Biomarkers

Pupillary light response (PLR) alterations have been observed in individuals with Alzheimer's disease and related dementias (ADRD). Little is known about the predictive utility of the PLR as a biomarker for ADRD or general cognitive decline. In the present study we determined if the PLR was cross-sectionally associated with mild cognitive impairment (MCI) during late midlife, as well as whether it was predictive of conversion to MCI over a 6-year follow-up.

Data were utilized from waves 2 (mean age=61.7) and 3 (mean age=67.6) of the Vietnam Era Twin Study of Aging (VETSA), a population-based cohort of men. MCI status was based on Jack-Bondi criteria with impairment defined as performance >1.5 SD below the mean on 2+ tests within a cognitive domain. Pupil response was assessed at wave 2 with NeurOptics PLR-200 pupillometers. PLR measures included peak constriction amplitude, constriction latency, mean constriction velocity, recovery time, and dilation velocity. All analyses controlled for age, race/ethnicity, initial pupil diameter, device, total number of anticholinergic medications, and clustering of twin pairs. Participants reporting a significant history of eye injury, eye surgery, ocular medications, or glaucoma were excluded. Longitudinal analyses were restricted to participants designated as cognitively normal at the first assessment.

In cross-sectional analyses (N = 1070) reduced peak constriction amplitude was significantly associated with higher likelihood of having MCI (OR = 1.76; 95% CI = 1.22; 2.53). The association was observed for both amnestic and non-amnestic MCI subtypes. In longitudinal analyses (N = 734) dilation velocity was significantly associated with conversion to amnestic MCI at the 6-year follow-up (OR = 1.97; 95% CI = 1.22; 3.17).

These results demonstrate that aspects of the pupillary light response are significantly associated with MCI at late midlife and predictive of conversion to amnestic MCI over a 6-year follow-up, suggesting its utility as an easily acquired, non-invasive biomarker for risk of cognitive decline and ADRD prior to overt impairment. The observed associations are consistent with either hypoactivity in parasympathetic anticholinergic systems and/or hyperactivity in locus coeruleus-norepinephrine systems in preclinical AD, and possibly dysfunction in photosensitive melanopsin expressing retinal ganglion cells in preclinical AD.