The presence of multiple frontal release signs (FRS), or primitive or regressive reflexes, in older adults who are cognitively intact, was associated with an increased risk of developing dementia.

In a longitudinal cohort of more than 800 community-dwelling older adults, participants who were cognitively normal at baseline but had two or more FRS were nearly twice as likely to develop dementia as those without multiple FRS. Moreover, the presence of two or more FRS was associated with lower baseline cognitive performance in some tests and a faster rate of decline.

“The widespread examination of FRS in the aging population has ecological validity as a tool to augment preclinical detection of impending cognitive decline,” the investigators led by Lauren G. Bojarski, DO, MS, assistant professor of cognitive neurology at the West Virginia University in Morgantown, West Virginia, wrote.

“FRS may serve as accessory evidence heightening clinical suspicion of imminent cognitive decline as we search for more effective and practical methods to screen the aging population at risk for development of a degenerative dementia,” the researchers added.

The study was published online on June 5 in JAMA Network Open.

Testing Prognostic Value

FRS are normally present in infancy and gradually disappear as the brain matures in early life. This includes grasp, rooting, snout, glabellar tap (Myerson sign), and palmomental reflexes. Their reemergence later in life has been associated with neurologic injury and neurodegenerative disease, including dementia.

Although individual FRS are relatively common in otherwise healthy older adults, prior studies have shown that the presence of multiple FRS is more strongly associated with neurologic dysfunction.

Given the growing burden of dementia and the need of early detection, investigators assessed whether FRS could serve as a practical screening tool to identify individuals at risk for future cognitive decline before dementia onset.

The investigators analyzed longitudinal data from the University of Kentucky Alzheimer’s Disease Research Center research cohort collected between 2005 and 2024. The study included 873 adults aged 70 years or older (mean age, 76.9 years; 60.4% women).

Participants had a mean of 16.1 years of education. At baseline, 672 participants had intact cognition, and 201 participants had mild cognitive impairment (MCI) or other mild cognitive deficits. Individuals with dementia at baseline were excluded.

Neurologists evaluated participants annually for the presence of grasp, palmomental, Gegenhalten, snout, glabellar, suck, and jaw-jerk reflexes. Participants were classified as FRS positive if they had at least two reflexes and FRS negative if they had one or none.

Average follow-up was 7.2-7.5 years in cognitively intact participants and 4.0-4.4 years in those with MCI.

At baseline, FRS positivity was observed in 8.8% of cognitively normal participants and 23.9% of those with mild impairment.

Participants underwent annual cognitive assessments and consensus diagnostic reviews.

The primary outcome was dementia. The investigators used cause-specific hazard models that accounted for the competing risk for death and adjusted for age, sex, education, Mini-Mental State Examination score, and gait abnormalities.

FRS Tied to Dementia Risk

Among participants who were cognitively normal at baseline, 25.4% of those who were FRS positive progressed to dementia during follow-up compared with 14.5% of those who were FRS negative.

FRS positivity was associated with a significantly increased risk for dementia in this group, with an adjusted hazard ratio (HR) of 1.80 (95% CI, 1.04-3.13). The unadjusted HR was 1.78 (95% CI, 1.02-3.09).

Among participants with baseline mild impairment, FRS positivity was not significantly associated with dementia risk (adjusted HR, 1.13; 95% CI, 0.74-1.74).

Longitudinal analyses suggested that cognitively normal participants with multiple FRS experienced faster decline in certain cognitive domains. Memory performance declined more rapidly among FRS-positive participants, with a mean annual change in memory z score of -0.025. Executive function also declined more rapidly, with a mean annual change of -0.017. These findings were unchanged in sensitivity analyses adjusting for APOE epsilon 4 status.

The investigators also found that participants who were cognitively normal and FRS positive had poorer baseline performance in attention, executive function, and language compared with their FRS-negative counterparts.

The most commonly observed reflexes were palmomental and glabellar reflexes.

Limitations of the study include its single-center design and a cohort that was predominantly White and highly educated, potentially limiting generalizability. FRS assessments may also have been influenced by inter-rater variability, and the use of two versions of the Uniform Data Set cognitive battery may have introduced measurement differences.

A Preclinical Screening Tool?

The investigators suggested that FRS may be most useful during the preclinical stage of cognitive decline rather than after impairment has already developed.

Given that FRS assessment can be completed in < 2 minutes during a standard neurologic examination, “FRS positivity may serve to be an excellent adjunct tool in screening individuals with intact cognition once treatment is developed and approved for those with preclinical AD [Alzheimer’s disease],” they wrote.

As a next step, the investigators suggested evaluating the relationship between FRS and emerging blood-based AD biomarkers to determine whether bedside findings are associated with underlying neurodegenerative changes.

The study was funded by the National Institute on Aging through the University of Kentucky Alzheimer’s Disease Research Center. Disclosure information for study authors is available in the original study publication.