Find all causes of Alzheimer's disease and a cure

by Cure Alzheimer's Fund
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Find all causes of Alzheimer's disease and a cure
Find all causes of Alzheimer's disease and a cure
Find all causes of Alzheimer's disease and a cure
Find all causes of Alzheimer's disease and a cure
Find all causes of Alzheimer's disease and a cure

Despite evidence demonstrating that impairments in the clearance of toxic waste in the brain contribute to late-onset Alzheimer’s disease, the science of lymphatic system dysfunction and the systems regulating entry and exit through the blood-brain barrier has been largely overlooked in Alzheimer’s disease — until now. The Brain Entry & Exit Consortium bring together an international team of scientists to consider the following question: how do different barriers within the brain communicate?

The recent discovery of lymphatic vessels in the brain has raised important questions.  How are fluids, such as cerebrospinal fluid and various molecules, exchanged between different parts of the brain? How are toxic waste and other byproducts cleared from the brain? It took more than 200 years and the application of cutting-edge imaging techniques for the observation in the 18th century by Paoli Mascagni to be confirmed: the membranes that line the skull and enclose the brain and spinal cord contain lymphatic vessels that drain fluids from the brain.

The brain is comprised of multiple barriers including the blood-brain barrier, the blood-choroid plexus barrier, meningeal lymphatics, and the blood-meningeal barrier. The meningeal lymphatic vessels carry waste from the cerebrospinal fluids (CSF) to the lymph nodes and facilitate the removal of byproducts from the brain. While it is known that the brain recirculates the CSF, the details for how this process might change during aging, and the role of CSF and recirculation in neurodegeneration, requires more investigation. The CSF also regulates intracranial pressure, removal of waste such as amyloid-beta, and neuroinflammation. A decrease in CSF production and clearance is thought to contribute to the dysregulation in the brain that arises with aging and neurodegenerative diseases.

With grants from Cure Alzheimer’s Fund, a group of international scientists are embarking on research that will determine how dysfunction in one of the brain barriers might impact others. And, since many drugs and antibodies do not make it to the brain because they are blocked by the blood-brain barrier, this research is critical for designing better systems of drug delivery.

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Tauopathies, neurodegenerative disorders characterized by the presence of tau protein in the brain, are more likely to emerge in individuals harboring the APOE4 gene. Compared to other APOE variants, the expression of APOE4 significantly increases neuronal loss, decreases brain volume, and increases glial inflammatory signals. In the absence of APOE, however, these consequences largely disappear, suggesting that APOE4 is a precipitating factor.

Although apoE is secreted by both astrocytes and microglia, previous studies have shown that astrocytic apoE particles are larger and contain more lipids than microglial-derived apoE. As a result, some researchers have wondered whether astrocytic-derived apoE might be playing a unique role in the brain. Now, a new study published in Neuron by a team of researchers from Brigham and Women’s Hospital (Oleg Butovsky, Ph.D.) and Washington University School of Medicine in St. Louis (Jason Ulrich, Ph.D., and David Holtzman, M.D.) reports on the role that astrocytic APOE4 plays in tau-mediated neurodegeneration.

To begin with, the research team generated transgenic mice that expressed either Tau/APOE3 (TAFE3) and Tau/APOE4 (TAFE4)—specifically in astrocytes. Once the mice were 5.5 months old (the age of tau pathology onset), they injected mice either with oil (as a control) or tamoxifen to reduce astrocytic APOE mRNA. Indeed, when the team analyzed cortical tissue from both groups four weeks later, they found the tamoxifen-injected group had >80% reduced apoE protein levels compared to the oil-injected group.

After confirming that the tamoxifen-injection strategy sufficiently and specifically reduced astrocytic apoE mRNA and protein, the team examined the effect of astrocytic apoE on tau-driven neurodegeneration. Although overall brain volume was preserved between APOE3 and APOE4 groups, the ventricular volume (typically expanded in the presence of APOE4 and indicative of brain tissue atrophy) was reduced in female tamoxifen-treated TAFE4 mice, compared to oil-treated TAFE female mice, indicating a reduction in brain atrophy. This difference in ventricular volume was not reported between oil-treated and tamoxifen-treated male TAFE4 mice.

Next, the researchers evaluated the effects of decreased astrocytic APOE4 on mouse behavior.

Under normal conditions, healthy mice will spontaneously build nests out of nesting material. In cases of neurodegeneration, this behavior is typically disrupted. Predictably, then, APOE4 mice also showed disrupted nest-building behavior. Interestingly, however, when the researchers injected APOE4 mice with tamoxifen, effectively decreasing astrocytic APOE4 expression, the mice began normally building their nests. The result strongly suggests that APOE4 negatively impacts both the brain and behavior.

The researchers also measured plasma protein levels of neurofilament light chain (NFL), a marker of neuroaxonal damage and neurodegeneration. Compared to oil-injected mice, tamoxifen-treated mice exhibited lower levels of NFL, indicating that APOE4 removal improves markers of neurodegeneration. Cortical tissue analysis of phosphorylated Tau (pTau) revealed that removal of astrocytic APOE4 significantly decreased tau phosphorylation in females, but not in APOE4 males or APOE3 mice (females or male), consistent with the observation that removal of APOE3 confers no neuroprotection, but APOE4 does. Collectively, these experimental results indicate that astrocyte-derived APOE4 is a major factor in driving tau-dependent neurodegeneration in females.

Experiment after experiment in the study revealed that removal of astrocytic APOE4 benefited the brain, preventing damage otherwise expected in APOE4-carrying animals. Astrocytes moved from active states to homeostatic states; oligodendrocytes that were once reactive in the presence of tau protein were healthier and more stable, and microglia that were once active and phagocytosing synapses could now rest easy. Given this set of intriguing results, the researchers are optimistic that new treatment strategies targeting astrocytic APOE4 could slow neuronal and synaptic loss and preserve function. Perhaps, most encouragingly, such an intervention, in principle, could be effective even after the onset of neurodegenerative symptoms.


Published in: Neuron

Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia


Oleg Butovsky, Ph.D., Brigham and Women’s Hospital

Jason Ulrich, Ph.D., Washington University School of Medicine in St. Louis

David Holtzman, M.D., Washington University School of Medicine in St. Louis

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Throughout a single lifetime, the brain undergoes many changes. In early development, brain circuits are connected and pruned; in adolescence circuits mature and, in midlife, the menopause transition (MT) impacts a host of brain functions—from energy metabolism to synaptogenesis. Despite the clear link between MT and brain function, very little data exists on how different stages of the MT (pre-, peri-, and post-menopause) impacts the brain.

In a new study led by Lisa Mosconi, Ph.D., from the Weill Cornell Medical College/New York-Presbyterian Hospital, a team of researchers conducted a neuroimaging study with a total of 182 female participants at pre-, peri- and post-menopausal stages to determine the effect of MT on a panel of brain biomarkers related to structure, connectivity, energy metabolism, and Aβ deposition. To ensure that any changes the researchers observed were really the result of MT, specifically, and not due to chronological aging, each female MT group of participants was compared to an age-matched group of male participants.

The researchers found that the post- and peri-menopausal groups had lower gray matter volume (GMV) in various cortical and subcortical regions compared to the control group. Interestingly, by post-menopause these GMV changes stabilized and had largely recovered in the precuneus—a brain region important for social processing, episodic memory and integration of information. In fact, over a 2-year span, GMV in the precuneus increased compared to both peri-menopausal female participants and age-matched male participants. This increased GMV in the precuneus was also correlated with increased memory scores. Interestingly, the precuneus has also been shown to dynamically change in late pregnancy and to recover back to normal by weaning, indicating that this brain region is generally susceptible to fluctuations in estrogen.

White matter volume (WMV) was also reduced in post- and peri-menopausal groups. However, the researchers note that despite this WMV reduction, all MT groups had higher fractional anisotropy (FA)—a reflection of fiber density, axonal diameter, and white matter myelination—in the corona radiata and fornix. Dr. Mosconi and colleagues interpret the higher FA values in post- and peri-menopausal groups as increased efficiency in WM and speculate that the MT results in refinement of white matter connectivity within some key brain structures.

In addition to brain structure, the researchers discovered differences in brain metabolism and energy. Both the post- and peri-menopausal groups showed hypometabolism in the parieto-temporal cortices. And cerebral blood flow and ATP production in these regions were elevated post-menopause. Although cerebral blood flow, cerebral glucose metabolism, and regional brain activity typically rise and fall together, these metrics can dissociate in cases of pathology, inflammation, or as the brain’s way of compensating in some way. Preclinical data from other researchers have shown that estrogen loss during MT triggers a decrease in cerebral glucose metabolism, likely as a compensatory mechanism. Thus, Mosconi and colleagues hypothesize that the hypometabolism observed in the post- and peri-menopausal groups in their study reflect similar compensatory mechanisms. Mitochondrial ATP production in the brain was higher in the post-menopausal group, indicating another potential adaptive change in response to MT.

Finally, the researchers looked at Aβ deposition across all groups and found increased deposition in the post- and peri-menopausal groups compared to both the pre-menopausal female group and age-matched male participants. Given that the chronology of MT frequently aligns with the pre-symptomatic accumulation of beta amyloid pathology, the researchers suspect that this increased Aβ exposure in peri- and post-menopausal female participants partly explains the higher prevalence of AD in female individuals. On the other hand, it’s possible that hormonal changes from MT are accelerating aging, which is then increasing Aβ deposition; the study did not try to differentiate between chronological and biological aging. Furthermore, Aβ deposition doesn’t always mean AD is around the corner; many individuals carry Aβ and function just fine.

Notably, all of the MT results were independent of whether or not participants received hormonal treatment (HT) or a hysterectomy. However, the authors also note a few caveats to their study. First, the educational status of participants in the MT groups was an average of 17 years, which is greater than the average of 12-13 years reported for the general U.S. population. Second, a large proportion of the participants in this study (42%) were APOE-4 carriers, compared to only 15-30% in the general population. Given that APOE4 carriers show accelerated aging on a variety of biological markers, the non-representative sample of participants in this study may be a confounding factor. Finally, because the groups were predominantly made up of White participants (80% in the pre-menopausal group; 77% in the peri-menopausal group and 89% in the post-menopausal group), the results of this study are not representative of the general population.

Regardless, the results of this study make it clear that the menopausal transition period is a dynamic period of change that impact key brain biomarkers. Future studies will need to address whether the changes in post-menopausal groups observed in this study replicate in other studies and, if they do, whether or not such changes explain the sex-dependent emergence and progression of Alzheimer’s disease.

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BETH STEVENS, PH.D., Boston Children’s Hospital

Alzheimer’s disease (AD) is the health challenge of our generation. The majority of AD cases are of late onset and result from the interaction of many genes and nongenetic risk factors, of which the most important is aging. Emerging genetic studies of late-onset AD implicate the brain’s resident immune cells, microglia, in the pathogenesis of AD. In fact, more than half the risk genes associated with late-onset AD are selectively expressed in microglia and peripheral myeloid cells, two cell types associated with the brain’s immune system; yet, we know shockingly little about their biology and how they contribute to AD pathogenesis. Under normal conditions, microglia actively survey the brain; they are highly sensitive to changes caused by injury, infection or other abnormalities. In this role, they can be beneficial by removing toxic proteins and cellular debris, but they also can promote detrimental forms of neuroinflammation leading to inappropriate and damaging synapse loss—one of the earliest changes in the AD brain, and the strongest correlate of cognitive decline.

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Women are twice as likely to develop late-onset Alzheimer’s disease (AD) as men, often attributed to women’s longevity. Recent evidence has emerged suggesting that gender-specific risk factors may drive this difference in addition to a longer lifespan. Attention has now shifted towards identifying the factors that put women at higher risk of late-onset AD. Once identified, these factors can be evaluated for potential modification through lifestyle changes or early medical intervention, or both. If modifiable, the time for prevention would likely be prior to the start of symptoms, possibly during midlife.

In a recent study, with support from Cure Alzheimer’s Fund, Dr. Lisa Mosconi of Weill Cornell Medicine and her team examined the late-onset risk factors associated most strongly with Alzheimer’s-related changes in the brains of cognitively normal middle-aged men and women. The results of the study appeared in the July 14, 2020 issue of the journal Neurology, a publication of the American Academy of Neurology.

The findings suggest that among a wide range of risk factors for late-onset AD, including depression, smoking, and AD family history, menopause status was second to female sex as most strongly associated with brain changes related to AD. Other strong associations were hormone therapy, thyroid disease, and hysterectomy status. The study included 85 women and 36 men between the ages of 40 and 65. The two gender groups did not differ by APOE4 status or family history of AD.

The researchers identified brain changes via amyloid PET scan detecting amyloid-beta levels, as well as FDG PET scan and structural MRI for detecting overall brain neurodegeneration. Results from the female and male groups that were matched for age (since age is the most significant risk factor of late-onset AD) showed that on average the women had 30% higher amyloid levels on the amyloid PET scans, 22% lower glucose metabolism on the FDG PET, and 11% lower grey and white matter volume detected by the MRI. The male group did not have any of the brain changes that were being examined, pointing to the fact that these were indeed female-specific.

Since the study participants had normal cognition, and the study was not designed to assess those that later experienced cognitive decline, more research would be needed to generalize the results. Dr. Mosconi is actively investigating why the menopause transition—both whether a woman has begun it and where she is along its spectrum—correlates with an increased risk of AD-related brain changes. 

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Cure Alzheimer's Fund

Location: Wellesley Hills, Ma - USA
Project Leader:
Laurel Lyle
Wellesley Hills, MA United States
$80,738 raised of $100,000 goal
1,492 donations
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