Previous studies have shown that the pathological accumulation process of Alzheimer's disease (AD) may last for many years, and cognitive impairment is not yet manifested in the early stages, but pathological changes have quietly occurred. In addition, the pathological state of AD and related dementias may not only lead to cognitive impairment, but may also have an impact on gait and hand strength in the elderly. However, there is a lack of evidence to account for the sequential changes in motor function decline and cognitive decline through the use of trajectories over time (i.e., "longitudinal trajectories").
The results of a study published in The Lancet Healthy Longevity showed a decline in overall cognitive ability and motor function (gait function and hand strength) in older adults. Moreover, the decline in gait function and hand strength preceded cognitive decline by up to 10 years. Decreased hand strength may help identify AD risk; Gait decline may be a biomarker of early vascular cognitive impairment rather than a preclinical biomarker of AD.
In addition, most cognitive decline is caused by brain pathology, while exercise decline is not entirely caused by age and brain pathology, and gait decline alone is not enough to predict dementia risk.
截图来源：The Lancet Healthy Longevity
This cohort study used data from older adults from three cohort studies of chronic diseases of aging to describe the trajectory of cognitive and motor function decline over time in older adults and to explore its association with AD and related dementia pathology.
The inclusion criteria for all three cohort studies were: ≧ 65 years of age at the time of enrollment with no clinically diagnosed dementia, participants who agreed to donate their brains for posthumous evaluation of dementia pathology, and who agreed to have at least three annual assessments of cognitive ability and motor function (gait function and hand strength). The research team assessed participants' overall cognitive abilities based on 19 neuropsychological tests, assessed hand strength by grip and pinch, and scored gait based on the number of steps and time to walk 2.44 m and turn 360°.
A total of 1303 participants with cognitive ability and motor measurements were included in the analysis, with a mean age of death of 90.3 years, of whom 905 (69%) were women and 398 (31%) were men. At a median follow-up of 9 years, it was found that:
- Participants experienced a decrease in the average of cognitive ability, gait function, and hand strength.
- On average, the decline in gait function and hand strength precedes the decline in cognitive ability. Participants' cognitive abilities remained roughly stable for 25-15 years before death, after which the decline began and accelerated 5 years before death. In contrast, gait function and hand strength showed a consistent declining trend throughout the study period.
▲ Participants' cognitive ability (A) and motor function (B: gait function; C: Hand strength) decline trajectory (Image source: Reference [1])
Further analysis of the changes of 10 pathological features of AD and related dementias showed that the pathological manifestations of AD and related dementias were associated with the decline of cognitive ability and motor function, and the initiation time of the association was also different.
- Only tau tangles (accumulation of abnormal proteins associated with cognitive impairment), Parkinson's disease pathology, and massive cerebral infarction were associated with the decline of cognition, gait function, and hand strength, while cerebral amyloid angiopathy was not associated with any of these changes.
- Hand strength is more closely associated with pathological manifestations than gait decline. Only the above three pathological manifestations were associated with gait function decline, and there were three other pathological manifestations associated with hand strength decline, including hippocampal sclerosis, TDP-43, and arteriolar sclerosis.
- The association of tau tangles with cognitive decline predates its association with decline in gait function and hand strength. Specifically, tau tangle was associated with cognitive decline in the 11 years prior to death, with the association with hand strength decline beginning at 3.57 years before death and gait decline at 3.49 years before death.
- The association between massive cerebral infarction and gait function decline began 9.25 years before death (P<0.0001), earlier than its association with cognitive ability and hand strength decline, and its association with the latter two began at 6.65 years (P=0.0005) and 2.66 years (P=0.024) before death, respectively.
- The association of Parkinson's disease pathology with cognitive decline appeared earlier (from 7.93 years before death) and with the decline of gait function (from 4.60 years before death) or hand strength decline (from 5.80 years before death).
Similar results were obtained in four sensitivity analyses.
The research team also analysed the association between age at death and decline in cognitive ability and motor function. The results showed:
After excluding the influence of AD and related dementia pathologies, the association between age and cognitive decline was greatly weakened. These findings suggest that most of the cognitive decline observed in older adults is attributable to AD and related dementia pathological changes, including hippocampal sclerosis, TDP-43, Parkinson's disease pathology, massive cerebral infarction, microinfarction, and atherosclerosis.
However, even after excluding the effects of AD and related dementia pathologies, the association between age and motor function decline still exists, especially the magnitude of gait function decline is more pronounced than the decline in hand strength. This means that the decline in motor function, especially gait function, is not only related to age and brain pathology, but also that the decline in gait function alone is not sufficient to predict the various adverse health outcomes or types of AD and related dementias. This is also in line with current medical understanding, as the potential neural pathways related to cognition are almost exclusively contained within the brain, while the potential pathways related to motor function involve not only the brain, but also the brainstem, spinal cord, peripheral nerves, and muscles.
▲After excluding the pathological association of AD and related dementia, the association between age and cognitive decline was weakened (A), and the association between age and gait function decline (B) and hand strength decline (C) was still obvious, and the magnitude of gait function decline was more obvious (Image source: Reference [1])
Overall, the findings suggest that in older adults, the average decline in motor function precedes cognitive decline. Massive cerebral infarction rather than tau tangles are associated with the phenomenon that gait decline precedes cognitive decline. This suggests that there is a need for further research on whether gait impairment can be used as a clinical marker for preclinical vascular cognitive impairment, and other influencing factors associated with gait dysfunction, such as obesity, musculoskeletal disorders (including osteoarthritis of the back, hips, and knees), and other comorbidities, as well as the relationship between pathology of extracerebral motor pathways and gait decline.
Contemporaneous review articles of the study note that the study provides interesting insights into the association between motor decline and the neuropathological basis of dementia, adds evidence on the relationship between gait, vascular health, and dementia, and contributes to a better understanding of the observational evidence that has accumulated in future studies.