2015 Alzheimer’s Disease Facts and Figures Report Available

(Alzheimer’s Association) The 2015 Alzheimer’s Disease Facts and Figures report is  available. This is the definitive, yearly report from the Alzheimer’s Assocation. You can download copies here:

Download the full report: 4-9-2015 9-21-25 AM
Download the infographic: 4-9-2015 9-20-36 AM
Download quick facts 4-9-2015 9-17-40 AM


Please go to www.alz.org for information, resources, and ways you can help.



An estimated 5.3 million Americans of all ages have Alzheimer’s disease in 2015.

  • Of the 5.3 million Americans with Alzheimer’s, an estimated 5.1 million people are age 65 and older, and approximately 200,000 individuals are under age 65 (younger-onset Alzheimer’s).
  • Almost two-thirds of Americans with Alzheimer’s are women. Of the 5.1 million people age 65 and older with Alzheimer’s in the United States, 3.2 million are women and 1.9 million are men.
  • Although there are more non-Hispanic whites living with Alzheimer’s and other dementias than people of any other racial or ethnic group in the United States, older African-Americans and Hispanics are more likely than older whites to have Alzheimer’s disease and other dementias.

The number of Americans with Alzheimer’s disease and other dementias will grow each year as the size and proportion of the U.S. population age 65 and older continue to increase. By 2025, the number of people age 65 and older with Alzheimer’s disease is estimated to reach 7.1 million — a 40 percent increase from the 5.1 million age 65 and older affected in 2015. By 2050, the number of people age 65 and older with Alzheimer’s disease may nearly triple, from 5.1 million to a projected 13.8 million, barring the development of medical breakthroughs to prevent or cure the disease.


In 2015, an estimated 700,000 people in the United States age 65 and older will die with Alzheimer’s.

As the population of the United States ages, Alzheimer’s is becoming a more common cause of death. Although deaths from other major causes have decreased significantly, official records indicate that deaths from Alzheimer’s disease have increased significantly. Between 2000 and 2013, deaths attributed to Alzheimer’s disease increased 71 percent, while those attributed to the number one cause of death—heart disease—decreased 14 percent.

Alzheimer’s is the only disease among the top 10 causes of death in America that cannot be prevented, cured or even slowed.

Impact on Caregivers

In 2014, friends and family of people with Alzheimer’s and other dementias provided an estimated 17.9 billion hours of unpaid care, a contribution to the nation valued at $217.7 billion. This is approximately 46 percent of the net value of Walmart sales in 2013 and nearly eight times the total revenue of McDonald’s in 2013.

  • Approximately two-thirds of caregivers are women and 34 percent are age 65 or older.
  • Forty-one percent of caregivers have a household income of $50,000 or less.
  • Over half of primary caregivers of people with dementia take care of parents.
  • It is estimated that 250,000 children and young adults between ages 8 and 18 provide help to someone with Alzheimer’s disease or another dementia.

Alzheimer’s takes a devastating toll on caregivers. Nearly 60 percent of Alzheimer’s and dementia caregivers rate the emotional stress of caregiving as high or very high; about 40 percent suffer from depression. Due to the physical and emotional toll of caregiving, Alzheimer’s and dementia caregivers had $9.7 billion in additional health care costs of their own in 2014.

Cost to Nation

Alzheimer’s disease is one of the costliest chronic diseases to society.

  • In 2015, the direct costs to American society of caring for those with Alzheimer’s will total an estimated $226 billion, with half of the costs borne by Medicare.
  • Average per-person Medicare spending for people age 65 or older with Alzheimer’s and other dementias is three times higher than for seniors without dementia. Medicaid payments are 19 times higher.
  • Nearly one in every five Medicare dollars is spent on people with Alzheimer’s and other dementias. In 2050, it will be one in every three dollars.

Unless something is done, in 2050, Alzheimer’s is projected to cost over $1.1 trillion (in 2015 dollars). This dramatic rise includes a five-fold increase in government spending under Medicare and Medicaid and a nearly five-fold increase in out-of pocket spending.

Disclosing a Diagnosis

Most people living with Alzheimer’s are not aware of their diagnosis.

Despite widespread recognition of the benefits of clear and accurate disclosure, less than half (45 percent) of seniors diagnosed with Alzheimer’s disease or their caregivers report being told the diagnosis by a health care provider, compared with 90 percent or more of those diagnosed with cancer and cardiovascular disease.

Health care providers routinely encounter the situation of having to deliver a frightening or upsetting diagnosis to patients and perhaps to relatives, friends and loved ones. Yet there is broad agreement among physician organizations that patients have the right to know and understand their diagnosis. Benefits of disclosing a diagnosis include better diagnosis (opportunity for a second opinion), better decision-making about their lives for both the present and the future, and better medical care.



Copyright © 2015  Alzheimer’s Association®. All rights reserved.


Subtracting Gravity from Alzheimer’s

(NASA.gov) Alzheimer’s disease is a global problem.  In the United States alone, more than 5 million people have the disease and a new diagnosis is made every 67 seconds—numbers that are just a fraction of worldwide totals.  Among medical researchers, Alzheimer’s is a top priority.

Researchers working with astronauts on the International Space Station are embarking on a mission to discover the origin of Alzheimer’s. Although the details are still a little fuzzy, researchers believe that Alzheimer’s and similar diseases advance when certain proteins in the brain assemble themselves into long fibers that accumulate and ultimately strangle nerve cells in the brain.

“They’re sort of like the crankcase sludge of the human body,” explains Dan Woodard of NASA’s Kennedy Space Center. “The fibers are not active, so they’ll be around forever because your body doesn’t have any way to get rid of them.”

These fibers take decades to form and accumulate—hence the link between Alzheimer’s and aging. In laboratories on Earth, researchers have figured out how to make protein fibers accumulate more quickly, so they can study the process without waiting so long.  On the space station, accumulated fibers do not collapse under their own weight, which makes the station an even better place to study them.

A four-inch cube containing the experiment, which was selected in an ISS research contest by Space Florida and Nanoracks, and built at the Florida Institute of Technology, blasted off to the International Space Station onboard the SpaceX-5 cargo resupply mission on Jan. 10th. The experiment itself, SABOL, or Self-Assembly in Biology and the Origin of Life: A Study into Alzheimer’s, will be fully automated.

However, observations from this experiment alone won’t lead directly to the discovery of a cure. SABOL is geared more towards understanding the way that Alzheimer’s progresses, not towards creating a pill to stop it from happening. Although this experiment is only the first in what will surely be a series, Woodard is optimistic that it could be an extremely valuable learning experience.

“Everybody wants a cure, but without knowing the actual cause of the disease, you’re basically shooting in the dark,” Woodard says.

“We don’t understand the true mechanism of the disease. If we’re lucky, then we’ll find out whether proteins will aggregate in space. Only in weightlessness can you produce an environment free of convection so you can see whether they form on their own. We expect to learn incrementally from this.”

Eventually, projects like SABOL could lead to the discovery of a method to slow down the rate at which the harmful fibers grow, thereby opening a window for a cure. The results of the experiment will be seen after the samples are returned to Earth and are examined underneath an atomic force microscope. Woodard speculates that the cause of Alzheimer’s could surprise us by being deceptively simple.

Says Woodard, “There have to be chemicals or processes that hinder or encourage the growth of protein fibers. It may be something as simple as temperature or salt concentration of the fluid in the brain.”

Strange but true: The key to unraveling the mysterious cause of Alzheimer’s disease may not lie in the recesses of the human brain, but rather in the weightless expanse of space. If an answer is ultimately found, it could very well spring from the microgravity of Earth orbit.  The experiment begins soon.


Author: Rachel Molina

Production Editor: Dr. Tony Phillips



Antipsychotics May Be Deadlier Than Thought for Dementia Patients

(University of Michigan) Drugs aimed at quelling the behavior problems of dementia patients may also hasten their deaths more than previously realized, a new study finds.

Psychiatric drugs used to change problem behaviors in Alzheimer’s patients could carry more risks than previously thought.

The research adds more troubling evidence to the case against antipsychotic drugs as a treatment for the delusions, hallucinations, agitation and aggression that many people with Alzheimer’s disease and other dementias experience.

In the new issue of the journal JAMA Psychiatry, researchers report findings from nearly 91,000 American veterans over the age of 65 with dementia.

Data from each patient who took a psychiatric medication was matched to data from a similar patient who didn’t take drugs to calm behavior, by researchers from the University of Michigan Medical School and VA Center for Clinical Management Research.

Those taking drugs called antipsychotics had outsize risks of death. Among those taking the newer, more commonly used antipsychotics, the risk climbed along with the dose.

The study also examined other psychiatric medications. The risk of death seen with the mood stabilizer valproic acid was similar to the antipsychotics. Antidepressants had less risk compared with antipsychotics and valproic acid, but it was still higher than that of those not taking any psychiatric medications to treat behavior issues in dementia.

Antipsychotic drugs have significant risk of side effects, and the U.S. Food and Drug Administration warns that their use in people with dementia is associated with increased risk for cardiovascular adverse events and the risk of death.

“The harms associated with using these drugs in dementia patients are clear, yet clinicians continue to use them,” says lead author and U-M/VA psychiatrist Donovan Maust, M.D., M.S. “That’s likely because the symptoms are so distressing. These results should raise the threshold for prescribing further.”

This new study and a recent state-of-the-art review by Maust’s co-author Helen Kales, M.D., show that mortality risk of antipsychotics is higher, and benefit lower, than previously thought.

But the distress caused by uncontrolled symptoms probably explains why one-third of older adults with dementia who had long-term nursing home stays in 2012 were prescribed an antipsychotic medication, according to a recent U.S. Government Accountability Office report. About 14 percent of dementia patients in the community were prescribed an antipsychotic that same year, the GAO found.

Patients, families and their care teams deserve better to prevent and treat distressing dementia symptoms, Maust says.

The “DICE” approach to assess and manage behavioral symptoms in dementia that has been put forth by Kales and colleagues could help.

This approach emphasizes putting non-pharmacological strategies first. But the approach takes more time than writing a prescription, and its use will depend on the support of policy-makers and alignment of reimbursement strategies.

“In other words, non-pharmacologic approaches will only succeed if we as a society agree to pay front-line providers for the time needed to ‘do the right thing’,” says Kales.

Maust, Kales and their colleagues hope to continue studying the issue of mortality risk from the use of psychotropic drugs in dementia, and prescription patterns for these drugs, using other datasets.

In addition to Maust and Kales, the study’s authors are Hyungjin Myra Kim, Sc.D., Lisa S. Seyfried, M.D., M.S., Claire Chiang, Ph.D., and Janet Kavanagh, M.S., all of U-M, and Lon Schneider, M.D., M.S. of the University of Southern California.

All the U-M authors except Kim are in the Medical School’s Department of Psychiatry; Kim is in the Center for Statistical Consultation and Research. Maust, Kim, Chiang and Kales are member of the CCMR, and Maust and Kales are members of the U-M Institute for Healthcare Policy and Innovation.

The study was funded by the National Institute of Mental Health (MH08107) and the National Institute on Aging (AG048321). Both are part of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.


Reference: JAMA Psychiatry. 2015;72(5):-. doi:10.1001/jamapsychiatry.2014.3018


Copyright 2015 University of Michigan


Healthy Eating, Exercise, and Brain-Training Program Results in Slower Mental Decline for Older People

(The Lancet via ScienceDaily) A comprehensive program providing older people at risk of dementia with healthy eating guidance, exercise, brain training, and management of metabolic and vascular risk factors appears to slow down cognitive decline, according to the first ever randomised controlled trial of its kind, published in The Lancet.

In the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) study, researchers led by Professor Miia Kivipelto from the Karolinska Institutet in Stockholm, Sweden, National Institute for Health and Welfare in Helsinki, and University of Eastern Finland, assessed the effects on brain function of a comprehensive intervention aimed at addressing some of the most important risk factors for age-related dementia, such as high body-mass index and heart health.

1260 people from across Finland, aged 60-77 years, were included in the study, with half randomly allocated to the intervention group, and half allocated to a control group, who received regular health advice only. All of the study participants were deemed to be at risk of dementia, based on standardised test scores.

The intensive intervention consisted of regular meetings over two years with physicians, nurses, and other health professionals, with participants given comprehensive advice on maintaining a healthy diet, exercise programs including both muscle and cardiovascular training, brain training exercises, and management of metabolic and vascular risk factors through regular blood tests, and other means.

After two years, study participants’ mental function was scored using a standard test, the Neuropsychological Test Battery (NTB), where a higher score corresponds to better mental functioning. Overall test scores in the intervention group were 25% higher than in the control group.

For some parts of the test, the difference between groups was even more striking — for executive functioning (the brain’s ability to organise and regulate thought processes) scores were 83% higher in the intervention group, and processing speed was 150% higher.

Based on a pre-specified analysis, the intervention appeared to have no effect on patients’ memory. However, based on post-hoc analyses, there was a difference in memory scores between the intervention and control groups.

According to Professor Kivipelto,

“Much previous research has shown that there are links between cognitive decline in older people and factors such as diet, heart health, and fitness. However, our study is the first large randomised controlled trial to show that an intensive program aimed at addressing these risk factors might be able to prevent cognitive decline in elderly people who are at risk of dementia.”

The study participants will now be followed for at least seven years to determine whether the diminished cognitive decline seen in this trial is followed by reduced levels of dementia and Alzheimer’s diagnoses. The researchers will also be investigating possible mechanisms whereby the intervention might affect brain function.


Story Source:

The above story is based on materials provided by The Lancet. Note: Materials may be edited for content and length.

Journal Reference:

Tiia Ngandu, Jenni Lehtisalo, Alina Solomon, Esko Levälahti, Satu Ahtiluoto, Riitta Antikainen, Lars Bäckman, Tuomo Hänninen, Antti Jula, Tiina Laatikainen, Jaana Lindström, Francesca Mangialasche, Teemu Paajanen, Satu Pajala, Markku Peltonen, Rainer Rauramaa, Anna Stigsdotter-Neely, Timo Strandberg, Jaakko Tuomilehto, Hilkka Soininen, Miia Kivipelto. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. The Lancet, 2015; DOI: 10.1016/S0140-6736(15)60461-5

The Lancet. (2015, March 11). Healthy eating, exercise, and brain-training program results in slower mental decline for older people. ScienceDaily. Retrieved March 15, 2015 from www.sciencedaily.com/releases/2015/03/150311210415.htm


World Alzheimer Report 2014: Dementia and Risk Reduction

(Alzheimer’s Disease International) The World Alzheimer Report 2014, Dementia and Risk Reduction: An analysis of protective and modifiable factors critically examines the evidence for the existence of modifiable risk factors for dementia.

world-report-cover-2014It focuses on sets of potential modifiable risk factors in four key domains: developmental, psychological and psychosocial, lifestyle and cardiovascular conditions. The report makes recommendations to drive public health campaigns and disease prevention strategies.

The report which was researched and authored by Prof Martin Prince, Prof Emiliano Albanese, Dr Maëlenn Guerchet and Dr Matthew Prina on behalf of the Global Observatory for Ageing and Dementia Care which is hosted at the Health Service and Population Research Department, King’s College London.

Read the report

Additional materials


The report was funded by Bupa, for which we are very grateful.





A Year in Alzheimer’s Research — Top 10 Trends of 2014

(Alzheimer’s Research Forum) Are you good more exercise and losing five pounds, but forgot all about making New Year’s resolutions for your science? Ponder the past year’s advances, setbacks, and surprises in AD research, and use them as fodder for new ideas in 2015.

Trials, Therapies, and Diagnostics

Depending on one’s perspective, 2014 was a glass half-empty or half-full. For those expecting approval of a new drug among the various Aβ antibodies in the running, the year started out on a low when in January, papers in the New England Journal of Medicine made it official that Phase 3 trials of bapineuzumab and solanezumab had missed their primary goals. These papers renewed debate that lasted throughout the year and flared up loudly at the Clinical Trials on Alzheimer’s Disease (CTAD) conference in November. Some diagnosed a body blow for the amyloid hypothesis; others spotted in the wreckage some encouraging signals that treatment in the mildest patients engaged biomarkers, improved cognition, and slowed disease. Bapineuzumab is on the scrap heap, but solanezumab is being tested in another Phase 3 trial of mild AD, as well as in a prevention trial by the Dominantly Inherited Alzheimer Network of people carrying early onset mutations in APP and presenilin.

July brought word that Phase 2 trials of crenezumab had similarly fallen short of primary endpoints of cognition and function. Much like solanezumab, this antibody, too, gave faint signs of life with a cognitive benefit at the higher dose in the mildest patients. The crenezumab program emphasized how biomarker analysis in AD trials still requires much refinement. For example, amyloid PET showed no difference between placebo and treatment groups when AD regions were compared to cerebellum, but did begin to show a separation when compared with white matter. Crenezumab is being evaluated in an Alzheimer Prevention Initiative (API) trial in families carrying an autosomal-dominant presenilin mutation and is moving into new trials in earlier-stage sporadic AD, as well.

12.17_CTAD_Part_4_0Spatial distribution of amyloid PET tracer binding in Alzheimer’s disease. [Image courtesy of Felix Carbonell, Biospective Inc.]

The year ended on another bust, when Roche announced just before Christmas that it was ending an ongoing Phase 2/3 trial of gantenerumab in prodromal AD because it failed to meet the bar in a pre-specified futility analysis. The gantenerumab arm of the DIAN-TU prevention trial will continue.

Other immune-based treatments are still in the running. For example, Novartis’ CAD106, an active immunotherapy, completed Phase 2 and was chosen for an upcoming API secondary prevention trial of aged ApoE4 carriers. For its part, Biogen decided to push its antibody aducanumab straight from Phase1b to Phase 3, and other antibody trials are ongoing.

The failures thus far prompted extensive debate among scientists. Some felt the data showed that Aβ antibodies simply do not work. Other scientists cited specifics of antibody-Aβ binding characteristics, effector function, brain exposure, dosing, target engagement, and disease stage as the reasons antibodies have not worked yet. They insist the field is learning from each trial and immunotherapy evaluation should continue for the time being.

Bioavailability continues to be a problem for immunotherapy on AD, because only trace amounts of injected antibodies make it into the brain. The solution? Hitch the antibody to a protein that freely crosses the blood-brain barrier. Last January, two groups reported progress in delivering anti-Aβ or anti-BACE antibodies into mouse brain by way of transferrin, and November brought news that the system worked in primates.

On the small-molecule front, BACE inhibitors have become the next big thing. Merck’s MK-8931 is furthest along, being tested in two Phase 3 trials, one in prodromal and one in mild to moderate AD. Lilly teamed up with AstraZeneca to run a Phase 2/3 trial of the BACE inhibitor AZD3293 and, at CTAD in November, presented Phase 1 data suggesting strong target engagement and Aβ-lowering in AD patients. Vitae Pharmaceuticals announced top-line data from a single-dose Phase 1 study of its BACE inhibitor, VTP-37948, which lowered CSF Aβ by up to 80 percent. Both the API ApoE and DIAN prevention trials will use a BACE inhibitor, but which one remains unclear. Novartis presented preliminary data on NB-360 at the AAIC meeting in July.

All the while, academic researchers have continued to urge caution in blocking BACE while potential side effects are still being studied, lest a similar fate meet these inhibitors as befell their γ-secretase counterparts. The year 2014 saw γ-secretase inhibitors slide into oblivion. They had been considered dead as a doornail since investigators stopped the semagacestat Phase 3 in 2013 because of safety concerns; however, a nagging regret expressed largely in private discussion found publication in November 2014, when Bart de Strooper, KU Leuven, Belgium, analyzed why that trial failed. He urged the field to learn much more about the pharmacokinetics of secretase inhibition, and use the semagacestat experience to fill knowledge gaps about γ-secretase as a target rather than simply abandoning it and rushing toward a new, just-as-poorly understood target in BACE1 (De Strooper, 2014).

Some good news came from studies of drugs aimed at calming agitation in AD patients. Both AVP-923, aka Nuedexta, and citalopram showed some promise. Nuedexta is a mixture of dextromethorphan hydrobromide, the active ingredient in the cough syrup Robitussin, and quinidine sulfate, which prevents the liver enzyme cytochrome P450 from breaking down dextromethorphan. Citalopram, a selective serotonin reuptake inhibitor, carries a risk of arrhythmia, and the FDA recommends elderly patients take only 20 mg a day, whereas 30 mg was found to reduce agitation in AD. Other researchers claimed that in general, too many meds are given to end-stage AD patients. Last year brought bad news for PBT2, a compound Prana Biotechnology is developing, when its latest Phase 2 trial was negative.

Given how long Phase 3 AD trials take to read out, several continued through 2014 without new announcements. For example, FORUM Pharmaceuticals (formerly EnVivo) continued testing an α7 nicotinic acetylcholine receptor agonist, Encenicline, and Lundbeck a serotonin receptor agonist called Idalopirdine. The TOMMORROW study is testing whether variants in the Tomm40 gene predispose to AD and if the insulin sensitizer pioglitazone can prevent it.

Interest in drugs targeted at tau grew considerably in 2014. They included Phase 3 trials of LMT-X, a methylene blue derivative purported to prevent tau aggregation in people with AD or frontotemporal dementia, as well as a new antibody, ACI-35, in Phase 1. More broadly, 2014 saw FTD research blossom with presentations at the International Conference on Frontotemporal Dementias revealing how far the field has come toward understanding the pathology, genetics, clinical presentation, and other aspects of the disease. FORUM Pharmaceuticals’ HDAC inhibitor FRM-0334 moved into Phase 2 testing in patients with FTD caused by progranulin mutations.

There was a renewed call for combination therapies. A trial of vitamin E as an adjunct to memantine returned a small functional benefit, and a combination of two approved medications is underway in France.

Perhaps the most radical argument in 2014 about how to speed up the search for better medications came from Rusty Katz, formerly of the FDA. Katz urged the field to focus squarely on achieving large therapeutic effects, even to the point where trials build in futility analyses that set a high bar so that drugs which achieve a small therapeutic benefit get discontinued early in favor of putting efforts toward other drugs or combinations of investigational drugs that might make a much bigger impact. This, Katz said, is the way to realize the treatment goals of the U.S. National Plan to Address Alzheimer’s Disease. Thus far, the AD field has mostly paid lip service to the idea of combination trials. Katz reminded trialists that regulatory hurdles are not the holdup, as FDA guidance is in place.12.24_Nanobubble_0Powerful Packages. Charged ions line the surface of nanobubbles filled with oxygen in this depiction of the structure of RNS60. [Image courtesy of Roy et al., PLOS One, 2014.]

In the year’s curiosity department, researchers at AFFiRiS AG claimed that their placebo worked better than their active vaccine, while a small company in Tacoma, Washington, said it planned to test nanobubbles, teeny packets of oxygen, in AD trials soon.

Others posit that exercise, specific diets, and maintaining cardiovascular health may work as well as drugs. Resveratrol, cocoa flavanols, and control of midlife high blood pressure were all reported to protect against cognitive decline. The FINGER trial underway in Finland offered the strongest evidence to date that lifestyle intervention can improve cognitive function, and perhaps protect against AD.

With the field pushing to test interventions earlier in the disease progression, finding suitable tests to identify patients and measure their progress has been a prime challenge, but 2014 brought much progress there. In June, researchers reported that the ADCS Preclinical Alzheimer Cognitive Construct might fit the bill. Over three years, scores on the ADCS-PACC dropped in “cognitively normal” people who had amyloid in their brain. The ADCS-PACC is being used in the A4 secondary prevention trial, which dosed its first patient in June 2014. Other public-private secondary prevention trials that are up and running, such as DIAN and API, have developed their own, similar composites tapping into the domains of episodic memory, attention, and executive function.

In its effort to open the door to a CSF-based diagnostic for early AD, the Global Biomarkers Standardization Consortium made a step when it published a standardized reference protocol for measuring cerebrospinal fluid Aβ42. The goal is a certified test that performs robustly in multi-center trials and even routine clinical practice worldwide.

Brain Imaging

In 2014, the field sprinted toward an approved diagnostic tracer for in vivo imaging of tau fibrils in the brain. Eli Lilly’s T807 and two classes of compound being developed in Japan, THK-5117 from Tohoku University and PBB3 from the National Institute of Radiological Sciences, Chiba, all look like suitable PET ligands for human tau. Binding of T807 in the brain jibes with the Braak staging pathologists have described in postmortem study, as well as with the areas responsible for cognitive deficits in AD. It also appears to show that tau tangles are limited to the medial temporal lobe during aging, but spread to the cortex when amyloid pathology kicks in.

In Aβ imaging, florbetaben joined florbetapir and flutemetamol in the ranks of approved imaging ligands. Regulatory agencies have defined their use such that they serve to exclude an AD diagnosis in people who test negative for the tracer, however, diagnosing physicians are only slowly beginning to subjugate their clinical impressions to amyloid imaging. Amyloid imaging in 2014 was in a transition phase, with researchers gathering data to show its usefulness in clinical practice in the hopes that the Centers for Medicare & Medicaid Services will reconsider and recommend reimbursement of amyloid PET scans more broadly in clinical settings.

Meanwhile, data from large prospective studies confirmed that people with amyloid in their brains are much likelier to decline cognitively, and research is now focusing on understanding the factors, such as ApoE genotype or cardiovascular comorbidities, that determine how quickly this happens.

Last but by no means least, researchers may have finally cracked the door open on imaging neuroinflammation. GE180, a fluorine-18 ligand that binds a mitochondrial transporter protein and labels activated microglia in mouse brain, is being tested in healthy volunteers and in people with AD and relapsing/remitting multiple sclerosis. Look to data from those trials in 2015.


Researchers continue to seek alternative biomarkers to expensive PET imaging and invasive cerebrospinal fluid analysis. At the Alzheimer’s Association International Conference in July, researchers reported that they can detect Aβ in the retina using a fluorescent dye and a specialized camera. Some scientists believe this may be a more reliable diagnostic than an eye lens-based test, since blood vessels innervate the retina where they may deliver and clear Aβ much like they do in other parts of the brain.

A blood-based test for AD seems no closer to reality despite much effort in this area. A new twist on that approach emerged in the form of lipid analysis. While many labs have analyzed the blood proteome to identify an AD signature, researchers reported in March that plasma phospholipids may hold the key. A panel of 10 blood lipids predicted which patients would develop cognitive problems during the next two to three years. It remains to be seen if this panel specifically detects early AD or other neurodegenerative diseases. Many previous panels of factors in the blood have not translated into diagnostics.


Researchers surprised the AD field in March when they reported that in the DIAN longitudinal study of families with early onset AD, tau in the cerebrospinal fluid tracked lower over time once people showed symptoms of cognitive impairment. Earlier cross-sectional studies had predicted that tau would continue to creep up in the CSF as the disease progressed, but this study, along with a few others, made scientists rethink how to use tau as a biomarker in efficacy trials. CSF tau is no longer considered a dynamic marker of progression. Tau has long been considered a marker of neurodegeneration, released by dead or dying cells, but its story became much more complex, and interesting, when researchers discovered that normal neurons appear to release the protein when stimulated. Others reported that tau, a microtubule protein found in axons and soma, might play a physiological role in dendrites. In response to electrical stimulation, tau appeared to promote synaptic plasticity in dendrites by modifying the actin cytoskeleton.

Scientists are trying to identify the most toxic forms of tau. One group reported a cell-based assay that detects species that promote aggregation of the protein. This biosensor detected tau seeds in transgenic mice long before tau aggregated in the animals’ brains. Extracts from human AD brain tissue, but not CSF, also tested positive in this test. The researchers do not yet know if the tau seeds they can measure are toxic.

10.09_FRET_2_1Seed Sensors. Tau inclusions (green, right) speckle tau biosensor cells one day after treatment with tau fibrils. FRET signals in these cells detect seeds at femtomolar concentrations. [Image courtesy of Holmes et al., PNAS 2014.]

Tau undergoes complex processing steps in neurons, being phosphorylated, acetylated, and cleaved by a variety of proteases. Add asparagine endopeptidase to the latter mix. Researchers reported that knocking out this peptidase prevents cleavage of tau in several places and protects transgenic mice that express mutant forms of human tau. Similarly, others reported that blocking calpain proteases protects mice from tau toxicity, and a small-molecule calpain inhibitor has finally entered Phase 1 testing for AD. Pharmaceutical companies are intrigued by tau glycosylation and are testing inhibitors of the glycoside hydrolase O-GlcNAcase in preclinical experiments. By blocking removal of sugars from tau, these small molecules may prevent tau from forming oligomers or larger aggregates. The year also saw progress in the development of active and passive tau immunotherapies.

In 2014, the momentum of mechanistic research in neurodegenerative diseases shifted away from Aβ in favor of tau and other misfolding proteins. No AD research roundup would be complete without a mention of Aβ, however. In February, the link between the endocytic receptor SORLA and AD pathology grew stronger when researchers found genetic variants in SORLA that associate with early onset AD slowed Aβ clearance. The G511R mutation of SORLA failed to escort Aβ to the lysosome for degradation. In related news, small molecules that stabilize the retromer appeared to quell Aβ production in neurons. The retromer is a protein machine that whisks APP out of endosomes and away from the influence of β-secretase. In neurons, the retromer stabilizer R55 steered APP toward non-amyloidogenic processing via α-secretase.

In 2015, make sure to get your beauty sleep. Evidence continued to build last year that the brain drains Aβ through the glymphatic system, and that this happens best when we sleep and less well as we age. Other support grew for the idea that sleep disturbances put people at risk of AD, as well.

The field still struggles to identify the most toxic form of Aβ in the brain. A carbon fiber microelectrode that can detect Aβ in the brain debuted at the Society for Neuroscience meeting in Washington, D.C. The device can measure concentrations of the peptide every 30 seconds, giving researchers a tool to measure rapid fluctuations in Aβ levels. It potentially could be modified to measure specific Aβ species or other proteins, such as tau.

10.10_Jessica_1_1Deposition in a Dish. After six weeks in three-dimensional gel culture, neurons (green) expressing familial Alzheimer’s mutations form extracellular amyloid deposits (red/yellow). [Image courtesy of Choi et al., Nature 2014]

A cell culture model introduced in 2014 might help researchers pinpoint toxic Aβ species. This model recapitulates the two hallmarks of AD, amyloid plaques and neurofibrillary tangles, in a three-dimensional, gel-based neuron culture. One downside is the model relies on overexpression of APP, a criticism of most of the animal models used for preclinical studies. Two new knock-in APP models that develop amyloid plaques, gliosis, synaptic loss, and cognitive impairment without overexpressing the precursor protein may help with translational research. A BACE1 knock-in model debuted as well. It also develops some of the hallmarks of AD without overexpressing APP or BACE1.


Although geneticists are largely done conducting genome-wide association studies in AD, they continue to glean information from the data, reporting that some GWAS hits not only predispose to AD but accelerate its onset. Others linked GWAS hits to epigenetic changes that may regulate the expression of nearby genes. Scientists have developed different methods to find new genes that increase risk for AD. While GWAS identify commonly inherited sequences, they miss rare variants. For example, a family based approach using whole-genome sequencing identified a single nucleotide polymorphism in the UNC5C gene that predisposes to late-onset AD and potentially other neurodegenerative diseases. UNC5C encodes a protein that promotes apoptosis, or programmed cell death, and the single amino acid change seems to keep the protein turned on. Others have adopted whole-exome sequencing to find variants that might protect against AD in the people most susceptible to it, namely those who are homozygous for ApoE4. In a widely praised study, researchers combined exome sequencing with network analysis to find rare genetic variants that cause hereditary spastic paraplegia. They linked those variants to common biological pathways that underlie neurodegenerative diseases, including AD. Pundits predicted that similar approaches could be used to identify AD-specific genes.


Hexanucleotide repeat extensions in intron 1 of C9ORF72 underlie a quarter of familial FTD cases and about 40 percent of familial ALS cases. In 2013, researchers reported that the intron is transcribed and translated into dipeptide repeats in both sense and antisense directions. Scientists were left to puzzle over which of five potential poly-dipeptides and two RNAs with expanded repeats might explain why this mutation is toxic. Last year brought ample data, but no closure on this question. Some researchers implicated arginine-rich dipeptide repeats, but others favored the RNA. The guanine-rich hexanucleotides in mutant C9ORF72 form structures called G-quadruplexes. These may interfere with similar quadruplexes formed when angiogenin cleaves transfer RNAs, which appear to promote RNA/protein granules that protect cells from stress. Expansions in C9ORF72 cropped up in multiple-system atrophy and pseudodementia, though their involvement in the pathology of these disorders remains uncertain. Researchers investigated small molecules that bind RNA hexanucleotide repeats as a potential treatment for ALS/FTD, and one dipeptide repeat as a potential biomarker in cerebrospinal fluid.

TREM2 and Microglia

After ApoE4, variants in TREM2 are the strongest genetic risk factors for late-onset AD. While the biology behind this association remains murky, 2014 saw both advances and surprises in TREM2 research. In June, researchers revealed that knocking out one copy of this cell surface receptor limited the number of microglia surrounding amyloid plaques in the cortex of APP/PS1 models of AD. Curiously, this dearth of microglia had no effect on plaque burden. Others repeated this data, reporting that mice lacking both copies of the TREM2 gene mounted little microglial response around plaques in APP/PS1 mice and that plaque numbers in the cortex were similar to those in TREM2-positive control animals. Experts in the field are unsure what to make of these data, and rumor has it that other labs have seen greater plaque numbers in TREM2 knockouts. Add to this confusion over which cells make TREM2. At the Society for Neuroscience meeting, researchers claimed that cells in the brain that express this receptor are not brain-resident microglia, but monocytes that infiltrate from the periphery.

Researchers finally got a handle on the function of TREM2, reporting that mutations linked to neurodegenerative diseases scupper phagocytosis. The problem seems rooted in a breakdown in TREM2 processing at the cell surface. The extracellular domain of the protein is shed by α-secretases, much like the soluble extracellular domain of APP. The intramembrane stub goes on to be processed a la Notch and APP C-terminal fragments. The mutations trap TREM2 in the endoplasmic reticulum, the protein never matures, and the extracellular domain never sheds. The shed part of TREM2 ends up in the cerebrospinal fluid, but not in people who carry the disease mutations. Interestingly, some people with AD who have normal copies of TREM2 have less of the soluble domain in the CSF, hinting that the fragment might be a valuable diagnostic marker for weak microglial function. In early 2014 geneticists reported that the R47H TREM2 variant associated with AD also doubled the odds of developing amyotrophic lateral sclerosis.

In 2014 researchers reported that microglial progenitors exist in the brain. This came as a surprise since microglia are believed to arise during development from the yolk sac. Theory had it that cells from this sac made their way to the brain where they became microglia, and then were cut off from other immune cells as the blood-brain barrier formed. But researchers reported that after wiping out all microglia in the brain, their numbers bounced back within two weeks, and the new cells seemed to originate from within the brain. The progenitor cells tested positive for nestin, a neuronal marker, suggesting a wholly unrecognized source of microglia in the brain. In other microglial news, researchers found that when these cells lack progranulin, they fail to clear up deposits of Aβ. This could explain why mutations in the progranulin gene increase the risk for Alzheimer’s.

Connectivity Networks and Neurodegeneration

The last decade has seen evidence grow that Alzheimer’s is as much a disease of cortical neural networks as of neurodegeneration. For example, while the hippocampus atrophies in both semantic dementia and AD, only people with the latter have episodic memory problems. Researchers traced those memory issues to a breakdown in connectivity between the hippocampus and the posterior cortex, rather than to local hippocampal atrophy. Similar breakdowns in neural connectivity in both familial AD and late-onset disease strengthened the idea that Aβ pathology underlies both. In keeping with this, others found that Aβ causes hyperactivation of the entorhinal cortex during memory tasks and that the frontoparietal cortex begins to atrophy early in AD, just as Aβ in the CSF begins to fall, a sign the peptide has begun to accumulate in the brain parenchyma. Some investigators have devised therapies to correct network failures. Transcranial magnetic stimulation designed to improve connections between the hippocampus and other brain regions reportedly strengthened associated memories in healthy volunteers, hinting that one day it may help AD patients remember.

0530_Synaptosome_2The Fabric of a Synapse. A section of a synaptic bouton, containing 60 different proteins, shows crisscrossing actin filaments (purple, from top), and vesicles (cream, right) that travel toward the synapse (bottom, orange). [Image courtesy of Wilhelm et al., 2014, Science.]

Scientists studying human brain connectivity hope to learn much from the Brain Activity Map Project launched in 2013. In the meantime, they are learning more about how the mouse brain is wired, and this should help them better characterize rodent models of human diseases. In the spring, scientists were treated to a high-resolution map of the mouse brain connectome and to the most detailed look yet at the synapse, reporting that a single one contains 300,000 proteins of about 1,000 different types. A whole-body clearing method allowed researchers to visualize entire networks of cells in the mouse, including neurons in the brain and spinal cord. Last but not least, a reconstruction of a famous brain in neuroscience promised to shed new light on human memory. Henry Molaison, known to researchers as H.M., died in 2008 and last January scientists published a three-dimensional digital reconstruction of his brain. In 1953 Molaison had had much of his hippocampus removed to prevent uncontrollable seizures. He was 27. Post-surgery anterograde memory problems presented scientists with their first solid evidence that the hippocampus was essential for memory, and this led to a wealth of research. The three-dimensional reconstruction revealed that the surgery had left much more of the hippocampus intact than had been believed.

Funding and Global Coordination

While researchers continued to lament a poor NIH payline and insufficient funds to support the National Plan, there was a modicum of good news. Biomarkers Across Neurodegenerative Diseases, or BAND, announced $2 million in grants to mine data from the Alzheimer’s Disease Neuroimaging Initiative and the Parkinson’s Progression Markers Initiative. The Accelerating Medicines Partnership, a collaboration among the NIH and 10 industry partners, promised $129.5 million to study biomarkers and therapeutic targets in AD. Congress passed a budget, signed by President Obama, that slated an additional $80 million for the NIA, most of which was to go to fund the National Plan. Perhaps the coolest funding news was the Ice Bucket Challenge, a simple idea that went viral and raised more than $100 million for ALS research. In Europe, the Innovative Medicines Initiative slated €64 million for the European Prevention of Alzheimer’s Dementia Consortium. EPAD will help select at-risk people for secondary prevention trials and assess which interventions should move forward for further testing. Globally, the World Dementia Council, which grew from U.K. Prime Minister David Cameron’s presidency of the G8 in 2013, continued its efforts to coordinate initiatives to accelerate and improve therapy development.


Tom Fagan and Gabrielle Strobel


Note:  Article edited for brevity. See source (above) for list of references.

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The Dementia That Is Not Alzheimer’s Disease

(Science Daily) Lewy body dementia (LBD) — a complex, challenging and surprisingly common brain disease — is often misdiagnosed as its “cousin,” Alzheimer’s disease. And that could lead to devastating results.

According to the Lewy Body Dementia Association (LBDA), accurate and early diagnosis is critical because people with LBD typically have sensitivities to medication, and many drugs prescribed for Alzheimer’s can be very harmful to those with LBD.

Although, LBD is the second most common cause of progressive dementia it is not well recognized by physicians, especially primary care and general health care providers.

“While the symptoms of LBD may be similar to Alzheimer’s and Parkinson’s disease, the treatment strategy is more challenging because fewer medications can be used safely,” warns Howard I. Hurtig, M.D., Chair, Department of Neurology, Pennsylvania Hospital, and member of the LBDA Scientific Advisory Council.

“I cannot overemphasize the need to avoid medications that can worsen the symptoms of LBD. Every patient with this disease and their caregivers should be familiar with the list of acceptable and forbidden drugs.”

Is it Alzheimer’s or LBD?

These two diseases share some clinical and biological similarities that can make them difficult for many physicians to distinguish. Dementia experts are more experienced at differentiating between dementia types.

Alzheimer’s disease affects cognitive function, including making new experiences into memories. The disorder in LBD affects different aspects of cognition, such as problem solving and complex reasoning and movement.

LBDA has just issued a new brochure — Lewy Who? Recognizing when it’s not Parkinson’s or Alzheimer’s Disease — that offers a symptom comparison chart that can help clarify the confusion. It can be downloaded from the LBDA.org website.

A Different Diagnosis

Lewy body dementia, which affects 1.4 million Americans, refers to two related diagnoses: dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). Both DLB and PDD are considered Lewy body dementias.

With DLB, cognitive (thinking) symptoms appear before Parkinson-like movement problems. With PDD, disabling cognitive symptoms do not develop until more than a year after movement problems begin.

LBD is characterized by an abnormal build up of Lewy bodies (alpha-synuclein protein deposits) in the areas of the brain that regulate behavior, memory, movement and personality. The most prominent symptoms of Parkinson’s disease affect motor abilities. Alzheimer’s disease primarily affects areas of the brain involving learning and memory. A specialist like a neurologist, geriatric psychiatrist or a neuropsychologist may be needed to distinguish the symptoms and provide an accurate diagnosis.


The above story is based on materials provided by Lewy Body Dementia Association. Note: Materials may be edited for content and length.

Lewy Body Dementia Association. (2014, December 19). The dementia that is not Alzheimer’s disease. ScienceDaily. Retrieved December 28, 2014 from www.sciencedaily.com/releases/2014/12/141219160457.htm

Copyright 2014 by ScienceDaily, LLC or by third-party sources, where indicated.


Large Studies Agree: Brain Amyloid Accelerates Cognitive Decline

(Alz Research Forum) With the advent of PET amyloid imaging, researchers discovered that as many as a third of cognitively healthy older adults go about their business with brains loaded with amyloid. What does this mean for their cognitive future? Are all these people destined to develop Alzheimer’s disease?

Initial studies suggested that brain amyloid greatly ramps up the risk for cognitive decline and a clinical diagnosis of dementia, but it was clear that settling the question would take more years of observational study in larger numbers of people. At the 7th Clinical Trials on Alzheimer’s Disease (CTAD) conference in Philadelphia November 20 to 22, speakers expanded the body of evidence, presenting data from large prospective studies.

All the researchers reported that in their samples of otherwise healthy older adults, people with high brain amyloid levels declined cognitively over periods of two to three years, while those without brain amyloid remain stable.

To be sure, the rate of cognitive decline varied from person to person, and some people with brain amyloid did stay sharp over these short time frames. It remains unclear whether these people are simply early in the trajectory of disease, or protective factors operate in their brain to help preserve cognition.

Speakers discussed some factors that accelerate or slow disease progression, including ApoE genotype and hypertension. Tantalizingly for trial designers, deeper analysis of the data pouring in from prospective studies of preclinical and prodromal stages suggest that people’s decline on biomarkers and clinical measures during this phase happens in a linear fashion, simplifying the necessary statistics for both disease modeling and trial design.

12.23_Last_CTADRegardless of ApoE genotype, older AIBL participants without brain amyloid stayed cognitively stable over 4.5 years. Among those with brain amyloid, ApoE4 carriers declined much faster. [Image courtesy of Paul Maruff.]

Several studies have found that brain amyloid associates with lower baseline cognitive scores and faster decline (see Snitz et al., 2013Mar 2014 news story), particularly when it occurs along with a marker of neurodegeneration (see Sep 2014 news story). However, these studies tended to be small, enrolling 200 people or fewer.

To see if the link would hold up in a larger sample, Ming Lu of Avid Radiopharmaceuticals, a subsidiary of Eli Lilly, analyzed data from 1,017 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who had undergone a florbetapir PET scan. Lilly manufactures florbetapir.

Almost half of the participants had been diagnosed with mild cognitive impairment (MCI) at baseline, and the remainder were either cognitively normal or diagnosed with Alzheimer’s disease.

At CTAD, Lu reported that over three years, participants whose brains were free of amyloid stayed stable on cognitive tests, including the ADAS-Cog11, MMSE, and CDR-SB. In contrast, people with positive amyloid scans declined, with MMSE scores diverging significantly from amyloid-negatives at six months, and ADAS-Cog11 scores at 24 months.

Moreover, for people with MCI, those with brain amyloid had almost five times the odds of progressing to AD over the course of the study than those without. However, Lu noted that brain amyloid explained only some of the individual variation in decline.

What determines how fast a given person declines? Lilly’s Paula Trzepacz combed through 24-month follow-up data from about 1,200 ADNI participants to hunt for clues. She used statistical analyses to look for subpopulations with different rates of decline, and identified four separate groups.

The 470 people without brain amyloid fell into two categories of unequal numbers. About 90 percent remained cognitively stable, and they were equal parts cognitively normal or diagnosed with MCI. The remaining 10 percent of the amyloid-negatives surprised Trzepacz. Their cognitive scores dropped sharply over the study period. Most had been clinically diagnosed with MCI or AD; however, given the absence of amyloid it is likely that this was incorrect, and they suffered from a non-amyloid form of neurodegeneration, Trzepacz suggested.

Other studies have identified people with “suspected non-amyloid pathology” (SNAP) as well (see Aug 2013 conference storyNov 2013 news storyNov 2014 news story). This potential SNAP group also had somewhat different symptoms from typical AD, having more difficulty with daily activities than memory, Trzepacz noted.

Trzepacz showed that the 722 people with brain high amyloid fell into two groups. One-quarter of them declined significantly during the study; most of these people had been diagnosed clinically with AD, some with MCI. The remaining three-quarters declined only slightly on the cognitive measures. They included mostly people who had been clinically diagnosed with MCI, and close inspection showed that they had higher cognitive scores at baseline. This cohort may be earlier in the trajectory of Alzheimer’s disease, Trzepacz suggested.

The factor that best predicted rapid cognitive decline among amyloid-positive people was a low cognitive score at baseline, pointing perhaps to cognitive reserve as protection against the long-term cognitive effects of brain amyloid. Overall, the presence of amyloid does affect the trajectory of cognitive decline, and this occurs independently of the person’s diagnosis, Trzepacz concluded.

Paul Maruff of Cogstate in Melbourne, Australia, showed data from the Australian Imaging, Biomarker, and Lifestyle Flagship Study of Ageing (AIBL) that supported the hypotheses that factors in addition to amyloid level influence the rate of cognitive decline in early AD.

AIBL is one of several prospective imaging and cognition studies that are generating empirical data to test and flesh out the hypothetical Alzheimer’s biomarker staging scheme. AIBL data show that once a person crosses the threshold of amyloid positivity, additional amyloid accumulates at a linear rate for about the next 20 years until Alzheimer’s symptoms appear.

Importantly, this finding allows researchers to use linear models to predict progression in prodromal stages—the time period on which preventions trials increasingly are going to focus. “Think of the otherwise sigmoid Jack staging curves without the little bit at the beginning and the little bit at the end,” Maruff quipped.

Maruff analyzed AIBL data from some 200 healthy controls and 50 people with MCI who were being followed over three years. People without brain amyloid remained cognitively stable during this time, regardless of whether they were diagnosed as healthy or with MCI, he reported. On the other hand, people with amyloid all declined at about the same average rate, regardless of diagnosis (see Lim et al., 2014Lim et al., 2014).

How do the rates of amyloid accumulation and memory loss compare to each other, and to other biomarker change? To relate these very different measures, Maruff calculated the standard deviations of each marker based on the population averages at baseline. He found that in preclinical AD (cognitively normal controls with brain amyloid), amyloid and cognition both worsened by about half a standard deviation over three years.

Hippocampal volume shrank only by about one-tenth of a standard deviation. By contrast, in prodromal AD (mild cognitive symptoms and brain amyloid), amyloid, cognition, and hippocampal volume all worsened at the same rate, again half a standard deviation over three years. The acceleration of hippocampal atrophy thus represents a big biomarker difference between the two conditions, Maruff said. He noted that because all three biomarkers change at equivalent rates in prodromal AD, they might all be useful as progression markers in clinical trials.

On the other hand, subjective memory assessments made by patients or caregivers change more slowly, and therefore may be a less-sensitive marker, Maruff added (see Hollands et al., 2015). This finding appears to pour some cold water on recent hopes that subjective memory concerns could be formalized into a useful predictor early on in the symptomatic phase (see Sep 2014 news story).

Maruff noted inconsistencies between the AIBL finding that subjective memory may be insensitive to early amyloid-related changes and the findings in other cohorts, for example the Harvard Aging Brain Study, that subjective memory is a sensitive indicator of abnormal amyloid. These, he said, may result from the different ways in which the samples were recruited. Healthy older adults in the AIBL study were recruited from the community and hence may have been less aware of subtle changes in their memory than volunteers recruited from hospital outpatient clinics.

Maruff also clarified that although the average rate of decline is the same in these groups, quite a bit of individual variation occurs. One factor influencing this is ApoE genotype. ApoE4 carriers with amyloid decline faster than non-carriers with amyloid, Maruff said.

Other speakers dug more deeply into the role of ApoE and other modifying factors. For example, Karen Rodrigue of the University of Texas at Dallas had previously reported that ApoE4 carriers with hypertension accumulated amyloid faster than carriers with normal blood pressure, particularly if the hypertension was uncontrolled (see May 2013 news story). That study involved only 118 people, raising the question of whether the findings would hold up in a larger sample.

At CTAD, Rodrigue described her analysis of 1,013 ADNI participants with normal cognition, MCI, or AD. Forty-four percent had at least one copy of ApoE4, and 65 percent had high blood pressure. In agreement with earlier findings, Rodrigue found that people with both risk factors had significantly more amyloid than those who had one or neither. Among the ApoE4 carriers, hypertension nearly doubled the risk of having a positive amyloid scan.


In this analysis, a person’s clinical diagnosis did affect the relationship. Specifically, among cognitively normal people, having both risk factors worsened amyloid only if they were over 70. In the MCI group, the interaction between ApoE, hypertension, and amyloid load did not reach statistical significance. In ADNI, the MCI cohort was defined by clinical diagnosis, and biomarker analysis later revealed that many of them did not have brain amyloid. People with AD had the strongest interaction between these factors.

Overall, the data presented at CTAD strengthened the case that amyloid hastens cognitive decline, but also underscored that pure clinical diagnoses poorly capture the underlying pathology. In many current clinical trials, researchers screen potential participants for amyloid pathology or an Aβ/tau CSF signature to ensure that their symptoms are most likely due to Alzheimer’s (see Part 4 of this series).


Madolyn Bowman Rogers


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