Pharmacogenetic Analyses of Therapeutic Effects of Lipophilic Statins on Cognitive and Functional Changes in Alzheimer’s Disease

Abstract

Background:

Pharmacogenetic effects of statins on clinical changes in Alzheimer’s disease (AD) could be mediated by epistatic interactions among relevant genetic variants involved in cholesterol metabolism.

Objective:

To investigate associations of HMGCR (rs3846662), NR1H2 (rs2695121), or CETP (rs5882&rs708272) with cognitive and functional changes in AD, with stratification according to APOE ɛ4 carrier status and lipid-lowering treatment with lipophilic statins.

Methods:

Consecutive outpatients with late-onset AD were screened with cognitive tests, while caregivers scored functionality and global ratings, with prospective neurotranslational associations documented for one year.

Results:

Considering n = 190:142 had hypercholesterolemia, 139 used lipophilic statins; minor allele frequencies were 0.379 (rs2695121-T:46.3% heterozygotes), 0.368 (rs5882-G:49.5% heterozygotes), and 0.371 (rs708272-A:53.2% heterozygotes), all in Hardy-Weinberg equilibrium. For APOE ɛ4 carriers: rs5882-GG protected from cognitive decline; rs5882-AA caused faster cognitive decline; carriers of rs2695121-CC or rs5882-AA were more susceptible to harmful cognitive effects of lipophilic statins; carriers of rs5882-GG or rs708272-AG had functional benefits when using lipophilic statins. APOE ɛ4 non-carriers resisted any cognitive or functional effects of lipophilic statins, while invariability of rs3846662 (all AA) prevented the assessment of HMGCR effects. When assessing CETP haplotypes only: rs5882-GG protected from cognitive and functional decline, regardless of lipophilic statin therapy; lipophilic statins usually caused cognitive and functional harm to carriers of rs5882-A and/or rs708272-A; lipophilic statins benefitted cognition and functionality of carriers of rs5882-G and/or rs708272-G.

Conclusion:

Reportedly protective variants of CETP and NR1H2 also slowed cognitive and functional decline particularly for APOE ɛ4 carriers, and regardless of cholesterol variations, while therapy with lipophilic statins might affect carriers of specific genetic variants.

Keywords

Alzheimer’s disease dementia drug therapy hydroxymethylglutaryl-CoA reductase inhibitors neuropsychiatry pharmacogenetics

INTRODUCTION

Progressive mesial temporal cortical atrophy is the most widely known anatomic predictor of risk of Alzheimer’s disease (AD) [1], while diagnosis of amnestic mild cognitive impairment is a major clinical predictor of such risk [2]. Whereas APOE ɛ4 carrier status is a major genetic risk factor for cerebral amyloid-β deposition [3], the rate of change of mesial temporal lobe volume [4], incidence and earlier onset of late-onset AD in different populations [5, 6], other genetic variants could also account for these phenomena.

Neuroinflammation is a key pathological mechanism leading to amyloidogenesis and tau hyperphosphorylation in AD [7, 8]. Statins have anti-inflammatory and vasodilatory effects in addition to their lipid-lowering properties [9] but could also benefit these patients by the following alternative mechanisms: stimulation of the non-amyloidogenic pathway of the amyloid-β protein precursor by boosting the activity of the α-secretase [10], and enhanced secretion and release of amyloid-β-degrading enzymes from glial cells regardless of cholesterol-lowering effects [11]. In addition, lipophilic statins (but not hydrophilic ones) may inhibit tau hyperphosphorylation via anti-inflammatory effects [12]. Statins have no adverse cognitive effects in most well-designed studies, but evidence of benefits of statin therapy on clinical changes in AD is usually non-significant [13].

The brain contains about 25% of the body’s unsterified cholesterol, mostly residing in myelin sheaths and plasma membranes [14]. Accumulating evidence shows that atherogenic mechanisms and peripheral lipid profile variations are genetically-mediated [15], though phenotypically modulated by pharmacological therapy. Hypercholesterolemia has been consistently associated with onset [6] and progression [16] of AD, particularly when in combination with other cerebrovascular risk factors, though negative associations have also been reported [17]. In addition, late life measures of atherosclerosis such as higher long-term coronary heart disease risk may be neuroprotective due to associations with enhanced cerebral perfusion [18].

In the central nervous system, the hydrophobic cholesteryl ester transfer protein (CETP) is widely distributed and predominately localized in astrocytes [14]. Plasma CETP is involved in reverse cholesterol transport and promotes the uptake of cholesterol in the liver by mediating the exchange of cholesteryl esters from high-density lipoproteins to apolipoprotein B-containing lipoproteins [19]. Genetic variants of CETP on chromosome 16 impact phenotypic lipid profiles [20] due to associations of low plasma levels of CETP with large particle sizes of both high-density lipoproteins and low-density lipoproteins [19]. TaqIB (rs708272) and I422V (rs5882) are two of the most studied genetic variants of CETP with neurological implications over white matter integrity, cognition, and behavior [21]. Underexpression of the liver X receptor β (LXR-β) isoform, also present in neurons and astrocytes, and encoded by the NR1H2 gene close to APOE on chromosome 19, increases cellular cholesterol levels and amyloidogenesis by downregulating the apolipoprotein E [14]; rs2695121 in intron 2 of NR1H2 is one of the prime variants to have been associated with variable risk and neuropsychiatric features of AD [21]. Concerning HMGCR, the mechanistic gene that encodes the statin-binding domain of 3-hydroxy-3-methylglutaryl CoA reductase (the rate-limiting enzyme involved in cholesterol biosynthesis), the A allele of rs3846662 is associated with decreased enzyme activity as reflected by decreased low-density lipoprotein cholesterol, as well as with lower statin efficacy [22] and decreased risk of AD, particularly for APOE ɛ4 carriers [23].

Pharmacogenetics is the study of drug response as a function of DNA characteristics [24], potentially able to explain the diversity of results in studies of lipophilic statins in AD—adverse effects on memory have been described, but also null effects [13], as well as genetically-mediated cognitive and functional benefits [25]. While CETP, NR1H2, and HMGCR are intimately involved in cholesterol metabolism, some genetic variants may indirectly affect lipid metabolism pathways by way of functional variants in the same gene or in closely linked genes, thus resulting in pleiotropic effects over pathogenesis of AD [9]. In this preliminary observational translational study, we aimed to investigate whether CETP, NR1H2, and HMGCR polymorphisms are associated with functional and cognitive changes in patients with AD, while also taking APOE haplotypes and lipid-lowering treatment with lipophilic statins into account for stratification.

METHODS

Participants and clinical assessment

In this uncontrolled cohort, consecutive outpatients were prospectively recruited from October 2010 to May 2014 at the Behavioral Neurology Section of Hospital São Paulo, Federal University of São Paulo (UNIFESP). A clinical diagnosis of late-onset AD according to National Institute on Aging–Alzheimer’s Association criteria [26] was required from all included patients, while research criteria for probable AD were also followed [27]. Late-onset AD was considered when the dementia syndrome began after patients turned 60 years old [6]. Each patient was followed for one year, and all patients had a magnetic resonance exam to evaluate either medial parietal or medial, basal or lateral temporal atrophy or, in cases of claustrophobia or use of pacemakers, a computed tomography scan to exclude vascular lesions.

After diagnostic confirmation, all patients had at least three consultations throughout the year; in the first one, they were evaluated for sex, education, and estimated age at dementia onset, while lipid profile evaluations and assessments of pharmacological therapy (use of lipid-lowering drugs, cholinesterase inhibitors, and/or memantine) were conducted in all consultations. The age at dementia onset was determined following a review of medical records for functional and cognitive decline, and confirmed after an interview with the caregiver, so that patients with mild cognitive impairment would not be included [28]. Diagnosis of hypercholesterolemia was based on the results of blood tests, while specific guidelines from the National Institutes of Health [29] were followed for its management. Essentially, goals of total cholesterol (desirable < 200 mg/dl) and low-density lipoprotein cholesterol were based on the presence or not of coronary heart disease, clinical manifestations of non-coronary forms of atherosclerotic disease, diabetes mellitus, and other vascular risk factors in general: low-density lipoprotein cholesterol < 160 mg/dl for those with up to one risk factor, < 130 mg/dl for those with two or more risk factors, and < 100 mg/dl for those with coronary heart disease, diabetes mellitus, or coronary heart disease risk equivalents. Unless the 10-year estimated coronary heart disease risk according to the same guidelines was higher than 10%, drug therapy was introduced only if lifestyle therapy was unsuccessful after three months. Non-pharmacological recommendations including regular physical activity, dietary therapy, body weight control, and smoking cessation, which may reduce coronary heart disease risk by up to 50% [30], were simultaneously employed, whereas pharmacological therapy would be discontinued in case of side effects. All efforts were directed to reduce levels of cholesterol as much as possible to target goals. Participation of each patient was concluded when follow-up completed one year.

All participants were prospectively evaluated by way of the Mini-Mental State Examination (MMSE) [31] and the Severe Mini-Mental State Examination (SMMSE) [32], while their caregivers were queried for scores on the Index of Independence in Activities of Daily Living (ADL) [33] and the Clinical Dementia Rating sum-of-boxes (CDR-SOB) [34]. Scoring guidelines for these tests have been previously described [35]. All assessments were conducted on weekdays at morning time, by the same examiner (FFO). For statistics, only the baseline scores and the final scores after one year were taken into account.

Genotyping

Blood was collected from all patients in tubes with ethylenediaminetetraacetic acid 0.1%, then genomic DNA was extracted using a standard salting-out procedure for determination of rs3846662 (HMGCR), rs2695121 (NR1H2), rs5882 and rs708272 (CETP), rs7412 and rs429358 (APOE) by way of real-time polymerase chain reactions. Genotyping procedures were carried out only after clinical data were collected from all patients. TaqMan® SNP Genotyping Assays were used on the Applied Biosystems 7500 Fast Real-Time PCR System (Applied Biosystems®, USA), following the standard manufacturer protocols. After APOE haplotypes were determined by genotypes of rs7412 and rs429358, the presence of NR1H2 genotypes of rs2695121, HMGCR genotypes of rs3846662, and CETP genotypes of rs5882 or rs708272 or their represented haplotypes would be correlated with lipid-lowering therapy using lipophilic statins.

Outcome measures

The main outcome measure was the score variation in one year regarding cognition (MMSE, SMMSE), functionality (ADL), or a global rating (CDR-SOB), taking into account the following independent variables: use of a lipophilic statin and CETP genotypes or haplotypes and NR1H2 genotypes. Secondarily, isolated effects of specific genotypes were also assessed regardless of pharmacological therapy. When the impacts of lipophilic statin therapy or CETP or NR1H2 genotypes were measured, participants were stratified into groups of APOE ɛ4 carriers or APOE ɛ4 non-carriers.

Statistics

Paired Student’s t-test was employed for yearly variations of weight, total cholesterol, and test scores (taking baseline and final scores after one year into account). The Hardy-Weinberg equilibrium for HMGCR, NR1H2, and CETP genotypes was estimated by way of the Chi-square test, as well as sex differences regarding use of lipophilic statins. A general linear model, separately for APOE ɛ4 carriers and for APOE ɛ4 non-carriers, was employed for test score variations in one year, according to: CETP genotypes or haplotypes, NR1H2 genotypes, and use or not of a lipophilic statin. The general linear model was adjusted for sex, years of education, age, estimated baseline disease duration, total cholesterol, and weight variations in one year. Due to the preliminary nature of this study, levels of significance from the general linear model were not corrected for multiple correlations. Univariate analyses disclosed the effects of genetic variants over each test score variation regardless of pharmacological treatment, while multivariate analyses showed results of interactions among genetic variants and use or not of lipophilic statins, significance at p < 0.05.

Ethical aspects

All procedures of the research project 1067/10 (CAAE 0540.0.174.000-10) followed the ethical standards of the Ethics Committee of Hospital São Paulo, Federal University of São Paulo – UNIFESP, according to The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. All invited patients and their legal representatives agreed to participate on the research and signed the Informed Consent Form before the evaluation.

RESULTS

Overall, 214 patients were included. During follow-up, 14 patients (6.5%) passed away and 10 patients (4.7%) abandoned the study, resulting in a final sample of 190 patients.

Table 1 shows demographic and clinical results for all patients. More than 93% of them used a cholinesterase inhibitor during the study, while more than 73% used a lipophilic statin (Simvastatin, a natural statin, or Atorvastatin, a synthetic one) as lipid-lowering therapy [12]. There was no difference between men and women regarding use of lipophilic statins (p = 0.765). All patients who used Ezetimibe were also treated with a statin. Levels of total cholesterol and weight were significantly lowered after one year. Significant changes after one year were found for all test scores: increased CDR-SOB scores and decreased ADL, MMSE, and SMMSE scores.

Table 1

Demographic and clinical results

Assessed factors, n = 190		n (%)	Mean±SD	p ^a
Sex	Female	128 (67.4%)	–	–
	Male	62 (32.6%)	–	–
Years of education		–	4.23±3.7	–
Estimated age (y) at dementia onset		–	73.22±6.3	–
Age (y) at inclusion in the study		–	78.22±5.8	–
Estimated baseline disease duration (y)		–	4.99±2.9	–
Weight (kgf)	Baseline values	–	62.69±12.2	< 0.0001
	Final values	–	61.18±13.0
	Variation	–	–1.51±5.1	–
Diabetes mellitus		51 (26.8%)	–	–
Hypercholesterolemia		142 (74.7%)	–	–
Lipid-lowering therapy (mg/day)	Atorvastatin	14	28.57±22.8	–
	Rosuvastatin	2	10.00±0.0	–
	Simvastatin	125	18.56±9.2	–
	Ezetimibe	4	10.00±0.0	–
Total cholesterol (mg/dl)	Baseline values	–	197.10±45.7	< 0.0001
	Final values	–	181.37±38.3
	Variation	–	–15.73±36.4	–
Use of a cholinesterase inhibitor		178 (93.7%)	–	–
Use of memantine		142 (74.7%)	–	–
Clinical Dementia Rating sum-of-boxes (0.0–18.0 points)	Baseline scores	–	10.18±3.8	< 0.0001
	Final scores	–	11.77±4.0
	Variation	–	1.59±2.4	–
Index of Independence in Activities of Daily Living (0–6 points)	Baseline scores	–	5.03±1.5	< 0.0001
	Final scores	–	4.47±2.0
	Variation	–	–0.56±1.6	–
Mini-Mental State Examination (0–30 points)	Baseline scores	–	15.59±5.5	< 0.0001
	Final scores	–	14.34±6.3
	Variation	–	–1.25±3.1	–
Severe Mini-Mental State Examination (0-30 points)	Baseline scores	–	26.28±5.3	< 0.0001
	Final scores	–	24.67±7.2
	Variation	–	–1.61±3.9	–

^aPaired Student’s t-test for baseline scores and final scores after one year. SD, standard deviation.

Table 2 shows frequencies for all genotypes and haplotypes. All patients had the same HMGCR genotype for rs3846662, so we could not proceed with pharmacogenetic analyses taking this gene into account. Minor allele frequencies were 0.379 for NR1H2 rs2695121 (T), 0.368 for CETP rs5882 (G), and 0.371 for CETP rs708272 (A). All single nucleotide polymorphisms were in Hardy-Weinberg equilibrium.

Table 2

Genetic results

Genotypes and haplotypes, n = 190			n (%)	p ^a
APOE haplotypes	APOEɛ4 carriers, n = 100	ɛ4/ɛ4	21 (11.1%)	–
		ɛ4/ɛ3	71 (37.3%)	–
		ɛ4/ɛ2	8 (4.2%)	–
	APOEɛ4 non-carriers, n = 90	ɛ3/ɛ3	83 (43.7%)	–
		ɛ3/ɛ2	7 (3.7%)	–
		ɛ2/ɛ2	0 (0.0%)	–
HMGCR (intron 13): rs3846662 genotypes	APOEɛ4 carriers, n = 100	AA	100 (52.6%)	1.000
			AG	0 (0.0%)
			GG	0 (0.0%)
	APOEɛ4 non-carriers, n = 90	AA	90 (47.4%)
			AG	0 (0.0%)
			GG	0 (0.0%)
NR1H2 (intron 2): rs2695121 genotypes	APOEɛ4 carriers, n = 100	CC	43 (22.6%)	0.825
			CT	43 (22.6%)
			TT	14 (7.4%)
	APOEɛ4 non-carriers, n = 90	CC	31 (16.3%)
			CT	45 (23.7%)
			TT	14 (7.4%)
CETP: rs5882 genotypes	APOEɛ4 carriers, n = 100	AA	34 (17.9%)	0.385
			AG	52 (27.4%)
			GG	14 (7.4%)
	APOEɛ4 non-carriers, n = 90	AA	39 (20.5%)
			AG	42 (22.1%)
			GG	9 (4.7%)
CETP: rs708272 genotypes	APOEɛ4 carriers, n = 100	AA	11 (5.8%)	0.056
			AG	53 (27.9%)
			GG	36 (18.9%)
	APOEɛ4 non-carriers, n = 90	AA	9 (4.7%)
			AG	48 (25.3%)
			GG	33 (17.4%)
CETP haplotypes	rs5882 AA / rs708272 AA		3 (1.6%)	–
	rs5882 AA / rs708272 AG		36 (18.9%)	–
	rs5882 AA / rs708272 GG		34 (17.9%)	–
	rs5882 AG / rs708272 AA		10 (5.3%)	–
	rs5882 AG / rs708272 AG		55 (28.9%)	–
	rs5882 AG / rs708272 GG		29 (15.2%)	–
	rs5882 GG / rs708272 AA		7 (3.7%)	–
	rs5882 GG / rs708272 AG		10 (5.3%)	–
	rs5882 GG / rs708272 GG		6 (3.2%)	–

^aHardy-Weinberg equilibrium (Chi-square test). APOE, apolipoprotein E gene; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase gene; NR1H2, nuclear receptor 1 type H2 gene (liver X receptor β gene); CETP, cholesteryl ester transfer protein gene.

Table 3 shows test score variations according to genetic variants only. APOE ɛ4 carriers who carried CETP rs5882-AA had faster worsening of MMSE scores, while those who carried CETP rs5882-GG had slower worsening.

Table 3

Effects of genetic variants over test score variations in one year independently of pharmacological treatment

Genotypes		CDR-SOB variations		ADL variations		MMSE variations		SMMSE variations
		mean±SD	p ^a	mean±SD	p ^a	mean±SD	p ^a	mean±SD	p ^a
rs2695121 genotypes (APOEɛ4 carriers^b)	CC	1.59±2.8	0.315	–0.77±1.7	0.205	–1.77±3.5	0.635	–1.74±4.2	0.343
	CT	1.72±2.3	0.134	–0.44±1.4	0.873	–1.40±3.1	0.879	–1.72±4.0	0.402
	TT	0.89±2.1	0.501	–0.64±1.8	0.420	–1.43±3.6	0.704	–3.00±5.3	0.133
rs2695121 genotypes (APOEɛ4 non-carriers^c)	CC	1.37±2.4	0.356	–0.29±1.5	0.591	–1.00±2.8	0.167	–1.13±2.6	0.565
	CT	1.84±2.3	0.294	–0.64±1.5	0.278	–1.11±2.7	0.384	–1.62±4.1	0.257
	TT	1.61±2.6	0.938	–0.50±1.3	0.673	0.00±3.6	0.416	–0.50±3.2	0.158
rs5882 genotypes (APOEɛ4 carriers^b)	AA	1.87±2.8	0.279	–0.41±1.6	0.549	–2.97±3.3	0.019	–1.74±3.6	0.881
	AG	1.26±2.4	0.302	–0.77±1.6	0.279	–0.85±3.1	0.610	–2.33±4.8	0.217
	GG	1.86±2.2	0.770	–0.50±1.8	0.156	–0.79±3.3	0.046	–0.79±3.4	0.323
rs5882 genotypes (APOEɛ4 non-carriers^c)	AA	1.22±2.5	0.795	–0.46±1.4	0.814	–0.21±3.2	0.344	–0.69±2.0	0.617
	AG	2.20±2.3	0.205	–0.62±1.6	0.645	–1.76±2.5	0.315	–1.88±4.6	0.669
	GG	0.89±1.3	0.243	–0.11±1.7	0.937	0.11±2.5	0.748	–1.00±1.8	0.823
rs708272 genotypes (APOEɛ4 carriers^b)	AA	0.41±1.6	0.875	–0.36±1.3	0.843	–0.27±3.9	0.089	–1.64±3.9	0.636
	AG	1.84±2.7	0.463	–0.72±1.7	0.264	–1.81±3.2	0.825	–1.89±4.6	0.927
	GG	1.47±2.4	0.228	–0.53±1.6	0.756	–1.58±3.3	0.087	–2.03±4.1	0.211
rs708272 genotypes (APOEɛ4 non-carriers^c)	AA	2.44±2.3	0.289	–0.56±1.1	0.839	–2.00±1.9	0.676	–1.56±2.1	0.827
	AG	1.53±2.5	0.308	–0.62±1.5	0.264	–0.83±3.1	0.977	–1.46±4.2	0.727
	GG	1.59±2.3	0.868	–0.30±1.6	0.391	–0.70±2.7	0.681	–0.94±2.7	0.998

^aInter-genotype comparisons (general linear model adjusted for sex, years of education, age, estimated baseline disease duration, total cholesterol and weight variations in one year). ^bAPOE ɛ4 carriers (n = 100), carriers of APOE ɛ4/ɛ4, APOE ɛ4/ɛ3, or APOE ɛ4/ɛ2: for rs2695121 CC, n = 43; for rs2695121 CT, n = 43; for rs2695121 TT, n = 14; for rs5882 AA, n = 34; for rs5882 AG, n = 52; for rs5882 GG, n = 14; for rs708272 AA, n = 11; for rs708272 AG, n = 53; for rs708272 GG, n = 36. ^cAPOE ɛ4 non-carriers (n = 90), carriers of APOE ɛ3/ɛ3 or APOE ɛ3/ɛ2 (APOE ɛ2/ɛ2 was not represented in this sample): for rs2695121 CC, n = 31; for rs2695121 CT, n = 45; for rs2695121 TT, n = 14; for rs5882 AA, n = 39; for rs5882 AG, n = 42; for rs5882 GG, n = 9; for rs708272 AA, n = 9; for rs708272 AG, n = 48; for rs708272 GG, n = 33. CDR-SOB, Clinical Dementia Rating sum-of-boxes; ADL, Index of Independence in Activities of Daily Living; MMSE, Mini-Mental State Examination; SMMSE, Severe Mini-Mental State Examination; SD, standard deviation.

Table 4 shows that lipophilic statins modified outcomes for APOE ɛ4 carriers only: those who also carried NR1H2 rs2695121-CC or CETP rs5882-AA had faster worsening of SMMSE scores, while those who also carried CETP rs5882-GG or CETP rs708272-AG had slower worsening of basic functionality when using these drugs.

Table 4

Cognitive and functional responses to lipophilic statins in one year according to genotype frequencies for NR1H2 and CETP polymorphisms in APOE ɛ4 carriers and non-carriers

Genotypes		CDR-SOB variations (mean±SD)			ADL variations (mean±SD)			MMSE variations (mean±SD)			SMMSE variations (mean±SD)
		Lipophilic statin		p ^a	Lipophilic statin		p ^a	Lipophilic statin		p ^a	Lipophilic statin		p ^a
		Yes	No		Yes	No		Yes	No		Yes	No
rs2695121 genotypes (APOEɛ4 carriers^b)	CC	1.81±2.9	0.78±2.0	0.293	–0.68±1.7	–1.11±2.0	0.229	–1.76±3.7	–1.78±2.9	0.876	–2.53±4.2	1.22±2.9	0.016
	CT	1.43±1.9	2.32±3.0	0.425	–0.28±1.2	–0.79±1.9	0.400	–0.69±2.6	–2.86±3.5	0.124	–1.14±3.6	–2.93±4.5	0.239
	TT	1.21±1.4	0.57±2.8	0.667	–0.43±1.6	–0.86±2.0	0.563	–1.71±3.9	–1.14±3.5	0.573	–2.14±4.9	–3.86±6.0	0.644
rs2695121 genotypes (APOEɛ4 non-carriers^c)	CC	1.50±2.5	0.50±1.3	0.390	–0.33±1.6	0.00±0.0	0.819	–0.89±2.8	–1.75±3.1	0.373	–0.96±2.5	–2.25±3.9	0.381
	CT	1.56±2.6	2.54±1.5	0.252	–0.53±1.4	–0.92±1.8	0.407	–0.75±2.6	–2.00±3.0	0.377	–1.16±4.1	–2.77±3.9	0.256
	TT	1.00±2.8	3.12±0.3	0.084	–0.70±1.6	0.00±0.0	0.594	0.10±4.1	–0.25±2.2	0.345	–1.20±2.7	1.25±4.0	0.726
rs5882 genotypes (APOEɛ4 carriers^b)	AA	1.90±2.7	1.80±3.1	0.645	–0.42±1.7	–0.40±1.4	0.808	–2.88±3.5	–3.20±3.0	0.924	–2.33±4.0	–0.30±1.8	0.020
	AG	1.34±2.3	1.09±2.7	0.775	–0.66±1.5	–1.00±1.8	0.329	–0.29±2.8	–2.00±3.4	0.115	–1.83±4.3	–3.35±5.9	0.158
	GG	1.73±2.3	2.33±2.1	0.442	–0.09±1.0	–2.00±3.5	0.007	–1.18±3.4	0.67±2.9	0.485	–1.27±3.7	1.00±1.7	0.736
rs5882 genotypes (APOEɛ4 non-carriers^c)	AA	0.97±2.7	2.36±1.2	0.220	–0.44±1.4	–0.57±1.4	0.710	0.09±3.1	–1.57±3.2	0.176	–0.53±1.9	–1.43±2.4	0.510
	AG	2.11±2.5	2.45±1.7	0.858	–0.71±1.6	–0.36±1.5	0.605	–1.74±2.4	–1.82±2.9	0.872	–1.84±4.4	–2.00±5.3	0.832
	GG	0.67±1.0	1.33±2.1	0.608	0.50±1.2	–1.33±2.1	0.088	0.67±2.3	–1.00±3.0	0.371	–0.17±1.3	–2.67±1.5	0.261
rs708272 genotypes (APOEɛ4 carriers^b)	AA	0.45±1.6	0.00±0.0	0.784	–0.40±1.3	0.00±0.0	0.878	–0.70±3.8	4.00±0.0	0.234	–1.80±4.0	0.00±0.0	0.874
	AG	1.97±2.6	1.66±2.8	0.668	–0.39±1.4	–1.18±2.0	0.040	–1.55±3.3	–2.18±3.1	0.714	–2.39±4.8	–1.18±4.1	0.229
	GG	1.59±2.4	1.00±2.9	0.342	–0.62±1.7	–0.14±1.6	0.355	–1.28±3.3	–2.86±3.6	0.450	–1.45±3.1	–4.43±6.5	0.129
rs708272 genotypes (APOEɛ4 non-carriers^c)	AA	2.36±2.6	2.75±1.1	0.832	–0.29±0.8	–1.50±2.1	0.391	–2.29±1.8	–1.00±2.8	0.385	–1.57±1.9	–1.50±3.5	0.569
	AG	1.32±2.7	2.17±1.8	0.226	–0.56±1.5	–0.83±1.5	0.524	–0.56±3.2	–1.67±3.0	0.183	–1.31±4.0	–1.92±4.7	0.578
	GG	1.40±2.4	2.29±1.4	0.623	–0.42±1.7	0.14±1.2	0.515	–0.42±2.6	–1.71±3.1	0.272	–0.65±2.4	–2.00±3.5	0.225

^aGeneral linear model adjusted for sex, years of education, age, estimated baseline disease duration, total cholesterol, and weight variations in one year. ^bAPOE ɛ4 carriers (n = 100), carriers of APOE ɛ4/ɛ4, APOE ɛ4/ɛ3, or APOE ɛ4/ɛ2: for rs2695121 CC (n = 43): 34 used a lipophilic statin; for rs2695121 CT (n = 43): 29 used a lipophilic statin; for rs2695121 TT (n = 14): 7 used a lipophilic statin; for rs5882 AA (n = 34): 24 used a lipophilic statin; for rs5882 AG (n = 52): 35 used a lipophilic statin; for rs5882 GG (n = 14): 11 used a lipophilic statin; for rs708272 AA (n = 11): 10 used a lipophilic statin; for rs708272 AG (n = 53): 31 used a lipophilic statin; for rs708272 GG (n = 36): 29 used a lipophilic statin. ^cAPOE ɛ4 non-carriers (n = 90), carriers of APOE ɛ3/ɛ3 or APOE ɛ3/ɛ2 (APOE ɛ2/ɛ2 was not represented in this sample): for rs2695121 CC (n = 31): 27 used a lipophilic statin; for rs2695121 CT (n = 45): 32 used a lipophilic statin; for rs2695121 TT (n = 14): 10 used a lipophilic statin; for rs5882 AA (n = 39): 32 used a lipophilic statin; for rs5882 AG (n = 42): 31 used a lipophilic statin; for rs5882 GG (n = 9): 6 used a lipophilic statin; for rs708272 AA (n = 9): 7 used a lipophilic statin; for rs708272 AG (n = 48): 36 used a lipophilic statin; for rs708272 GG (n = 33): 26 used a lipophilic statin. CDR-SOB, Clinical Dementia Rating sum-of-boxes; ADL, Index of Independence in Activities of Daily Living; MMSE, Mini-Mental State Examination; SMMSE, Severe Mini-Mental State Examination; SD, standard deviation.

Table 5 shows CETP haplotype effects for the entire sample. Considering users of lipophilic statins only, carriers of rs5882-AA/rs708272-AA had faster worsening of MMSE scores, while carriers of rs5882-GG/rs708272-GG had improved MMSE scores. Carriers of rs5882-AG/rs708272-GG had slower worsening of SMMSE scores when using lipophilic statins, and faster worsening when not using these drugs. Carriers of rs5882-GG/rs708272-AG had slower worsening of basic functionality when using lipophilic statins, and faster worsening when not using these drugs. When using lipophilic statins, carriers of rs5882-AA/rs708272-AG and non-carriers of rs5882-AA/rs708272-GG had slower worsening of MMSE scores, while non-carriers of rs5882-AG/rs708272-GG had slower worsening of basic functionality. In addition, carriers of rs5882-AG/rs708272-GG had faster worsening of SMMSE scores (p = 0.035), while carriers of rs5882-GG/rs708272-GG had improved basic functionality (p = 0.034) and MMSE scores (p = 0.010), regardless of use of lipophilic statins.

Table 5

Response to lipophilic statins in one year according to each CETP haplotype

CETP haplotypes		Variations in test scores in one year (mean±SD)
		CDR-SOB Lipophilic statin^a		ADL Lipophilic statin^a		MMSE Lipophilic statin^a		SMMSE Lipophilic statin^a
		Yes	No	Yes	No	Yes	No	Yes	No
rs5882 AA / rs708272 AA	Yes (n = 3)	4.00±0.0	2.75±1.1	–4.00±0.0	–1.50±2.1	–9.00±0.0	–1.00±2.8	–13.00±0.0	–1.50±3.5
	No (n = 187)	1.51±2.5	1.74±2.4	–0.46±1.5	–0.73±1.7	–0.94±3.0	–1.96±3.2	–1.42±3.6	–1.92±4.5
	p ^b	0.423	0.579	0.172	0.620	0.029	0.644	0.083	0.526
rs5882 AA / rs708272 AG	Yes (n = 36)	1.35±2.8	2.33±2.8	–0.30±1.4	–0.44±1.5	–0.26 ± 3.7^c	–3.22 ± 3.4^c	–1.33±2.7	–0.56±1.4
	No (n = 154)	1.57±2.4	1.67±2.2	–0.53±1.5	–0.83±1.8	–1.18±2.9	–1.64±3.0	–1.54±3.9	–2.19±4.9
	p ^b	0.863	0.535	0.859	0.633	0.339	0.175	0.226	0.295
rs5882 AA / rs708272 GG	Yes (n = 34)	1.29±2.7	1.33±2.2	–0.43±1.5	–0.17±1.0	–1.79±3.0	–2.00±3.0	–0.86±2.7	–0.83±2.7
	No (n = 156)	1.59±2.4	1.84±2.4	–0.50±1.5	–0.84±1.8	–0.80 ± 3.1^c	–1.91 ± 3.2^c	–1.67±3.9	–2.04±4.7
	p ^b	0.450	0.406	0.894	0.281	0.089	0.939	0.245	0.298
rs5882 AG / rs708272 AA	Yes (n = 10)	1.50±2.6	–	–0.30±0.7	–	–1.10±2.6	–	–1.00±1.7	–
	No (n = 180)	1.53±2.5	1.78±2.3	–0.50±1.5	–0.76±1.7	–0.99±3.2	–1.92±3.1	–1.54±3.8	–1.90±4.5
	p ^b	0.829	–	0.836	–	0.668	–	0.726	–
rs5882 AG / rs708272 AG	Yes (n = 55)	1.60±2.5	1.53±2.5	–0.63±1.5	–1.10±1.7	–1.26±2.7	–1.70±3.0	–2.43±5.5	–1.95±5.4
	No (n = 135)	1.50±2.5	1.95±2.3	–0.43±1.5	–0.55±1.8	–0.91±3.2	–2.06±3.2	–1.19±2.9	–1.87±3.9
	p ^b	0.869	0.649	0.781	0.375	0.815	0.486	0.321	0.562
rs5882 AG / rs708272 GG	Yes (n = 29)	1.98±2.1	1.87±2.5	–0.95±1.9	0.13±1.6	–0.43±2.8	–2.50±3.7	–1.24 ± 2.6^c	–5.00 ± 6.0^c
	No (n = 161)	1.45±2.5	1.77±2.3	–0.40 ± 1.4^c	–0.93 ± 1.7^c	–1.10±3.2	–1.81±3.0	–1.55±3.9	–1.33±4.0
	p ^b	0.383	0.963	0.222	0.086	0.189	0.469	0.228	0.001
rs5882 GG / rs708272 AA	Yes (n = 7)	0.33±1.0	0.00±0.0	0.17±0.4	0.00±0.0	–0.50±2.7	4.00±0.0	–1.00±1.1	0.00±0.0
	No (n = 183)	1.58±2.5	1.82±2.4	–0.51±1.5	–0.78±1.7	–1.02±3.1	–2.04±3.0	–1.53±3.8	–1.94±4.5
	p ^b	0.325	0.744	0.417	0.773	0.734	0.084	0.974	0.923
rs5882 GG / rs708272 AG	Yes (n = 10)	3.20±2.6	2.20±1.9	–0.40 ± 1.5^c	–2.00 ± 2.7^c	–3.40±3.0	–1.00±2.1	0.00±3.4	–1.00±2.7
	No (n = 180)	1.46±2.5	1.74±2.4	–0.49±1.5	–0.63±1.6	–0.91±3.1	–2.02±3.2	–1.56±3.7	–2.00±4.6
	p ^b	0.209	0.511	0.648	0.024	0.093	0.770	0.179	0.947
rs5882 GG / rs708272 GG	Yes (n = 6)	0.83±1.1	–	0.50±1.2	–	1.83±1.2	–	–1.50±4.3	–
	No (n = 184)	1.56±2.5	1.78±2.3	–0.53±1.5	–0.76±1.7	–1.13±3.1	–1.92±3.1	–1.50±3.7	–1.90±4.5
	p ^b	0.410	–	0.058	–	0.023	–	0.863	–

^aLipophilic statins: for rs2695121 CC (n = 74): 61 used a lipophilic statin; for rs2695121 CT (n = 88): 61 used a lipophilic statin; for rs2695121 TT (n = 28): 17 used a lipophilic statin; for rs5882 AA (n = 73): 56 used a lipophilic statin; for rs5882 AG (n = 94): 66 used a lipophilic statin; for rs5882 GG (n = 23): 17 used a lipophilic statin; for rs708272 AA (n = 20): 17 used a lipophilic statin; for rs708272 AG (n = 101): 67 used a lipophilic statin; for rs708272 GG (n = 69): 55 used a lipophilic statin. ^bDifferences regarding use of a lipophilic statin for carriers versus non-carriers of each CETP haplotype: general linear model adjusted for sex, years of education, age, estimated baseline disease duration, total cholesterol and weight variations in one year. ^cSignificant differences regarding use of a lipophilic statin versus use of no lipophilic statin for carriers or non-carriers of specific CETP haplotypes (general linear model adjusted for sex, years of education, age, estimated baseline disease duration, total cholesterol and weight variations in one year): differences in MMSE changes for carriers of rs5882 AA / rs708272 AG – p = 0.023; differences in MMSE changes for non-carriers of rs5882 AA / rs708272 GG – p = 0.034; differences in ADL changes for non-carriers of rs5882 AG / rs708272 GG – p = 0.048; differences in SMMSE changes for carriers of rs5882 AG / rs708272 GG – p = 0.001; differences in ADL changes for carriers of rs5882 GG / rs708272 AG – p = 0.031. SD, standard deviation; CDR-SOB, Clinical Dementia Rating sum-of-boxes; ADL, Index of Independence in Activities of Daily Living; MMSE, Mini-Mental State Examination; SMMSE, Severe Mini-Mental State Examination.

Graphical representations of the most significant results of the analyses for specific genotypes are illustrated in Fig. 1, while those for CETP haplotypes are illustrated in Fig. 2; each graph represents test score variations in one year according to specific genetic variants and pharmacological treatment.

Fig. 1

Test score variations in one year according to specific genotypes and pharmacological treatment are graphically represented. A) Regarding Severe Mini-Mental State Examination score variations, APOE ɛ4 carriers who carried NR1H2 rs2695121-CC had faster worsening when using lipophilic statins (p = 0.016). B) Regarding Index of Independence in Activities of Daily Living score variations, APOE ɛ4 carriers who carried CETP rs5882-GG had slower worsening when using lipophilic statins (p = 0.007). C) Regarding Mini-Mental State Examination score variations, APOE ɛ4 carriers who carried CETP rs5882-AA had faster worsening (p = 0.019), while APOE ɛ4 carriers who carried CETP rs5882-GG had slower worsening (p = 0.046), regardless of pharmacological treatment. D) Regarding Severe Mini-Mental State Examination score variations, APOE ɛ4 carriers who carried CETP rs5882-AA had faster worsening when using lipophilic statins (p = 0.020). E) Regarding Index of Independence in Activities of Daily Living score variations, APOE ɛ4 carriers who carried CETP rs708272-AG had slower worsening when using lipophilic statins (p = 0.040).

Fig. 2

Test score variations in one year according to CETP haplotypes and pharmacological treatment are graphically represented. A) Regarding Mini-Mental State Examination score variations, carriers of rs5882-AA/rs708272-AA had faster worsening when using lipophilic statins (p = 0.029). B) Regarding Mini-Mental State Examination score variations, carriers of rs5882-AA/rs708272-AG had slower worsening when using lipophilic statins (p = 0.023). C) Regarding Mini-Mental State Examination score variations, non-carriers of rs5882-AA/rs708272-GG had slower worsening when using lipophilic statins (p = 0.034). D) Regarding Index of Independence in Activities of Daily Living score variations, non-carriers of rs5882-AG/rs708272-GG had slower worsening when using lipophilic statins (p = 0.048). E) Regarding Severe Mini-Mental State Examination score variations, carriers of rs5882-AG/rs708272-GG had slower worsening when using lipophilic statins (p = 0.001) and faster worsening when not using lipophilic statins (p = 0.001). F) Regarding Index of Independence in Activities of Daily Living score variations, carriers of rs5882-GG/rs708272-AG had slower worsening when using lipophilic statins (p = 0.031) and faster worsening when not using lipophilic statins (p = 0.024). G) Regarding Index of Independence in Activities of Daily Living score variations, carriers of rs5882-GG/rs708272-GG had improved scores (p = 0.031), but all of them used a lipophilic statin. H) Regarding Mini-Mental State Examination score variations, carriers of rs5882-GG/rs708272-GG had improved scores (p = 0.023), but all of them used a lipophilic statin.

DISCUSSION

In this study, little more than half of the patients were APOE ɛ4 carriers. We found that effects of CETP genotypes were significant only for APOE ɛ4 carriers: CETP rs5882-GG conferred protection from cognitive decline, while CETP rs5882-AA caused faster cognitive decline. In addition, APOE ɛ4 carriers who also carried NR1H2 rs2695121-CC or CETP rs5882-AA were more susceptible to harmful cognitive effects of lipophilic statins, while APOE ɛ4 carriers who also carried CETP rs5882-GG or CETP rs708272-AG had functional benefits when using lipophilic statins. APOE ɛ4 non-carriers resisted any cognitive or functional effects of lipophilic statin therapy, while the lack of variability in rs3846662 genotypes prevented us from assessing the effects of the HMGCR gene.

When assessing CETP haplotypes only, the presence of rs5882-GG was protective concerning cognitive and functional decline, regardless of therapy with lipophilic statins. For carriers of most CETP haplotypes, the presence of the A allele of rs5882 and/or the A allele of rs708272 led to cognitive and functional harm when using lipophilic statins, while these drugs benefitted carriers of the G allele of rs5882 and/or the G allele of rs708272 concerning cognitive and functional decline.

APOE ɛ4 carrier status

APOE ɛ4 carrier status modifies the effects of other cerebrovascular metabolism genes on neurological features in patients with AD, including genes related to arterial hypertension [36], insulin degradation [37], free-radical production [38], and cholesterol metabolism [25]. No significant pharmacogenetic associations were found for APOE ɛ4 non-carriers in the present study, possibly due to enhanced mechanisms of neural repair and amyloid-β clearance in such patients and reiterating the importance of sample stratification according to APOE ɛ4 carrier status [17]. Regarding significant findings from this cohort, some effects were boosted when haplotypes were present to strengthen the actions of independent genotypes or alleles.

The apolipoprotein E is the main cholesterol transporter in the brain, assisting amyloid-β deposition and tau-mediated network disruption with clinical consequences [39], and impacting cholinergic dysfunction and atherogenesis [14]. The apolipoprotein E has a strong affinity with the low-density lipoprotein receptor within the central nervous system, which is usually upregulated by statin therapy [25]. APOE ɛ4 alleles affect behavioral performance [21] and effects of cerebrovascular risk factors on clinical changes in late-onset AD, particularly considering lipid profile variations, but do not affect cognitive or functional response to lipophilic statins by themselves [40], suggesting that other genetic variants could be important for such effects.

CETP variants

The G allele of CETP rs5882 seems to be protective by enhancing myelin biosynthesis in the brain and has been associated with improved white matter integrity in young adults [41], with preserved cognition in cognitively healthy older people particularly in the presence of the APOE ɛ4 allele [42], and with less intense frontally mediated behaviors in patients with AD [21]. Protective CETP variants lead to lower CETP levels resulting in higher high-density lipoprotein cholesterol levels [43] which interact with amyloid-β to inhibit its fibrillization [14].

The G allele of CETP rs708272 is reportedly atherogenic, while its carriers usually have better lipid-lowering response to Simvastatin [44] and less intense frontally mediated behaviors [21]. In addition, one study had previously shown increased mortality after coronary artery bypass grafting for carriers of CETP rs708272-AG [45], a finding that could be in line with our result of functional benefits of lipophilic statins to APOE ɛ4 carriers who also carried this genotype.

NR1H2 variants

In line with our findings, the T allele of NR1H2 rs2695121 seems to be protective for APOE ɛ4 carriers only and associated with prospective blood pressure reductions [15], though it has also been associated with more neuropsychiatric symptoms in severely impaired patients with AD regardless of APOE ɛ4 carrier status [21]. Overexpression of NR1H2 rs2695121 in APOE ɛ4 carriers may upregulate the dysfunctional apolipoprotein E4 and reduce cholesterol efflux from astrocytes, thus increasing its availability to protect plasma membranes in the central nervous system [14].

Effects of drug therapy

Little less than three quarters of all patients had hypercholesterolemia in this study, almost all of them using lipophilic statins, thus confirming the burden of this risk factor contributing to cerebrovascular dysregulation in older people [40]. Since only two patients used a hydrophilic statin (Rosuvastatin), and only four used Ezetimibe, we could not specifically assess the effects of such therapies; in the end, users of a hydrophilic statin were considered non-lipophilic statin users. Some associations might have been biased by the high rates of statin therapy, but management recommendations regarding lipid-lowering therapy were strictly followed.

Treatment of cerebrovascular risk factors by itself (including hypercholesterolemia) has been associated with slower cognitive decline in AD [46]. The present study expands these concepts by revealing that neurological effects of statin therapy may be genetically mediated. However, not all studies show cognitive benefits with lipophilic statins, even after dose escalation [47]. In addition, one recent large, randomized trial showed no associations of statin use with cognitive decline or incident dementia in cognitively healthy older people, neither for hydrophilic nor for lipophilic statins [48].

The brains of patients with AD typically have low neuronal concentrations of cholesterol [12]. The largest amount of brain cholesterol results from local production by astrocytes; while high levels of cholesterol increase insoluble amyloid-β formation [10], enhancing the content of cholesterol in the neuronal membrane protects against the neurotoxicity of amyloid-β [12]. Statins lower plasma cholesterol concentrations by inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase [40]. Lipophilic statins cross the blood-brain barrier and may critically lower brain cholesterol causing synaptic dysfunction and neuronal injury, possibly explaining why carriers of less atherogenic genetic variants in the present study had more neurological harm when using lipophilic statins [10]. On the other hand, microvascular mechanisms could concur to affect brain perfusion and neuroinflammation causing lipid dyshomeostasis [14].

Final considerations

Due to operational and funding restrictions, we only studied APOE, CETP, NR1H2, and HMGCR as potential modifiers of cognitive and functional response in this cohort. Other cholesterol-related genes with significant importance for AD pathogenesis should be assessed in future pharmacogenomic studies.

The longitudinal design of this study is a major strength. Assessments of functional and cognitive decline, as well as lipid profile variations, were well documented throughout the follow-up, thus avoiding a classification bias that could have resulted from self-reports. All test scores were significantly different after one year, thus confirming that the duration of follow-up was proper for most measures. Though it is unknown whether age and sex affect the brain distribution of lipophilic statins, our general linear model was adjusted for these parameters. Since education may prospectively affect brain pathology according to APOE ɛ4 carrier status [49], adjustment for years of education confers an additional advantage to the analyses of this study.

Interpretation of the results of this preliminary study is limited by the fact that it was conducted in a single center with no randomization, lacking measures of the proteins that should be translated by the studied genes and stratification according to environmental factors. Small subgroups to assess haplotype effects affected the power of the associations, thus further studies with larger samples are recommended to validate these findings. Though functionality may be affected by cognitive performance in all stages of AD [50], only one test score variation was assessed at each time in the analyses. It is also unknown whether the neurological effects of lipophilic statins are different from those of hydrophilic statins (because too few patients used hydrophilic statins in this study) or dose-dependent; still, many patients were already under treatment when they were included in the study, thus rendering fruitless the assessment of whether these drugs would be more efficacious at the start of lipid-lowering therapy or not. These limitations were minimized by blinding observers to genetic data during the neurological evaluations, and also by indicating lipophilic statins only for patients with hypercholesterolemia. In addition, the use of cholinesterase inhibitors was sustained for most patients who did not have side effects, so that the results of this study could be attributed to the effects of lipophilic statins only. Nonetheless, this is a pioneering read on the evaluation of effects of lipophilic statins during the course of AD while taking into account APOE haplotypes, NR1H2 and HMGCR genotypes, and CETP genotypes and haplotypes. Future studies should also prospectively analyze neuroimaging parameters and gene expression according to the use of these drugs.

In conclusion, therapy with lipophilic statins might affect cognition and functionality of carriers of specific genetic variants. In the end, reportedly protective variants of CETP and NR1H2 also seemed to slow cognitive and functional decline particularly for APOE ɛ4 carriers, regardless of cholesterol variations. Further molecular studies and randomized controlled trials will be required to confirm any disease-modifying or pharmacogenomic effects of lipophilic statins in AD.

Footnotes

ACKNOWLEDGMENTS

This work was sponsored by CAPES – Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (grant #1067/10) and FAPESP – The State of São Paulo Research Foundation (grant #2015/10109-5). The sponsors had no role in study design, in data collection, in analysis and interpretation of the data, in the writing of the report, or in the decision to submit the paper for publication.

Authors’ disclosures available online ().

PRIOR PRESENTATION OF INFORMATION FROM THE PAPER

Preliminary aspects of this study were previously presented (and published in the form of abstracts) at the following meetings:

AAIC > 14 – Alzheimer’s Association International Conference 2014 (with an Alzheimer’s Association Travel Fellowship to the first author) (Alzheimer’s Association, Copenhagen/DENMARK, July 2014). https://doi.org/10.1016/j.jalz.2014.05.698

29th CINP World Congress of Neuropsychopharmacology (Collegium Internationale Neuro-Psychopharmacologicum, Vancouver/CANADA, June 2014). https://doi.org/10.1017/S1461145714000741

66th Annual Meeting of the American Academy of Neurology (American Academy of Neurology, Philadelphia/USA, April 2014). https://n.neurology.org/content/82/10_Supplement/P5.223

AD/PD 2013 – The 11th International Conference on Alzheimer’s & Parkinson’s Diseases (Kenes International, Florence/ITALY, March 2013). Alzheimer’s and Parkinson’s Diseases: Mechanisms, Clinical Strategies, and Promising Treatments of Neurodegenerative Diseases. Basel: Karger, 2013, v. 11, p. 700.

137th Annual Meeting of the American Neurological Association (American Neurological Association, Boston/USA, October 2012). https://doi.org/10.1002/ana.23769

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