Subscribe to eTOC

Falls Are Associated with Markers of Neurodegeneration in Cognitively Normal Adults

Article In Brief

Cognitively normal older adults who experienced falls also had markers of neurodegeneration, such as amyloid uptake and smaller hippocampal volume on imaging measures. The research suggest falls in cognitively normal older adults may serve as a behavioral biomarker of preclinical Alzheimer's disease.

Falls in cognitively normal older adults could potentially serve as a behavioral marker of preclinical Alzheimer's disease (AD), researchers suggested in a paper published September 15 in the Journal of Alzheimer's Disease.

The findings were based on a cross-sectional analysis of structural and functional MRI and PET measures of amyloid uptake, brain volumetrics, and global resting state-functional connectivity (rs-fc) intra-network signature on MRI in cognitively normal adults who kept a calendar of falls over a one-year period. (The global rs-fc intra-network signature measures connectivity between brain networks when subjects are in a resting state.) The researchers compared imaging data with similar measures from preclinical AD participants who had not recorded falls.

Falls in cognitively normal older adults correlated with markers of neurodegeneration, such as amyloid uptake and smaller hippocampal volume (p=0.004). Amyloid-positivity alone did not lead to more falls, however. Rather those who had increased amyloid and more disrupted connectivity (on rs-fc MRI), particularly in the somatomotor and primary sensory networks, had a greater risk of more falls.

“Not everyone who has a fall is going to develop AD, but it is something that you should be asking about among patients; we can't just think about memory complaints alone,” said study author Beau M. Ances, MD, PhD, MS. FAAN, the Daniel J. Brennan, MD professor of neurology at Washington University in St. Louis, MO.

Clinicians should inquire about other physical changes that individuals are experiencing. This information can help clinicians address the individual's needs, Dr. Ances said.

“We work with a great team of occupational therapists, and if individuals are having repeated falls, if they are having difficulties getting in and out of the bathroom or the tub, we can assess their home environment. We can do certain kinds of things so that individuals can stay in their homes and be comfortable and be safe, and that can make a huge difference for the family as well as the individual who may be developing AD,” he added

Study Details, Findings

To look closely at the association between neurodegeneration and falls, the study team evaluated 83 cognitively normal individuals who had been assessed by the Clinical Dementia Rating scale. The research used tailored calendar journals to collect data on falls on these individuals over a one-year period.

“We verified falls both with the individual as well as other caregivers who could report and be a collateral source for helping us evaluate that,” Dr. Ances explained.

Within two years of falls, the participants underwent structural functional MRI and amyloid PET. Using standard cutoffs, cognitively normal participants were dichotomized by amyloid PET status.

The team compared the relationship between the global rs-fc intra-network signature and amyloid accumulation among those who did and did not fall among amyloid-positive participants. In addition to having a smaller hippocampal volume, those who fell had a negative correlation between global rs-fc intra-network signature and amyloid uptake (R = -0.75, p=0.012).

“This means that within those individuals who had falls a loss of connections within the brain was associated with increased amyloid uptake,” Dr. Ances told Neurology Today.

The researchers also found a trend toward a positive correlation between global rs-fc intra-network signature and amyloid uptake among preclinical AD participants who didn't fall (R = 0.70, p=0.081).

“It's really the presence of amyloid and tau that is really starting to lead to changes in the brain, which are then reflected in those functional connections in the brain,” Dr. Ances said. “Because those functional connections are no longer as strong between these various brain networks, individuals may be more susceptible to having falls. This tells us that falls could be an important evaluation tool for individuals,” he added.

More research is underway in which the investigators are going into homes to evaluate these patients, noted Dr. Ances. “We are looking at these falls and the trajectories of these patients longitudinally,” he said. “We will continue to use these biomarkers, and other markers at home, to report on how they are doing in the home setting. That's where our next efforts are focused.”

Expert Commentary

This is a very useful and important cross-sectional study connecting neurodegeneration to factors other than cognition, said Sudha Seshadri, MD, FAAN, a professor of neurology and founding director of the Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases at the University of Texas Health Science Center in San Antonio.

“Obviously, we have achieved an understanding of amyloid-related neurodegeneration in the brain. And the most obvious and distressing part of AD is the loss of memory and thinking, but when the brain has changes, it affects more than just cognition,” she added.


“Not everyone who has a fall is going to develop AD, but it is something that you should be asking about among patients; we cant just think about memory complaints alone.”—DR. BEAU M. ANCES


“This study highlights the importance of understanding that association in terms of its biology. It may help us perhaps better prevent falls, and potentially use something like a simple gait test as a marker.”—DR. SUDHA SESHADRI

“Falls are the other big problem with older adults, and because falls were often dealt with by other physicians and geriatricians, we have tended to think of them as a related to muscle strength and bone density,” Dr. Seshadri said. “It is related to those things, but there is [also] a very important neurologic component to solve. This study highlights the importance of understanding that association in terms of its biology. It may help us perhaps better prevent falls, and potentially use something like a simple gait test as a marker,” Dr. Seshadri told Neurology Today.

“I'm excited by this study as I think it recognizes the need to look at the physical and other aspects of amyloid-related neurodegeneration as well as other types of neurodegeneration,” Dr. Seshadri said.

Douglas W. Scharre MD, CMD, FAAN, professor of clinical neurology and psychiatry in the Ohio State University Wexner Medical Center, who was not involved in the study, agreed. “Common sense may tell us that the more your brain is damaged by AD, the more likely it will not work as well to prevent falls. This study looks at volume loss of the brain in particular areas and looks for loss in neural networks and connections between different parts of the brain to see if that is associated with increased falls,” he said.

“The findings suggests that the more advanced the preclinical disease, the more at risk they are for falling. Practically speaking, it is universally good practice to educate patients on fall prevention as eliminating any falls is worthwhile,” Dr. Scharre added.

Dr. Scharre pointed out that this research team previously published work on falls in preclinical AD based on PIB amyloid PET and CSF tau-to-amyloid ratios and had previously associated increased amyloid in the brain with more falls. But this paper added functional and structural MRI to amyloid PET, he said.

“The study was underpowered in proving the association between falls and AD because some of the other neurodegenerative dementias may not have been entirely captured,” noted Kevin Conner, MD, a neurologist at the Texas Health Arlington Memorial Hospital and with Neurology Inpatient Physician Services, a Texas Health Physicians Group practice. Dr. Conner noted that the study duration was relatively short, and perhaps more positive findings would have been found with a longer duration.

Falls are difficult to assess because there can be many factors at play when a person falls, and just because a person falls doesn't mean they have AD, Dr. Conner noted. Falls may be related to a range of factors like peripheral neuropathies, amyotrophic lateral sclerosis, stroke, spinal cord injuries, or even vitamin deficiencies, Dr. Conner continued.

“I think what this study tells me is that if you have a patient, who is having falls, and you have ruled out some of the other reasons behind the falls that you need to think about AD as a potential etiology for the fall itself. If you have a patient who is cognitively impaired and is falling, then it may be worth doing additional studies looking specifically looking for AD or for some of the other neurodegenerative dementias that can cause falls, like Lewy Body disease, frontotemporal dementia, or Parkinson's disease,” Dr. Conner told Neurology Today.


Drs Ances and Conner reported no disclosures. Dr. Scharre disclosed relationships with Acadia, BrainTest, Biogen, InSightec, vTv therapeutics, Eisai, Eli Lilly, Biogen, Roche, AZTherapies, Biohaven, and Novartis. Dr. Seshadri disclosed relationships with Biogen.

Link Up for More Information

• Keleman A, Wisch JK, Bollinger RM, et al. Falls associate with neurodegenerative changes in ATN framework of Alzheimer's disease J Alzheimers Dis 2020; Epub 2020 Sept 15.