Abstract Body: Introduction: Autonomic nervous system dysfunction has been demonstrated in Alzheimer’s disease. Impaired autonomic function represented by aberrant heart rate variability (HRV) may precede cognitive decline in older age. However, longitudinal evidence linking midlife HRV to later-life cognition is limited, and prior studies have typically assessed only a narrow range of cognitive domains. We hypothesized that loss of normal HRV in late midlife would be associated with future cognitive decline, as evidenced by poorer performance on global cognitive tests such as Addenbrooke’s Cognitive Examination–III (ACE-III) and trajectories of decline in verbal memory and visual search speed.

Methods: The sample consisted of 1,032 participants from the Medical Research Council National Survey of Health and Development, a British cohort born in 1946. HRV measurements from a 3-lead ECG taken at age 60-64 included SDNN (standard deviation of normal-to-normal beats), HFn (normalised high frequency) power, LFn (normalised low frequency) power, PSD² (power spectral density) and HRV triangular index. The association of HRV with three types of cognitive outcomes were tested: single time point ACE-III score at 68-70 years using generalised linear models; and longitudinal verbal memory and visual search speed trajectories produced from four repeat tests between ages 43 and 70 using linear mixed models and growth curve modelling.

Results: LFn power, HFn power, and the LF/HF ratio were significantly associated with ACE-III scores in univariate models (p <0.05). In models adjusted for sex, socioeconomic position across life, psychological well-being, BMI, prior stroke, and systolic blood pressure, higher LFn power (β = 0.11, 95% CI 0.03, 0.20, p = 0.005) and lower HFn power (β = −0.09, 95% CI −0.20, −0.03, p = 0.007) remained independently associated with a higher ACE-III score. Increased PSD² predicted greater decline in verbal memory (β = −4.66, 95% CI −8.1, −1.2, p = 0.008), while reduced SDNN (β = 0.31, 95% CI 0.01, 0.62, p = 0.044) and HRV triangular index (β = 1.5, 95% CI 0.06, 2.9, p = 0.043) were associated with greater decline in visual search speed.

Conclusions: Vagally mediated HRV measures were associated with global cognitive dysfunction in later life and 27-year trajectories of decline in verbal memory and visual search speed. These findings suggest that aberrant HRV in late midlife may serve as a non-invasive biomarker of ongoing and future cognitive decline.