FOXO1 locus and acetylcholinesterase inhibitors in elderly patients with Alzheimer’s disease

Figures & data

Table 1 Characteristics of patients at baseline according to sex

	All (n=109)	Men (n=37)	Women (n=72)	P-value
Age (years)	78.72±6.49	78.25±6.26	78.97±6.64	0.591
Educational level (years)	4.46±3.39	6.10±4.49	3.60±2.22	<0.001
MMSE	15.96±4.06	17.57±4.41	15.14±3.64	0.003
ADL	3.84±1.93	4.30±1.69	3.61±2.02	0.193
IADL	1.84±2.33	2.50±2.59	1.51±2.15	0.120
ADAS-cog	37.19±9.47	40.93±10.27	35.27±8.47	0.003
CDR	1.68±0.61	1.51±0.65	1.76±0.57	0.041
Donepezil	44 (40.37%)	13 (35.14%)	31 (43.06%)	0.536
Rivastigmine (pill)	23 (21.10%)	9 (24.32%)	14 (19.44%)	0.622
Rivastigmine (transdermal patch)	40 (36.7%)	14 (37.84%)	26 (36.11%)	0.999
Rivastigmine (all)	63 (57.79%)	23 (62.16%)	40 (55.56%)	0.544
Galantamine	2 (1.83%)	1 (2.70%)	1 (1.39%)	0.999

Notes: Data are reported as means ± standard deviation and frequency and percentages for continuous and categorical variables, respectively. P-values are from Mann–Whitney U-tests or Pearson chi-square tests for continuous and categorical variables, respectively.

Abbreviations: ADAS-cog, Alzheimer’s Disease Assessment Scale-cognitive subscale; ADL, Activities of Daily Living; CDR, Clinical Dementia Rating; IADL, Instrumental Activities of Daily Living; MMSE, mini-mental state examination.

Table 2 Clinical evaluation of responders/nonresponders to AChEI treatment at the 6-month follow-up

Variable	Category	Responders (n=74)	P-value	Nonresponders (n=35)	P-value
Sex (M/F)		26/48		11/24	0.829
Age		78.31±6.92		79.60±5.47	0.333
MMSE	Baseline	15.78±4.14	<0.001	16.35±3.93	<0.001
	Follow-up	18.61±4.86		12.73±3.90
ADL	Baseline	3.89±2.00	<0.001	3.71±1.79	0.079
	Follow-up	4.42±1.66		3.20±1.47
IADL	Baseline	2.09±2.58	0.003	1.18±1.33	0.012
	Follow-up	2.40±2.68		0.47±0.61
ADAS-cog	Baseline	36.77±9.64	<0.001	38.10±9.15	0.001
	Follow-up	43.36±11.33		29.68±9.10
CDR	Baseline	1.65±0.63	0.111	1.74±0.56	0.005
	Follow-up	1.51±0.76		2.06±0.77

Notes: Data are reported as mean ± standard deviation. P-values are from paired Student’s t-tests.

Abbreviations: AChEIs, acetylcholinesterase inhibitors; ADAS-cog, Alzheimer’s Disease Assessment Scale-cognitive subscale; ADL, Activities of Daily Living; CDR, Clinical Dementia Rating; IADL, Instrumental Activities of Daily Living; MMSE, mini-mental state examination.

Table 3 Genotype distribution at FOXO1 locus according to the response to AChEI treatment and results from univariate and multivariate logistic regressions

	Responders		Nonresponders		Univariate analysis			Multivariate analyses§
	(n=74)		(n=35)					Age/sex			Age/sex/APOE
	N	%	N	%	P-value	OR	(95% CI)	P-value	OR	(95% CI)	P-value	OR	(95% CI)
rs2721069*
C/C	44	59.46	20	57.14	–	1.00	–	–	1.00	–	–	1.00	–
C/T	22	29.73	10	28.57	1.000	1.00	0.400–2.498	0.895	1.07	0.412–2.756	0.955	0.971	0.356–2.650
T/T	8	10.81	5	14.29	0.614	1.38	0.399–4.733	0.566	1.46	0.404–5.235	0.383	1.825	0.472–7.056
rs4943794#
G/G	53	71.62	28	80	–	1.00	–	–	1.00	–	–	1.00	–
G/C	19	25.68	6	17.14	0.325	0.60	0.214–1.667	0.311	0.58	0.203–1.662	0.415	0.636	0.214–1.890
C/C	2	2.7	1	2.86	0.965	0.95	0.082–10.899	0.990	0.94	0.087–13.889	0.935	0.899	0.069–11.698
rs7981045†
A/A	44	59.46	14	40	–	1.00	–	–	1.00	–	–	1.00	–
A/G	28	37.84	15	42.86	0.240	1.68	0.706–4.014	0.198	1.73	0.734–4.454	0.182	1.895	0.741–4.845
G/G	2	2.7	6	17.14	0.010	9.43	1.706–52.108	0.017	9.19	1.481–57.086	0.017	10.31	1.510–70.362

Notes:

§ Both analyses were also adjusted for the MMSE score at baseline and AChEI. Hardy-Weinberg equilibrium:

* P=0.067 (responders) and P=0.095 (nonresponders)

# P=0.679 (responders) and P=0.362 (nonresponders)

† P=0.447 (responders) and P=0.720 (nonresponders).

Abbreviations: AChEI, acetylcholinesterase inhibitor; CI, confidence interval; OR, odds ratio; MMSE, mini-mental state examination.

Table 4 Estimated haplotype frequencies at FOXO1 locus according to the response to AChEI treatment

rs2721069	rs4943794	rs7981045	Responders	Nonresponders	χ^2	P-value	All
C	G	A	0.346	0.531	6.51	0.01	0.47
C	G	G	0.368	0.212	5.96	0.014	0.26
T	C	A	0.114	0.155	0.659	0.417	0.14
T	G	A	0.154	0.098	1.477	0.224	0.12

Note: Only haplotypes with and estimated frequencies >1% are reported.

Abbreviation: AChEI, acetylcholinesterase inhibitor.

Figure S1 Estimated values of linkage disequilibrium coefficient r² at FOXO1 locus according to the response to AChEI treatment.

Abbreviation: AChEI, acetylcholinesterase inhibitor.

Table S1 Association of FOXO1 genotypes with the response to AChEI treatment assuming different genetic models of inheritance

+θ	Genotype/allele	Univariate model			Multivariate model*
					Age/sex			Age/sex/APOE
		P-value	OR	95% CI	P-value	OR	95% CI	P-value	OR	95% CI
rs2721069
0.0	C/C	–	1.00	–	–	1.00	–	–	1.00	–
	C/T + T/T	0.819	1.10	0.487–2.484	0.715	1.17	0.502–2.727	0.721	1.174	0.486–2.841
0.5	C/C + C/T	–	1.00	–	–	1.00	–	–	1.00	–
	T/T	0.602	1.375	0.415–4.555	0.576	1.424	0.412–4.917	0.364	1.841	0.493–6.869
1.0	C	–	1.00	–	–	1.00	–	–	1.00	–
	T	0.686	1.125	0.636–1.987	0.617	1.162	0.645–2.092	0.487	1.245	0.671–2.308
rs4943794
0.0	G/G	–	1.00	–	–	1.00	–	–	1.00	–
	G/C + C/C	0.352	0.631	0.239–1.665	0.352	0.622	0.229–1.690	0.436	0.662	0.235–1.866
0.5	G/G + G/C	–	1.00	–	–	1.00	–	–	1.00	–
	C/C	0.963	1.059	0.093–12.086	0.852	1.27	0.102–15.796	0.993	1.011	0.079–12.943
1.0	G	–	1.00	–	–	1.00	–	–	1.00	–
	C	0.433	0.714	0.308–1.656	0.605	1.168	0.648–2.107	0.508	0.741	0.305–1.800
rs7981045
0.0	A/A	–	1.00	–	–	1.00	–	–	1.00	–
	A/G + G/G	0.06	2.2	0.969–4.996	0.042	2.398	1.033–5.566	0.038	2.452	1.055–6.122
0.5	A/A + A/G	–	1.00	–	–	1.00	–	–	1.00	–
	G/G	0.018	7.448	1.420–39.069	0.027	7.675	1.256–46.885	0.028	8.511	1.265–57.258
1.0	A	–	1.00	–	–	1.00	–	–	1.00	–
	G	0.011	2.342	1.217–4.508	0.012	2.367	1.208–4.638	0.011	2.488	1.231–5.028

Notes:

* Both Student’s t-test analyses were also adjusted for the MMSE score at baseline and AChEIs. Where θ=0.0, dominante model; θ=0.5, recessive model; θ=1.0, additive model.

Abbreviations: AChEI, acetylcholinesterase inhibitor; CI, confidence interval; MMSE, mini-mental state examination; OR, odds ratio.