Falls are the leading cause of fatal injuries in older adults, causing more than 800,000 hospitalizations and about 30,000 deaths in the U.S. every year.

Some risk factors are well-known – advanced age, problems with vision or balance, muscle weakness – but an under-recognized factor is early Alzheimer’s disease.

Older people in the earliest stages of Alzheimer’s, before cognitive problems arise, are more likely to suffer a fall than people who are not on track to develop dementia.

Researchers at Washington University School of Medicine in St. Louis have found that, in older people without cognitive problems who experience a fall, the process of neurodegeneration that leads to Alzheimer’s dementia already may have begun.

The findings, available online in the Journal of Alzheimer’s Disease, suggest that older people who have experienced falls should be screened for Alzheimer’s and that new strategies may be needed to reduce the risk of falling for people in the disease’s early stages.

“In the world of fall research, we generally say that you’re at risk of falling if you lose strength and balance,” said co-senior author Susan Stark, Ph.D., an associate professor of occupational therapy, of neurology and of social work.

“If you lose strength and balance, the recommended treatment is to work on strength and balance.

But if someone is falling for another reason, maybe because his or her brain has begun accumulating Alzheimer’s-related damage, that person might need a different treatment entirely.

We don’t yet know what that treatment might be, but we hope we can use this information to come up with new treatment recommendations that will reduce the risk of falls in this population.”

In 1987, John C. Morris, MD, then a trainee at Washington University, discovered that older people with Alzheimer’s dementia are more than twice as likely to suffer a traumatic fall than people of the same age without dementia.

Morris is now the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology and head of the university’s Charles F. and Joanne Knight Alzheimer’s Disease Research Center.

Since Morris’ discovery more than three decades ago, scientists have learned that the brains of Alzheimer’s patients start undergoing changes decades before memory loss and confusion become apparent.

First, plaques of amyloid proteins form, then tangles of tau protein. Some brain areas begin to shrink, and communication networks between distant parts of the brain start to decay.

Stark and colleagues have shown that the link between Alzheimer’s and falling holds true even during the silent phase of the disease: People with so-called preclinical Alzheimer’s are at increased risk of falling despite having no apparent cognitive problems.

To better understand why people without cognitive symptoms are at risk of falling, first author Audrey Kelemen, a graduate student in Stark’s lab, and colleagues followed 83 people over age 65 for a year.

All participants were assessed as cognitively normal by a qualified neurologist at the beginning of the study. Each participant filled out monthly calendars recording any falls and underwent brain scans for amyloid and for signs of atrophy and impaired connectivity.

The researchers discovered that the presence of amyloid in the brain alone did not put people at increased risk of falling but that neurodegeneration did. Participants who fell had smaller hippocampi – brain regions that are devoted to memory and that shrink in Alzheimer’s disease.

Their somatomotor networks – webs of connections that are involved in receiving sensory inputs and controlling movement – also showed signs of decay. The researchers concluded that falling is most likely to occur in the neurodegeneration phase of preclinical Alzheimer’s – the last five years or so before memory loss and confusion arise.

“Since I started working on this project, I’ve started asking my patients about falls, and I can’t tell you how often that has helped me start understanding what is going on with the individual,” said co-senior author Beau M. Ances, MD, Ph.D., the Daniel J. Brennan, MD, Professor of Neurology and a professor of radiology and of biomedical engineering. Ances treats patients who have dementia and other neurological conditions on the Washington University Medical Campus.

“When a person’s mobility is being diminished, even though the person looks very normal, that could be a sign that something needs further evaluation,” Ances said. “It’s actually a really important potential marker that should make us say, ‘Wait a minute. Let’s dive into this more. Are there other things that go along with it?'”

The researchers have begun further experiments to better understand why brain changes in Alzheimer’s put people at risk of falling, so they can develop fall-prevention recommendations. In the meantime, simple changes could go a long way toward protecting older people from devastating falls, Stark said.

“You can prevent a lot of falls just by making the environment safer,” Stark said.

“Simple changes could help and can’t hurt: making sure the tub isn’t slippery; making sure you can get up easily off the toilet; balance and strength training; reviewing your prescriptions to see if certain medications or combinations of medications are increasing the risk of falling.

Until we have specific fall-prevention treatments for people with preclinical Alzheimer’s, there are still plenty of things we can do to make people safer.”

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The prevalence of neurodegenerative disorders is increasing due to changes in population demographics. It is estimated that by 2020 there will be 42 million people with a diagnosis of dementia worldwide,[1] in whom the most common causes of dementia will be Alzheimer’s disease (AD), Vascular dementia (VAD) and the Lewy body dementias.[2,3]

Falls are a significant cause of injuries, loss of confidence, increased morbidity, institutionalisation and mortality in all older people,[4,5] but particularly those with dementia.[6,7]

People with dementia recover less well after a fall than those without dementia.[8]

In view of the suffering caused by such falls, and the enormous cost of caring for people with dementia who have fallen, there is an urgent need to optimise the prevention of falls in this group.

Importantly, there have been no prospective studies of multifactorial risk factors for falling specific to the population with dementia.

Previous studies have identified multiple risk factors for falls in the older population as a whole, in a variety of settings. In multivariate studies significant risk factors include fall history, gait, balance and mobility impairments, visual impair- ment, cognitive impairment, fear of falling, environmental hazards, muscle weakness and incontinence.[9]

In community settings, impairment on various cognitive measures has been shown to be a risk factor for falls, although dementia itself has only been examined and shown to be a risk factor for falls in community dwelling people with Parkinson’s disease,[10] and in residents of extended care settings.[7,11]

The identification of potentially modifiable risk factors has been critical in the development of effective multifactorial falls intervention pro- grammes, particularly for older people at high risk of falling.[12] It is likely that falls in dementia are also multi-factorial in origin, possibly with risk factors similar to those identified in the general older population, but there may be other potentially modifiable factors specific to dementia.

It is thought that those with Lewy body (LB) dementias are at particular risk, and a history of recurrent falls is accepted as a supporting feature for the diagnosis of dementia with Lewy bodies (DLB).[13]

Only one previous multifactorial intervention study has exclusively recruited participants with dementia.[14] Interventions were based upon those used in successful trials in people without dementia, and the study did not show a significant reduction in falls or number of fallers.

However, 70% of the participants in this trial lived in institutional settings, most had moderate to severe cognitive impairment and all had already presented  to  hospital  with a fall. A recent systematic review of interventions to prevent falls in hospitals and care homes suggested that effect size was smaller in trials where the prevalence of dementia was high, but meta-regressions were limited by incomplete reporting of dementia prevalence.[15]

It remains possible that multifactorial interven-  tions would be successful in patients with less severe dementia, but we suggest that interventions in future trials should be tailored to potentially modifiable factors which can be shown to predict falls   in community dwelling people with mild-moderate  dementia. 

There is therefore an urgent need to understand risk factors for   falls in dementia to enable a more tailored and effective  intervention to be developed.

Participants in this study completed a multifactorial baseline assessment of putative predictors of falls and then completed prospective falls diaries for a period of 12 months, which is known to be a robust method of ascertainment of falls.

We aimed to identify potentially modifiable predictors of falls in older people with mild-moderate dementia, the majority of whom lived in the community.

Results

Participants

289 patients were considered for inclusion; 65 participants were excluded (Figure 1). 179 (80%) of 224 eligible participants agreed to take part (39 controls, 38 AD, 32 VAD, 30 DLB and 40 PDD). 116 (83%) of 140 participants with dementia and all of the controls were residing in the community. A summary of baseline characteristics of the participants is shown in table 1.

Prevalence of falls

81.6% of diaries were returned (82.9% in those participants with dementia). During the 12 month follow up period 65.7% of participants with dementia had at least one fall, compared with 35.9% of controls (relative hazard ratio (HR) adjusted for age and sex: 3.03, 95% confidence intervals (CI) 1.71–5.35). With respect to dementia subtypes, the prevalence of falls in AD was 47%; VAD 47%; DLB 77% and PDD 90%. Figure 2 shows the survival curves until the occurrence of a fall for each diagnosis.

Incidence of falls

The incidence of falls in dementia was 9118 per 1000 person years, which was significantly higher than in controls (1023; incidence density ratio (IDR) adjusted for age and sex: 7.58, 95% CI: 3.11– 18.5), (table 2). If participants living in care homes were excluded, the incidence of falls in dementia was 8763 which remained significantly higher than in controls (IDR: 9.56, 95% CI: 6.07–15.1).

With respect to dementia subtypes, the incidence of falls, adjusted for age and sex, was higher in all dementia subtypes than in controls (table 2): AD: 2486 falls/1000 person years (IDR: 1.95; 95% CI: 1.01–3.78), VAD: 3135 (IDR: 1.77, 95% CI: 1.17–2.69),DLB: 9087 (IDR: 6.06, 95% CI: 3.53–10.4) and PDD: 19000 (IDR: 20.5, 95% CI: 10.4–40.2). The incidence of falls in PDD was higher than in AD (IDR: 10.5, 95% CI: 3.32–33.1), VAD (IDR: 11.6, 95% CI: 5.73–23.3), and DLB (IDR: 3.38, 95% CI:2.66–4.31). The incidence of falls in DLB was also higher in AD (IDR: 3.10,  95%  CI: 1.16–8.28)  and VAD  (IDR: 3.41, 95% CI:1.96–5.95). The incidence of falls in VAD was not significantly higher than in AD (IDR: 0.907, 95% CI: 0.504–1.63).

Univariate predictors of falls in dementia

Significant modifiable and non-modifiable predictors of falls in all participants with dementia are shown in table 3. Significant predictors included diagnosis of Lewy body disorder, history of falls or recurrent falls in the preceding 12 months, use of cardioactive medication, abnormal gait or balance score, Cornell depression score $10, autonomic symptom scale .7, autonomic neuropathy, symptomatic OH and time taken for blood pressure to return to baseline on standing. Age and increased physical activity were protective.
However, when univariate analyses were stratified by diagnosis, only duration of dementia, history of falls or recurrent falls in the preceding 12 months, use of cardioactive medication, autonomic symptom scale greater than 7 and time taken for blood pressure to return to baseline on standing remained significant predictors of falls. Increased physical activity remained protective.

Multivariate predictors of falls and recurrent falls in dementia

Significant potentially modifiable predictors were entered into multivariate analyses in the order: age, gender, Tinetti gait score, Cornell depression score, physical activity score, autonomic symptom score, symptomatic orthostatic hypotension, use of cardioactive medication and time for systolic blood pressure to return to baseline on standing.

In the first model including all participants with dementia, predictors retained were Cornell depression score, total autonomic symptom score and symptomatic orthostatic hypotension. In the second model, stratified by diagnosis, predictors retained were symptomatic orthostatic hypotension, use of cardioactive medica- tion and physical activity score, which was protective (Table 4).

Discussion

In the largest prospective study of predictors of falls in dementia to date, we have demonstrated that older people with dementia experience 8 times more incident falls than those without dementia. These figures are even more striking when only community dwelling people with dementia are considered, with incidence in people with dementia nearly 10 times higher than in those without dementia. Patients with Lewy Body dementias (DLB or PDD) were at the highest risk, with DLB patients sustaining 6 times the number of falls in the control group and PDD 20 times

more falls. The annual incidence of falls was higher in the LB dementias than in all other groups studied and much higher than any previous reports in older people[33]. Incidence of falls was higher in PDD than in DLB.

To our knowledge, this is the first study which has identified predictors specific to dementia, including the identification of non- modifiable predictors such as a diagnosis of Lewy body disorder, longer duration of dementia and previous history of falls or recurrent falls.

These factors will be useful in identifying individuals at particular risk, who may benefit from further assessment and intervention. Even more importantly, a number of the predictors identified are potentially modifiable, and should be included as key elements of a multifactorial intervention.

These factors included use of cardioactive medications, autonomic symptoms, symptomatic orthostatic hypotension, depression and limitation of physical activity. We suggest that interventions targeted towards these predictors could reduce the burden of falls related morbidity and mortality in community dwelling people with mild-moderate dementia.

Our study has a number of strengths which reinforce our findings. This was a prospective study and the majority of participants had mild-moderate dementia and were residing in the community.

The incidence of falls was determined by completion of daily diaries, with the support of a caregiver where appropriate, with an adequate follow up period. The use of this method is particularly important because it has the highest sensitivity for accurate recording of falls.

The number of participants in our study was high (179); 80% of those approached agreed to take part and compliance with fall diary returns was also high. Statistical analysis was strengthened by the use of Cox regression models and loglinear analysis of incidence densities, thus taking account of censoring of falls diaries in some participants.

All analyses included adjustment for age and gender and the inclusion of multivariate analyses enabled efficient estimate of significant associations while adjusting for a number of confounding factors simultaneously.

There are some potential limitations to this study. Ideally, we would have recruited both groups using random sampling from a community population. Unfortunately the scale of such an exercise would have been well beyond the resources available for this study. Healthy older people volunteering for participation in research in response to advertisements are often fitter than the older population at large, but interestingly the incidence of falls in our control group was very similar to that found in most community based studies, suggesting that the control group was reasonably representative, despite the limitations of using this recruitment method.

The recruitment of the patient participants from secondary care clinics rather than from primary care may have biased the sample towards those with more progressive disease. However, in the northern region of the UK, suspected cases of Parkinson’s disease are routinely referred to a secondary care physician specialising in movement disorders (either a Neurologist or Geriatrician).

These patients should, therefore, be reasonably representative of all patients presenting to primary care physicians with symptoms suggestive of PD. There is a greater likelihood of patients with AD or VAD not being referred to secondary care as dementia is often undetected, or not managed by a specialist in memory disorders.

The reader should therefore bear in mind that participants in this study may have had more severe or progressive disease than those generally seen in primary care. In interpreting our results, consideration should be given to the need to stratify for dementia subtypes in univariate and multivariate analyses. Some of the predictors were not significant when analyses were stratified by dementia subtype, probably because these predictors were actually surrogate markers of a diagnosis of a Lewy body disorder, which itself predicted falls. In comparison with the proportions in the general population the LB dementias were over represented in our study, in order to make valid comparisons between dementia subtypes.

Prior to commencement of our study we identified only two studies of falls in dementia which included a fully multifactorial assessment of risk factors, the first of which had an inadequate follow up period,[34] and in the second the primary outcome was fall related serious injuries rather than falls.[35]

Both of those studies included fewer than 100 participants, and neither included a control group. Two studies published since we commenced our study have included multifactorial baseline assessments, but the first of these was small (only 42 participants with advanced AD).[36]

The second was a high quality study of 124 participants in which neuroleptic drug use and grade 2 white matter lesions predicted falls in multivariate analyses, but only participants with AD were included, and there was no control group[37]. The design of our study addressed these issues; to our knowledge, it is the first to examine falls in both AD and non-AD dementias over an adequate follow up period.

Exclusive to our study was the phasic measurement of blood pressure using beat-to-beat recordings, thus enabling detection of both magnitude and timing of blood pressure changes. Symptom- atic OH and the length of time blood pressure fell below baseline rather than the magnitude of the drop were predictive of falls.

Our group has previously shown an association between intermittent hypotension and white matter lesions,[38] and this resonates with the findings of Horikawa et al. that grade 2 white matter lesions predicted falls in multivariate analyses[37].

White matter lesions can be associated with abnormal gait,[39] and it is possible that intermittent symptomatic hypotension against  a  background  of  gait and balance instability exacerbates the likelihood that an older person will fall. A higher level of physical activity was a protective factor in our study.

The physical activity scale  measured  all  physical activity rather than wandering, which has been shown in one study to be a predictor of falls in dementia.[40] It is likely that the more active patients were those with fewer problems with mobility, whereas the participants with disturbed  mobility  restricted their activity because of fear of  falling,  thus  having  fewer opportunities to fall.

We believe that randomised multifactorial intervention trials to prevent falls in mild-moderate dementia should now be made a priority. Possible management strategies could include management of the potentially modifiable factors identified in this study;  for example, the use of selective serotonin reuptake inhibitors for depression, manipulation of cardiovascular medications, adequate hydration and targeted drug therapies such as fludrocortisone and midodrine for OH.

Such a focus would differ from multifactorial interventions in older people without dementia, which prioritise strength and balance exercises that are more  difficult  for  those with impairment of recall to continue following initial intervention. It is possible that encouragement of overall physical activity may    be successful in prevention of falls in dementia. However, such an

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More information: Audrey Keleman et al, Falls Associate with Neurodegenerative Changes in ATN Framework of Alzheimer’s Disease, Journal of Alzheimer’s Disease (2020). DOI: 10.3233/JAD-200192