoE4 does not influence brain function at young age"

Post by NF52 »

Tincup wrote:
NF52 wrote: Our results suggest that solely APOE ε4-carriership does not influence brain function at a young age.
My personal experience and observation of known ε4 carriers early in life would agree with this statement.

One anecdote, my mother was a very bright woman. She died with dementia at 87. I have no idea if she is the parent I got my ε4 from. She got a degree in theoretical physics in 1948. Went on soon after graduation to supervise the military's early use of computers to track missiles (she wryly would comment - they gave the job to a woman because they expected it to fail and they could pay me half as much). When she was around 60, she went back to school and picked up a degree in computer science. She was always setting the curve, competing with students in their teens and early 20's. She would comment to me that her brain worked so much slower than when she was 19. I wasn't very sympathetic, saying, "but mom, you are setting the curve, how slow can you be?" Knowing what I know now about ε4's and glucose metabolism would validate her statement. Her ability to set the curve came not just from IQ (which may have been diminished), but her organization, focus, motivation, grit and so on.
Thanks for sharing her inspiring story! One of the presentations I saw at AAIC (virtual conference; free to register with all presentations online for the next 30 days) included this statement (in my words) "Maybe people with elevated amyloid and tau who stay cognitively healthy into their 90's just have so many darn brain connections developed from capacity and use that their resilience is endless."
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Re: "ApoE4 does not influence brain function at young age"

Post by circular »

I've been looking at similar papers relating to brain networks and the DMN in particular (not that I've covered it all or digested much of it!). The brain science is so complicated the papers can't really be compared apples to apples. I'll just mention three here.

1)

This one ruled out an ApoE4 interaction but sure stood out as someone already at risk due to ApoE4 and other factors. If a young person is both ApoE4 and has indications of DMN imbalances, then I would be aware of compounding issues:

Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity (2017, large cohort)
The earliest Aβ accumulation is further associated with hypoconnectivity within the DMN and between the DMN and the frontoparietal network, but not with brain atrophy or glucose hypometabolism. Our results suggest that Aβ fibrils start to accumulate predominantly within certain parts of the DMN in preclinical AD and already then affect brain connectivity.
1 ...

The cause of Aβ aggregation within the DMN is currently unknown ... [the paper later states: 'In addition, the early Aβ- accumulating brain regions remained significant when adjusting for confounding factors such as longitudinal changes in cortical thickness, APOE genotype and clinical status.'] ...

This correlation between the disruption of functional connectivity and Aβ pathology has recently been described in AD 32, 33, but to our knowledge the present study is the first to show that this association is present already at the very earliest preclinical stages of AD when Aβ fibrils are just starting to accumulate.
Limitations are described in the paper itself as would be expected, followed by:
Nonetheless, a strength of the methodology is that we could detect similar early Aβ regions in two different cohorts using two different types of PET ligands ...

To conclude [in part] ... Our data indicated that Aβ starts accumulating before overt metabolic changes or atrophy, and that hypoconnectivity within the early Aβ-accumulating regions has already occurred when Aβ fibrils just start to accumulate. [Emphasis added]
In addition and for emphasis:
The relationship between early stage Aβ accumulation and whole-brain functional connectivity was examined in detail and revealed that hypoconnectivity, especially within the DMN and between DMN and the frontoparietal network, was associated with low CSF Aβ42 levels in individuals that still had normal Aβ PET scans [ie, before Aβ fibril accumulation in the DMN]. [Emphasis added]
2)

This next paper suggests the possibility that meditation improves the regulation of brain network connectivity and specifically between the DMN and the frontoparietal network. I've always thought that children should start learning child forms of meditation when they start brushing their own teeth.

The brain on silent: mind wandering, mindful awareness, and states of mental tranquility (2016; available on academia.edu)
The DMN [is] also described as the hippocampal cortical memory system ...

We describe a potential neu- rocognitive framework in which mental training associated with mindfulness allows the practitioner to more skillfully gain volitional control, flexibility, and awareness over mind wandering, evaluation, and associated DMN activity without necessarily suppressing or avoiding the flow ofmental content ...

The FPCN is specifically proposed to rapidly and flexibly couple with the DMN and other attentional networks for contextually appropriate engagement and disengagement with relevant objects in the ongoing stream of mental and sensory content. Thus, a sense of tranquility or stillness of mind involves the elimination of distortions and distractions in an effortless and sustained form of awareness and can have lasting effects on one’s mental habits, biases, and worldview in relation to the surrounding world.
Not to mention possibly fending off early Aβ accumulation. For those interested in meditation science and different types of meditation I found this paper really interesting. I've not yet had a chance to follow up on these citations that apparently address:
... research on the “resting state” is demonstrating how task-unrelated or stimulus-independent thought (SIT) [eg, DMN] may adaptively organize brain function 8 and how the intrinsic neural activity supporting SIT affects brain metabolism and neuroplasticity. 8–11'
8. Raichle, M.E. 2015.The restless brain: how intrinsic activity organizes brain function. Philos. Trans. R. Soc. Lond. B Biol. Sci. 370.

9. Raichle, M.E., J.B. Posner & F. Plum. 1970. Cerebral blood flow during and after hyperventilation. Arch. Neurol. 23: 394–403.

10. Magistretti, P.J. &L. Pellerin. 1999. Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging. Philos. Trans. R. Soc. Lond. B Biol. Sci. 354: 1155–1163.

11. Raichle, M.E. &M.A. Mintun. 2006. Brain work and brain imaging.

3)

This one isn't focused on younger brains but illustrates the importance of methodology while showing ApoE differences 'several years' before dementia:

Default Mode Network Analysis of APOE Genotype in Cognitively Unimpaired Subjects Based on Persistent Homology (2020, cross sectional)
The reason why findings of DMN on unimpaired individuals do not consistently demonstrate differences between APOE4+ and APOE4- is still debated in the literature (Chiesa et al., 2017). In our study, we found two measures could detect their differences significantly, which would further enhance the APOE research based on graph theory...

The significant differences between APOE4+ and APOE4- are identified within the left hemispheric DMN and in the whole brain DMN in two datasets, providing evidence that the APOE e4 genotype leads to distinct alterations of functional DMN several years before the occurrence of dementia symptoms. Moreover, our suggested approaches of persistent homology are more sensitive to APOE genotypic differences than standard graph-based network measures
ApoE 3/4 > Thanks in advance for any responses made to my posts.
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Re: "ApoE4 does not influence brain function at young age"

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circular wrote:I've been looking at similar papers relating to brain networks and the DMN in particular...

Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity (2017, large cohort)
The earliest Aβ accumulation is further associated with hypoconnectivity within the DMN and between the DMN and the frontoparietal network, but not with brain atrophy or glucose hypometabolism. Our results suggest that Aβ fibrils start to accumulate predominantly within certain parts of the DMN in preclinical AD and already then affect brain connectivity....

to our knowledge the present study is the first to show that this association is present already at the very earliest preclinical stages of AD when Aβ fibrils are just starting to accumulate.
In addition and for emphasis:...

Default Mode Network Analysis of APOE Genotype in Cognitively Unimpaired Subjects Based on Persistent Homology (2020, cross sectional)
The significant differences between APOE4+ and APOE4- are identified within the left hemispheric DMN and in the whole brain DMN in two datasets, providing evidence that the APOE e4 genotype leads to distinct alterations of functional DMN several years before the occurrence of dementia symptoms. ...
Circular, many thanks for doing the hard work of reading and annotating the key sections of these papers! I hope that you don't mind that I added even more emphasis, since I heard exactly the same information about early changes in the default mode network (DMN) in sessions at the virtual Alzheimer's Association International Conference (AAIC) a few weeks ago. Two ideas seem to be gaining traction: One: The TYPE of amyloid beta may be important to the success of impacting the trajectory of preclinical AD and may, in fact, explain why removing amyloid from the brains of people with moderate AD has been less successful, because it's too late in the process. Two: Correcting or preventing synapse dysfunction may preserve brain connectivity even with amyloid beta in the brain; some drugs to focus on this are likely to be in trials within a year or so.

Here's recent news about the AHEAD 3/45 trials of a drug targeting proto-fibrils:
Novel anti-amyloid drug BAN2401 enters Phase III trial in Alzheimer’s patients
Experimental Alzheimer’s treatment, BAN2401, has entered Phase III trials in individuals in preclinical, asymptomatic stages of the disease. The trial will test the therapeutic effect of BAN2401 on the progression of Alzheimer’s disease (AD).

BAN2401 is an anti-amyloid beta (Aβ) protofibril antibody, designed to selectively bind to, neutralize and eliminate toxic Aβ protofibrils thought to be one of the causes of neurodegeneration in AD.

The trial is a collaboration between Biogen, Eisai, BioArctic and the Alzheimer’s Clinical Trials Consortium (ACTC).
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Re: "ApoE4 does not influence brain function at young age"

Post by Jaque »

APOE4 does in fact influence the brain function - BUT in a positive way. I had posted a paper while back about increased cognitive ability of people with APOE4. Here is the abstract and the paper citation.
Abstract:
A potential candidate gene that could contribute to the education process is the apolipoprotein E (apo E) gene that has been shown to correlate with memory function and memory decline. We measured apo E polymorphism in groups of probands with different levels of education selected from a population sample. In the group of probands with higher education (n = 82), 24.4% had the e4 allele, compared with 7.3% who had the e2 allele. A reverse association was found in the group that left school aged 15 (n = 36) – 8.3% had the e4 allele and 13.9% had the e2 allele. Eighty-seven percent of the probands with the allele e4 reached higher education, compared to only 54.5% with the allele e2. The difference between the groups is statistically significant (p = 0.039), and this may indicate some role for the apo E polymorphism in subjects` intelligence or ability to learn.
Source: Hubacek J, A, Pitha J, Škodová Z, Adámková V, Lánská V, Poledne R: A Possible Role of Apolipoprotein E Polymorphism in Predisposition to Higher Education. Neuropsychobiology 2001;43:200-203. doi: 10.1159/000054890
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