Our findings show that quantitative gait dysfunction predicts risk of cognitive decline in initially non‐demented older adults. The pace factor predicted decline in executive function, the cognitive domain primarily involved in vascular dementia.30
A 1 point increase in the pace factor predicted decline on executive function measured by the Digit Symbol Substitution18
(by 29%) and the Letter Fluency tests19
(by 92%). A 1 point increase in the rhythm factor was associated with episodic memory17
decline (by 107%). Quantitative gait dysfunction also predicted risk of dementia. A 1 point increase in both the rhythm (by 48%) and variability factors (by 37%) predicted risk of developing dementia, adjusted for age, sex and education. The associations remained robust after additional adjustments for other potential confounders, such as medical illnesses, cerebrovascular disease, baseline cognitive status, preclinical dementia and neurological gaits.
This study has a number of limitations that need to be considered. While our gait variables were selected based on our and prior studies,5,6,7,8,9
all possible aspects of gait were not measured or analysed. However, most other gait variables (such as step length) either can be derived or are highly correlated with our selected variables. Subjects walked at their normal pace. In future studies, walking at different speeds, or using stressors such as the walking while talking test31
could be studied as predictors of cognitive decline. This nested cohort study was necessarily restricted to subjects who received quantitative assessments since 2001 in our study, but subjects seen previously in our cohort were not differentially excluded and our analyses accounted for staggered entry.29
Our small sample size, short follow‐up and multiple analyses necessitate caution. However, to our knowledge, this is among the first and largest study to report longitudinal associations between multivariate quantitative gait measures and cognition.5,6,7,8,9
The confidence intervals for significant associations in our analyses were narrow, but we may have seen stronger associations with additional follow‐up. While some diagnostic misclassification is inevitable, we have reported good reliability for our dementia diagnostic procedures using pathology as the gold standard.2,25,26
The upper brainstem contains neurons that control musculature for gait through their projections to the lower brainstem and spinal cord.32
These brainstem nuclei are, in turn, under the influence of descending inputs from the basal ganglia, cerebellum and cortical motor areas.32,33
It is assumed that stride length and velocity (pace) are controlled supraspinally by phasic output from the basal ganglia to the supplementary motor area, whereas spinal and brainstem mechanisms may determine cadence (rhythm).32,33
Neural substrates of gait variability are less understood.11
It has been suggested that regulation of gait variability is automated and requires minimal cognitive input in healthy adults, but may be perturbed in the presence of disease.11,12
The specificity of the association of pace with executive function and vascular dementia (and not incident dementia overall) favours a vascular aetiology. We have reported a higher prevalence of mixed vascular pathology with advancing age in subjects with dementia in this cohort.25
It is possible that some of our associations reflect mixed pathology although neuroimaging was used to assign dementia subtypes. Decreased velocity and stride length (which load on the pace factor) in older adults were associated with white matter disease and strokes on neuroimaging in a prior study.34
Then again, the association of gait rhythm and variability with dementia in our study was significant even when controlled for cerebrovascular disease or excluding subjects with strokes. The presence of temporal lobe atrophy on imaging studies has been previously correlated with poor mobility, independent of cerebrovascular disease.35
Gait rhythm predicted memory decline, which can start many years before Alzheimer's disease is diagnosed.1
Increased gait variability has been reported in individuals with Alzheimer's disease.11,12
However, Alzheimer involvement of the motor cortex is said to occur only late in the disease process and gait disturbances early in the disease is considered an exclusion criterion.2,36,37,38
The low prevalence of neurological gaits among subjects in the worst factor score tertiles suggests that quantitative gait abnormalities may not have clinical correlates. Alternatively, non‐specific gait patterns associated with quantitative gait abnormalities may be under‐recognised by clinicians. Our study protocol2,3
required clinicians to judge whether gait is normal or abnormal (including non‐specific unsteady gaits) before assigning subtypes, minimising this possibility. A recent clinicopathological study reported that Parkinsonian gait in the absence of idiopathic Parkinson disease was correlated with substantia nigra neurofibrillary tangles, even in cases without clinical Alzheimer's disease or with minimal Alzheimer pathology.39
These findings raise the possibility that Alzheimer pathology may involve brain regions regulating gait early but the subtle quantitative gait abnormalities may be overshadowed by behavioural symptoms. The unique relationships of individual gait factors with specific cognitive domains suggest aetiological roles for both vascular and neurodegenerative mechanisms. These findings also identify potential gait pathways, which may be amenable to intervention if our results are validated.
The strengths of this study include our validated diagnostic procedures,2,13,25,26
systematic quantitative assessments2,3,9
and minimal attrition. We conducted a number of sensitivity analyses to account for potential confounders such as preclinical dementia and neurological gaits. Given the limitations of categorical clinical gait classifications, the continuous quantitative gait measures may better help characterise motoric manifestations of the preclinical stages of dementia. Clinicians were blinded to quantitative gait data before and at the diagnostic conferences, minimising bias and diagnostic circularity. The quantitative measures are easily collected, do not require attached monitoring devices and do not require extensive training or specialised personnel.
Gait factors may be conceptualised as summary risk scores that can be easily derived for use in clinical or research settings. A 1 point (1 SD) increase in the factor score is associated with SD unit changes in all component variables with a larger contribution from higher loading variables. Factor analysis has been used to explain other complex physiological phenomenon,40
and appears to be well suited for studying gait, as suggested by our findings and others.41
This approach enabled us to identify empirically defined and statistically independent factors representing distinct gait domains. The single gait variables identified from the three factors support our main findings, and will facilitate comparisons with other studies.5,6,7,8
We also identified single variables other than velocity,5,6,7,8
such as swing time, that predicted dementia.
In conclusion, quantitative gait dysfunction is a marker for preclinical stages of dementia. The quantitative gait abnormalities and neuropsychological impairments at study onset can be interpreted as the consequence of accumulating dementia pathology. Quantitative gait performance predicts dementia even after accounting for baseline cognitive performance. However, our intent is not to replace neuropsychological tests in dementia assessment but to understand motoric manifestations of early dementia stages.2,5,6,7,8,9
Vascular and non‐vascular substrates, neuroanatomical pathways and physiological processes underlying quantitative gait dysfunctions should be further explored to develop effective preventive interventions to reduce the burden of dementia.