The time course of motor and cognitive decline in older adults and their associations with brain pathologies: a multicohort study

Abstract

Background: Many studies have reported that impaired gait precedes cognitive impairment in older people. We aimed to characterise the time course of cognitive and motor decline in older individuals and the association of these declines with the pathologies of Alzheimer's disease and related dementias.

Methods: This multicohort study used data from three community-based cohort studies (Religious Orders Study, Rush Memory and Aging Project, and Minority Aging Research Study, all in the USA). The inclusion criteria for all three cohorts were no clinical dementia at the time of enrolment and consent to annual clinical assessments. Eligible participants consented to post-mortem brain donation and had post-mortem pathological assessments and three or more repeated annual measures of cognition and motor functions. Clinical and post-mortem data were analysed using functional mixed-effects models. Global cognition was based on 19 neuropsychological tests, a hand strength score was based on grip and pinch strength, and a gait score was based on the number of steps and time to walk 8 feet and turn 360°. Brain pathologies of Alzheimer's disease and related dementias were assessed at autopsy.

Findings: From 1994 to 2022, there were 1570 eligible cohort participants aged 65 years or older, 1303 of whom had cognitive and motor measurements and were included in the analysis. Mean age at death was 90·3 years (SD 6·3), 905 (69%) participants were female, and 398 (31%) were male. Median follow-up time was 9 years (IQR 5-11). On average, cognition was stable from 25 to 15 years before death, when cognition began to decline. By contrast, gait function and hand strength declined during the entire study. The combinations of pathologies of Alzheimer's disease and related dementias associated with cognitive and motor decline and their onsets of associations varied; only tau tangles, Parkinson's disease pathology, and macroinfarcts were associated with decline of all three phenotypes. Tau tangles were significantly associated with cognitive decline, gait function decline, and hand function decline (p<0·0001 for each); however, the association with cognitive decline persisted for more than 11 years before death, but the association with hand strength only began 3·57 years before death and the association with gait began 3·49 years before death. By contrast, the association of macroinfarcts with declining gait function began 9·25 years before death (p<0·0001) compared with 6·65 years before death (p=0·0005) for cognitive decline and 2·66 years before death (p=0·024) for decline in hand strength.

Interpretation: Our findings suggest that average motor decline in older adults precedes cognitive decline. Macroinfarcts but not tau tangles are associated with declining gait function that precedes cognitive decline. This suggests the need for further studies to test if gait impairment is a clinical proxy for preclinical vascular cognitive impairment.

Funding: National Institutes of Health.

Figure 1:. Trajectories of cognitive and motor decline

The blurred grey lines illustrate the trajectories of participants’ repeated measures of cognition (A), gait function (B), and hand strength (C). The superimposed blue curves show the mean functional mixed-effects model-derived trajectories of the three functions, and the shaded blue areas surrounding the blue curves indicate 95% CIs.

Figure 2:. Associations of tau tangles and macroinfarcts with cognitive and motor decline

(A) Association of tau tangle with cognitive decline. (B) Association of tau tangles with gait function decline. (C) Association of tau tangles with hand strength decline. (D) Association of macroinfarcts with cognitive decline. (E) Association of macroinfarcts with gait function decline. (F) Association of macroinfarcts with hand strength decline. The solid blue lines indicate the associations and the shaded blue areas indicate 95% point-wise CI. The dashed line represents zero, and by comparing its course with the blue line and shaded blue area an association between a brain pathology and cognitive or motor decline can be inferred. Only trajectories below the dashed line indicate a significant association. Please note that the y-axis scale is different in the panels showing the associations with cognitive decline vs motor decline because of the stronger associations between pathologies of Alzheimer’s disease and related dementias and cognitive decline. This figure includes only the associations of tau tangles and macroinfarcts to illustrate the differences in association of a neurodegenerative and a cerebrovascular brain pathology with cognitive and motor decline. Associations of all the pathologies with cognitive and motor decline are in the appendix (pp 18–23).

Figure 3:. Association between age at death and cognitive and motor decline

(A) Association of age with cognition. (B) Association of age with gait function. (C) Association of age with hand strength. Each chart shows the results from two functional mixed-effects models: one model included age alone and one included brain pathologies and age. Blue and red lines indicate the associations and the shaded blue and red areas indicate 95% point-wise CI. The dashed line represents zero, and by comparing its course with the blue and red lines and shaded blue and red areas, an association between age at death and cognitive or motor decline can be inferred. Only trajectories below the dashed line indicate a significant association.

Figure 4:

Residual cognitive and motor decline after regressing out the associations of the brain pathologies of Alzheimer’s disease and related dementias without and with demographics The charts show the residual cognitive function decline (A), gait function decline (B), and hand strength decline (C) after regressing out the associations of the brain pathologies, and the residual cognitive function decline (D), gait function decline (E), and hand strength decline (F) after regressing out the associations of the brain pathologies together with age at death, sex, education, and race using functional mixed-effects models. The grey lines show person-specific residual decline, the superimposed blue curves show the mean residual decline derived from the same models, and the shaded blue area around the curves shows the 95% CIs.