It has been reported that slowing of gait may precede development of cognitive impairment.^5,6,7,8 However, gait is a complex motor behaviour with many measurable facets besides velocity, and with an intricate relationship to different aspects of cognition.⁹ Moreover, single gait variables are often highly correlated with one another so that their independent effects on risk of cognitive decline and dementia may be hard to observe while adjusting for other gait variables. To address this issue, we used factor analysis to identify independent gait domains derived from quantitative assessments.^9,10 Gait variability has been linked to multiple adverse outcomes in older adults, including Alzheimer's disease.^11,12 However, its role in predicting dementia is not established. Hence we included gait variability measures in our analyses.

Based on our and other studies^2,5,6,7,8,9 we hypothesised that quantitative gait assessments may help reveal subtle alterations in brain function early in the course of the dementia. Our aim was to examine the relationship of quantitative gait parameters with decline in general and specific cognitive domains in a population of non‐demented older adults. We also studied whether quantitative gait parameters could predict risk of incident dementia. Identifying quantitative gait markers of preclinical dementia may provide new insights into early biological stages of dementia, improve diagnosis and risk assessment procedures, and facilitate development of novel preventive strategies.

Table 2​2 shows the characteristics of the participants at enrolment. Subjects with incident dementia were older at entry. There were no significant group differences in abnormal gait subtypes.^2,3 Most gait abnormalities were of mild severity (61.9%). Moderate (35.4%) and severe (2.7%) gait abnormalities were less common in this community based sample as previously reported.³ A higher proportion of subjects who developed dementia reported limitations on instrumental but not basic activities of daily living. While the mean scores on the cognitive test scores were in the normal range, subjects who developed dementia had worse scores compared with controls at enrolment.

Table 3​3 shows impairment in multiple baseline gait variables compared with controls in initially non‐demented subjects who went on to develop dementia.

Factor analysis with varimax rotation yielded exactly three orthogonal factors that accounted for 87% of the variance in baseline quantitative gait performance (table 4​4).¹⁰ The factor with the highest variance had strong loadings by velocity and length measures, and was termed “pace” factor. The second loaded on variables reflecting gait rhythm such as cadence and timing, and was termed “rhythm” factor. The final factor loaded heavily on gait “variability” measures.^11,12 Mean factor score was 0 (SD 1). The factors can be conceptualised as summary risk scores with higher scores denoting worse performance.

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 protocol^2,3 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 assessments^2,3,9 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.