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

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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One of the most enduring mysteries in Alzheimer’s disease (AD) is closer to being resolved due to new work from the lab of Dr. Berislav Zlokovic: how the gene variant APOE4 increases the risk for cognitive decline and dementia.

APOE4 is one of three major genetic variants (also known as alleles) of the apolipoprotein E gene, abbreviated as APOE. Each cell in a human body starts with two APOE alleles, one from each parent; these alleles may be the same or different from one another. Cells make proteins from gene “blueprints”; an APOE4 allele will yield a slightly different APOE protein than an APOE3 allele will yield. The following three points are from the National Institutes of Health regarding the APOE alleles:

  • APOE2 is relatively rare and may provide some protection against the disease. If Alzheimer’s disease occurs in a person with this allele, it usually develops later in life than it would in someone with the APOE4 gene.
  • APOE3, the most common allele, is believed to play a neutral role in the disease—neither decreasing nor increasing risk.
  • APOE4 increases risk for Alzheimer’s disease and is also associated with an earlier age of disease onset. Having one or two APOE4 alleles increases the risk of developing Alzheimer’s. About 25 percent of people carry one copy of APOE 4, and 2 to 3 percent carry two copies.

In the 1990s, scientists recognized that the APOE4 gene variant was overrepresented in patient populations with late-onset AD and identified APOE4 as the common genetic variant associated with the greatest risk of developing the disease in the cohorts studied. (Rare variants of other genes with greater risk impact have been identified, but they are carried only by a very small number of people.)

How does APOE4 increase the risk of developing Alzheimer’s disease? While the APOE protein has many roles in the brain, as well as the rest of the body, it is not well understood how or why the different versions of the APOE protein encoded by different APOE alleles may behave differently in these roles. The new work from Dr. Zlokovic’s laboratory presents the theory that APOE4 may increase AD risk through at least two separate pathways, including one that does not involve amyloid or tau pathology, the hallmarks of AD.

The field has long recognized that people carrying one or two copies of APOE4 have earlier and elevated amyloid-beta deposition in the brain—a precursor of the Alzheimer’s pathology amyloid plaques—and that these carriers develop mild cognitive impairment and dementia at a higher and earlier rate than non-APOE4 carriers.  The breakdown of the protective cellular border lining the brain’s blood vessels that keeps the bloodstream and brain apart, known as the blood-brain barrier, has been shown to occur in patients with Alzheimer’s disease. Work in animal models suggests that APOE4 may contribute to the barrier’s break down.  A “leaky” blood-brain barrier allows otherwise-blocked substances to pass from the blood into the brain, where they can be toxic and trigger a pathological immune response.

On the whole, the relationships among the observed consequences of carrying the APOE4 variant have been unclear:

  • Does the increased amyloid deposition lead to a leakier blood-brain barrier, or does a leakier blood-brain barrier increase amyloid deposition?
  • Is early cognitive decline caused by either or both?

These questions remain a matter of continued investigation, and, with support from Cure Alzheimer’s Fund, answers are beginning to emerge.

Dr. Berislav Zlokovic—Cure Alzheimer’s Fund Research Leadership Group member and Director of the Zilkha Neurogenetic Institute—leads a team of scientists at the University of Southern California to investigate how damage to the blood-brain barrier may underlie cognitive decline.

Findings published in Nature suggest that people carrying at least one copy of APOE4 showed earlier and greater damage to the blood-brain barrier than did non-carrier. This level of damage was predictive of future cognitive decline. Further, the team proposed a mechanism by which APOE4 can contribute directly to blood-brain barrier damage. In their paper, the scientists compared results from a series of neuroimaging and biochemistry tests administered over several years to APOE4 carriers (homozygous APOE4/4 and heterozygous APOE3/4) and non-carriers (homozygous APOE3/3).

First, the researchers used advanced brain imaging technology to show that early damage to the blood-brain barrier in individuals with APOE4 occurred in the hippocampus and parahippocampal gyrus, the learning and memory centers of the brainThis damage was present in people with the variant with no memory loss but was more severe in those with signs of cognitive decline.

The scientists also demonstrated that greater blood-brain barrier breakdown in APOE4 carriers occurred independently of the presence of Alzheimer’s disease pathology. Measures of blood-brain barrier damage in specific brain areas predicted cognitive impairment for APOE4 but not APOE3/3 carriers even after accounting for amyloid-beta and tau burden.

The data from the next set of experiments were particularly exciting: they suggest a new potential diagnostic tool to determine susceptibility to cognitive decline for APOE4 carriers before decline is observed clinically.

To this end, the researchers used a test they previously developed to assess the breakdown of the blood-brain barrier from samples of cerebrospinal fluid (CSF)—the liquid around the brain and spinal cord. On the molecular level, the assay measures a biomarker—in this case, a specific protein that indicates injury to specialized cells that help make up the blood-brain barrier, called pericytes. When pericytes are injured, the protein shed’s their surface and becomes loose in the cerebrospinal fluid. Therefore, an increase in levels of this loose protein in a person’s CSF implies the blood-brain barrier has been damaged.

In their investigation, the researchers divided the APOE4 participants into two groups based on initial testing—one with lower levels of the pericyte injury biomarker and the other with higher levels. For each group, cognitive abilities were evaluated and recorded. The participants’ cognition was tested again over several years. The researchers found that initial higher levels of the biomarker were predictive of cognitive decline severity in the later time points. Also, elevated biomarker levels correlated with increased damage to the blood-brain barrier in the hippocampus and parahippocampal gyrus.

The team performed additional experiments to address the underlying mechanisms behind APOE4-linked injury to pericytes and confirmed that APOE4 activates an inflammatory pathway—ultimately speeding up the breakdown of the blood-brain barrier.

These groundbreaking findings made by Dr. Zlokovic and his lab suggest that drugs or other treatments that can protect or improve the blood-brain barrier’s integrity—perhaps by blocking inflammation in pericytes—could protect cognitive health in people carrying APOE4. The Zlokovic lab is pursuing this investigation in its ongoing work.

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A new study from Drs. Iadecola and Faraco published in Nature offers new insights into why and how skipping the salt-shaker might protect your cognitive health. The National Institute of Health has long advised that high-salt diets are associated with high blood pressure and can raise the risk for heart disease, stroke, kidney failure, and can cause immune-related changes in the gut. This most recent study suggests that high salt intake can also impact cognitive function by causing a deficiency in a compound – nitric oxide – that is crucial for maintaining vascular health in the brain and that new findings tie to tau, one of the hallmark Alzheimer’s proteins.

A study in 2018 from the same team found that a high-salt diet contributed to cognitive deficits in mice. The mice in this study had memory impairment and were unable to complete the tasks of daily living such as building their nests. The conclusion from this earlier study was that the high-salt diet caused cells in the small intestine to release a molecule known as interleukin-17 (IL-17) which promotes inflammation as part of the body’s immune response. IL-17 enters the bloodstream where it prevented cells in the walls of the blood vessels from providing the brain with nitric oxide. Nitric oxide is crucial for relaxing and widening the blood vessels to allow blood to flow; a shortage of nitric oxide can restrict blood flow.

Following up on these initial findings, the study recently published in Nature takes the research a step farther by investigating how a change in nitric oxide production in the blood vessels affects the stability of tau proteins in neurons.

In an interview about the research, Dr. Iadecola said: “tau becomes unstable by coming off the cytoskeleton. Tau is not supposed to be free in the cell. Once tau detaches from the cytoskeleton, the protein can accumulate in the brain, causing cognitive problems.” The research provides evidence for nitric oxide playing a role in keeping tau in check.

In a crucial experiment, the researchers gave mice eating a high-salt diet an antibody to promote tau stability. Despite restricted blood flow in these mice, the researchers observed that they had normal cognition. This experiment demonstrated that the cognitive deficits in the mice on the high-salt diet were due to the effect of tau rather than restricted blood flow alone.

This research paves the way to conduct research on how salt intake affects cognition in humans – specifically Alzheimer’s patients. CureAlz is actively supporting research investigating the links among dietary salt, cardiovascular function, tau deposition, and cognitive decline.


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New research shows that measuring proteins in the blood may predict both health and lifespan. The research was published in Nature Medicine with support from a grant from Cure Alzheimer’s Fund. Tony Wyss-Coray, PH.D. and a team of scientists have used advances in protein profiling technology to measure thousands of proteins in the plasma at points across the human lifespan in order to determine what profiles are associated with healthy aging and with disease.

Blood has cells that transport oxygen, fight infectious disease, and carry messenger molecules with information across organ systems. The blood contains hormone-like factors that promote growth and survival; the composition of these factors changes during aging and with disease. The hormone-like factors involved in cell injury, repair, and inflammation increase during aging while those involved in the maintenance and development of tissue decrease with age. Blood tests are beginning to be used as a diagnostic and prognostic tool for many diseases including cancer, brain trauma, and heart failure, as well as amyloid plaque levels in the brain.

Using a technology called SOMAmer the researcher team measured the levels of nearly 3,000 different plasma proteins from more than 4,000 healthy individuals ages 18 – 95. As a key part of the study, the team identified 373 proteins in the blood that showed consistent changes with age across the lifespan of both mice and humans. Using machine learning techniques, this protein change data was used to train an artificial intelligence tool to predict biological age based on a sample donor’s protein profile.  In validation testing, the tool predicted a biological age that was younger than a person’s chronological age for individuals who were indeed healthier both cognitively and physically than individuals of the same chronological age but for whom the tool predicted a correct or older biological age.  The authors hope that this proteomic clock may someday be used to identify individuals at risk for disease.


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Cure Alzheimer's Fund

Location: Wellesley Hills, Ma - USA
Project Leader:
Laurel Lyle
Wellesley Hills, MA United States
$74,205 raised of $100,000 goal
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