PRND 3′UTR polymorphism may be associated with behavioral disturbances 
in Alzheimer disease

Figures & data

Table 1 Baseline demographic and behavioral characteristics of the study population

	AD (n = 99)	MCI (n = 48)	p value
Age, years (±SD)	76.63 ± 6.17	71.02 ± 6.61	<0.001
Female gender, n (%)	67 (67.7)	38 (79.2)	0.176
Education, years (±SD)	9.68 ± 3.68	11.83 ± 4.13	0.001
MMSE, points (±SD)	19.65 ± 4.63	27.6 ± 1.71	<0.001
CDR, points (±SD)	1.34 ± 0.48	0.5 (0)	<0.001
Behavioral symptoms during the study, n (%)	89 (89.9)	34 (70.8)	0.007
Mean number of NPI symptoms, n (±SD)	4.19 ± 2.76	1.44 ± 1.27	<0.001
Significant behavioral burden (>3 symptoms on the NPI), n (%)	54 (54.5)	4 (8.3)	<0.001
Delusions, n (%)	29 (29.3)	2 (4.2)	<0.001
Hallucinations, n (%)	21 (21.2)	0	<0.001
Agitation/aggression, n (%)	40 (40.4)	2 (4.2)	<0.001
Depression/dysphoria, n (%)	49 (49.5)	8 (16.7)	<0.001
Anxiety, n (%)	38 (38.4)	14 (29.2)	0.36
Elation/euphoria, n (%)	4 (4)	0	0.30
Apathy/indifference, n (%)	60 (60.6)	10 (20.8)	<0.001
Disinhibition, n (%)	13 (13.1)	1 (2.1)	0.03
Irritability/emotional lability, n (%)	62 (62.6)	14 (29.2)	<0.001
Aberrant motor behavior, n (%)	30 (30.3)	0	<0.001
Sleep and night-time behavior change, n (%)	40 (40.4)	14 (29.2)	0.25
Appetite and eating change, n (%)	29 (29.3)	4 (8.3)	<0.001

AD, Alzheimer disease; CDR, Clinical Dementia Rating; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; NPI, Neuropsychiatric Inventory; SD, standard deviation

Table 2 Genotypic distribution and allele frequencies of the studied polymorphisms

Genotype/allele frequencies, n (%)	AD (n = 99)	MCI (n = 48)	p value
APOE-ε4 dose
ε4 (-)	43 (43.4)	34 (70.8)	0.004
1 × ε4	46 (46.5)	10 (20.8)
2 × ε4	10 (10.1)	4 (8.3)
ε4 (-)	43 (43.4)	34 (70.8)	0.003
ε4 (+)	56 (56.6)	14 (29.2)
CYP46-rs754203
C/C	18 (18.2)	7 (14.6)	0.55
C/T	41 (41.4)	17 (35.4)
T/T	40 (40.4)	24 (50)
C allele frequency	0.39	0.32	0.4
T allele frequency	0.61	0.68
CYP46-i2 new
C/C	83 (83.8)	37 (77.1)	0.4
C/T	12 (12.1)	10 (20.8)
T/T	4 (4.1)	1 (2.1)
C allele frequency	0.9	0.875	0.8
T allele frequency	0.1	0.125
PRNP-codon 129
M/M	37 (37.4)	19 (39.6)	0.96
M/V	51 (51.5)	24 (50)
V/V	11 (11.1)	5 (10.4)
M allele frequency	0.63	0.65	1.0
V allele frequency	0.37	0.35
PRND AD (n = 64) MCI (n = 28)
Codon 26
C/C	58 (90.6)	25 (89.3)	1.0
C/T	6 (9.4)	3 (10.7)
Codon 56
C/C	63 (98.4)	26 (92.9)	0.2
C/T	1 (1.6)	2 (7.1)
Codon 174
C/C	15 (23.4)	6 (21.4)	0.9
C/T	31 (48.5)	13 (46.4)
T/T	18 (28.1)	9 (32.2)
C allele frequency	0.48	0.45	1.0
T allele frequency	0.52	0.55
3′UTR
C/C	20 (31.2)	7 (25)	0.8
C/T	30 (46.9)	15 (53.6)
T/T	14 (21.9)	6 (21.4)
C allele frequency	0.55	0.52	1.0
T allele frequency	0.45	0.48

AD, Alzheimer disease; MCI, mild cognitive impairment

Table 3 Associations between genetic polymorphisms and neuropsychiatric symptoms in Alzheimer disease

Polymorphism	BPSD symptom in AD, n (%)		Statistics
No significant associations between APOE ε4 presence or dose and NPI items
No significant associations between CYPrs754203 or CYPi2 new polymorphisms and NPI items
No significant associations between PRNPcodon 129 polymorphism and NPI items
No significant associations between PRNDcodons 26, 56, 174 polymorphisms and NPI items· a trend for PRNDcodon 56 C/T genotype to increase depression risk; p = 0.08
PRND 3′UTR and delusions*
PRND 3′UTR	Delusions present (n = 17)	Delusions absent (n = 47)
C/C	1 (5.9)	19 (40.4)
C/T	12 (70.6)	18 (38.3)	p = 0.015
T/T	4 (23.5)	10 (21.3)
T allele present	16 (94.1)	28 (59.6)	RR = 6.6
			(95% CI 1.3–43.6)
T allele absent	1 (5.9)	19 (40.4)	p = 0.02
PRND 3′UTR and anxiety*
PRND 3′UTR	Anxiety present (n = 28)	Anxiety absent (n = 36)
C/C	4 (14.3)	16 (44.4)
C/T	17 (60.7)	13 (36.1)	p = 0.03
T/T	7 (25)	7 (19.5)
T allele present	24 (85.7)	20 (55.6)	RR = 2.6
			(95% CI 1.2–6.8)
T allele absent	4 (14.3)	16 (44.4)	p = 0.02
PRND 3′UTR and agitation/aggression*
PRND 3′UTR	Agitation present (n = 26)	Agitation absent (n = 38)
C/C	3 (11.55)	17 (44.7)
C/T	16 (61.55)	14 (36.8)	p = 0.02
T/T	7 (26.9)	7 (19.5)
T allele present	23 (88.45)	21 (55.3)	RR = 3.3
			(95% CI 1.3–10.2)
T allele absent	3 (11.55)	17 (44.7)	p = 0.01
PRND 3′UTR and apathy*
	PRND 3′UTR	Apathy present (n = 40)	Apathy absent (n = 24)
C/C	8 (20)	12 (50)
C/T	23 (57.5)	7 (29.2)	p = 0.03
T/T	9 (22.5)	5 (20.8)
T allele present	32 (80)	12 (50)	RR = 1.8
			(95% CI 1.2–3.0)
T allele absent	8 (20)	12 (50)	p = 0.02
PRND 3′UTR and irritability/emotional lability*
	PRND 3′UTR	Irritability present (n = 47)	Irritability absent (n = 17)
C/C	11 (23.4)	9 (52.9)
C/T	25 (53.2)	5 (29.4)	p = 0.08
T/T	11 (23.4)	3 (17.7)
T allele present	36 (76.6)	8 (47.1)	RR = 1.4
			(95% CI 1.0–2.4)
T allele absent	11 (23.4)	9 (52.9)	p = 0.05
PRND ′UTR and aberrant motor activity (AMB)*
PRND ′UTR	AMB present (n = 17)	AMB absent (n = 47)
C/C	2 (11.8)	18 (38.3)
C/T	8 (47)	22 (46.8)	p = 0.04
T/T	7 (41.2)	7 (14.9)
T allele present	15 (88.2)	29 (61.7)	RR = 2.9
			(95% CI 1.1–12.4)
T allele absent	2 (11.8)	18 (38.3)	p = 0.05

* controlled for age, gender and the presence of APOE ε4 allele. AD, Alzheimer disease; BPSD, behavioral and psychological symptoms of dementia; NPI, Neuropsychiatric Inventory.

Table 4 Associations between genetic polymorphisms and neuropsychiatric symptoms in mild cognitive impairment

Polymorphism	BPSD symptom in MCI, n (%)		Statistics
APOE ε 4 and sleep/night-time behavior change
APOE ε 4	Sleep problems present (n = 14)	Sleep problems absent (n = 34)
ε4 present	1 (7.1)	13 (38.2)
			p = 0.04
ε4 absent	13 (92.9)	21 (61.8)
No significant associations between CYP rs754203 or CYP i2 new polymorphisms and NPI items
No significant associations between PRNP codon 129 polymorphism and NPI items
No significant associations between PRND polymorphisms and NPI items
· a trend for PRND codon 56 C/T genotype to increase the risk of sleep change; p = 0.07
· a trend for PRND codon 174 C/T genotype to protect from irritability; p = 0.07
· a trend for PRND ′UTR C allele to increase the risk of anxiety; p = 0.07

BPSD, behavioral and psychological symptoms of dementia; MCI, mild cognitive impairment; NPI, Neuropsychiatric Inventory.