Pupillary response test as a potential early diagnosis biomarker of Alzheimer’s disease

Shen, Robert; Turana, Yuda; Handajani, Yvonne Suzy; , Lukas; Widjaja, Nelly Tina; Budiyanta, Nova Eka; Sumarta, Reiner Adi Putra; Wahyudi, Celine Gabriella; Wijaya, Hans Timothy; Barus, Jimmy Fransisco Abadinta; Suryakusuma, Linda; Sasmita, Poppy Kristina; Sani, Tara Puspitarini

doi:10.1590/1980-5764-DN-2024-0153

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Original Article • Dement. neuropsychol. 19 • 2025 • https://doi.org/10.1590/1980-5764-DN-2024-0153 linkcopy

Pupillary response test as a potential early diagnosis biomarker of Alzheimer’s disease

Exame do reflexo pupilar como potencial biomarcador para diagnóstico precoce da doença de Alzheimer

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Psychometric tests as the gold-standard for diagnosing Alzheimer’s disease (AD) tend to be inefficient, nonreproducible, and are affected by many factors. Research on pupillary response in AD is not novel; however, there has not been a single study providing the diagnostic value of pupillary response parameters as a recommendation for their potential use for early AD diagnosis.

Objective To investigate pupillary response parameters as clinical biomarkers of AD that are dynamic, affordable, efficient, and objective (non-operator dependent).

Methods A cross-sectional study on pupillary response parameters was conducted, with comparative and correlation-analytical tests between pupillary response and the Mini-Mental State Examination cognitive score. The diagnostic value of pupillary response parameters was obtained by determining the cutoff point of each parameter by calculating the sensitivity, specificity, Youden’s maximum index, Area Under the Curve (AUC) value from the Receiver Operating Characteristic (ROC) curve, positive predictive value, and negative predictive value. Pupillary response parameters were classified into four types: size, response time, velocity, and acceleration.

Results There were 128 respondents in total, consisting of cognitively-unimpaired young adults, cognitively-unimpaired older adults, and cognitively-impaired older adults. The pupillary response values without involving acceleration parameters were reliable. The diagnostic value of change in pupil size, the maximum and the average constriction velocity parameters have normal cognitive cutoff scores of 1.77 mm (sensitivity: 61.3%; specificity: 80%; positive predictive value [PPV]: 47.76%; negative predictive value [NPV]: 86.88%), ≥4.43 mm/s (sensitivity: 70.4%; specificity: 58.5%; PPV: 46.93%; NPV: 78.48%), and 3.12 mm/s (sensitivity: 70.4%; specificity: 55.0%; PPV: 45.83%; NPV: 77.5%), respectively.

Conclusions Pupillary response, in particular changes in constriction and velocity, can be potentially used as an early diagnostic biomarker for AD.

Keywords
Alzheimer Disease; Biomarkers; Dementia

Variables		n (%) Total	n (%) Cognitively-unimpaired young adults	n (%) Cognitively-unimpaired older adults	n (%) Cognitively-impaire older adults (MCI or AD)
Age group (years)	Young adults (≤40)	51 (39.84)	51 (39.84)	-	-
Age group (years)	Older adults (≥60)	77 (60.16)	-	37 (28.91)	40 (31.25)
Sex	Men	41 (32.03)	14 (10.93)	19 (14.84)	8 (6.25)
Sex	Women	87 (67.97)	37 (28.90)	18 (14.06)	32 (25.00)
Years of education	<9 years	65 (50.78)	0 (0)	27 (21.09)	38 (29.68)
Years of education	≥9 years	63 (49.22)	51 (39.84)	10 (7.81)	2 (1.56)
Cognitive group	Cognitively-unimpaired (MMSE 24-30)	88 (68.75)	51 (39.84)	37 (28.91)	-
	Cognitively-impaired (MMSE 0-23)	40 (31.25)	-	-	40 (31.25)

	Cronbach’s alpha*	Item-rest correlation	Median (Minimum–Maximum)			p-value Kruskal-Wallis
	Cronbach’s alpha*	Item-rest correlation	Cognitively-unimpaired young adults	Cognitively-unimpaired older adults	Cognitively-impaired older adults (MCI or AD)	p-value Kruskal-Wallis
D1	0.6328	0.7443	6.150 (3.427-7.568)	5.445 (2.897-6.778)	5.032 (3.350-7.171)	0.0001
D2	0.7708	0.1016	3.566 (2.070-6.287)	3.815 (2.343-4.900)	3.588 (2.420-5.545)	0.8826
ΔD	0.6619	0.6882	2.335 (1.057-4.648)	1.510 (0.176-2.883)	1.325 (0.510-2.742)	0.0001
LT	0.7583	0.1480	0.267 (0.067-0.700)	0.267 (0.133-0.667)	0.300 (0.167-1.700)	0.0761
CT	0.7687	0.4714	0.167 (0.067-0.367)	0.167 (0.067-0.267)	0.200 (0.100-0.467)	0.1112
MCV	0.6408	0.7374	5.690 (3.529-10.210)	4.161 (1.016-6.988)	4.089 (1.862-19.454)	0.0001
ACV	0.6188	0.7562	4.024 (2.046-9.633)	3.077 (1.012-4.382)	3.0715 (1.636-13.041)	0.0001
MCA	Excluded (alpha<0.6)		43.560 (14.597-124.401)	26.604 (4.536-26.360)	27.299 (8.322-115.034)	0.0001
ACA	Excluded (alpha < 0.6)		27.014 (9.496-66.273)	15.411 (3.369-36.603)	16.4965 (3.962-103.907)	0.0001
MMSE	-	-	30	27 (24-30)	19.5 (9-23)	0.0001

	Participants (n)		Normal cutoff value (% ROC)	Sv (%)	Sp (%)	Maximum Youden’s Index	PPV (%)	NPV (%)	OR (95%CI)
	Cognitively-impaired	Cognitively-unimpaired	Normal cutoff value (% ROC)	Sv (%)	Sp (%)	Maximum Youden’s Index	PPV (%)	NPV (%)	OR (95%CI)
ΔD	Impaired	32	≥1.77 mm (73.11)	61.3	80.0	0.413	47.76	86.88	6.05 (0.64–0.82)
ΔD	Normal	8	≥1.77 mm (73.11)	61.3	80.0	0.413	47.76	86.88	6.05 (0.64–0.82)
MCV	Impaired	23	≥4.43 mm/s (65.07)	70.4	58.5	0.289	46.93	78.48	3.23 (0.55–0.75)
MCV	Normal	17	≥4.43 mm/s (65.07)	70.4	58.5	0.289	46.93	78.48	3.23 (0.55–0.75)
ACV	Impaired	22	≥3.12 mm/s (61.75)	70.4	55.0	0.254	45.83	77.5	2.91 (0.51–0.73)
ACV	Normal	18	≥3.12 mm/s (61.75)	70.4	55.0	0.254	45.83	77.5	2.91 (0.51–0.73)

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Academia Brasileira de Neurologia, Departamento de Neurologia Cognitiva e Envelhecimento R. Vergueiro, 1353 sl.1404 - Ed. Top Towers Offices, Torre Norte, São Paulo, SP, Brazil, CEP 04101-000, Tel.: +55 11 5084-9463 | +55 11 5083-3876 - São Paulo - SP - Brazil
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[1] Abbreviation: MMSE, Mini-Mental State Examination; n, Number.