Effects of LDL Cholesterol and Statin Use on Verbal Learning and Memory in Older Adults at Genetic Risk for Alzheimer’s Disease

Abstract

Background:

The apolipoprotein epsilon 4 (APOE4) allele is a well-established genetic risk factor for Alzheimer’s disease (AD). However, there are mixed findings as to how the APOE4 allele modifies the effects of both higher low-density lipoprotein cholesterol (LDL) and statin use on cognitive functioning.

Objective:

This study sought to examine the effects of LDL levels and statin use on verbal learning and memory, as modified by the presence of the APOE4 allele, in a sample of cognitively unimpaired, older adults at risk for AD.

Methods:

Neuropsychological, LDL, statin use, and APOE4 data were extracted from an ongoing longitudinal study at the Banner Alzheimer’s Institute in Arizona. Participants were cognitively unimpaired based on Mini-Mental State Examination scores within a normal range, aged 47–75, with a family history of probable AD in at least one first-degree relative.

Results:

In the whole sample, higher LDL was associated with worse immediate verbal memory in APOE4 non-carriers, but did not have an effect on immediate verbal memory in APOE4 carriers. In APOE4 non-carriers, statin use was associated with better verbal learning, but did not have an effect on verbal learning in APOE4 carriers. Among women, higher LDL in APOE4 carriers was associated with worse verbal learning than in APOE4 non-carriers, and statin use in APOE4 non-carriers was associated with better verbal learning and immediate and delayed verbal memory but worse performances on these tasks in APOE4 carriers.

Conclusion:

LDL and statin use may have differential effects on verbal learning and/or memory depending on genetic risk for AD. Women appear to be particularly vulnerable to statin use depending on their APOE4 status.

Keywords

at risk for alzheimer’s disease immediate and delayed verbal memory LDL cholesterol statins verbal learning

INTRODUCTION

Elevated levels of low-density lipoprotein cholesterol (LDL) are associated with negative health-related risks including cardiovascular disease and stroke [1]. However, the relationship between LDL and Alzheimer’s disease (AD) is uncertain, with some studies showing higher LDL associated with increased risk of AD [2, 3], increased risk of vascular dementia [4], or no associations with all types of dementia [5, 6]. It is well established that the apolipoprotein epsilon 4 (APOE4) allele is a risk factor for late onset AD and vascular dementia, particularly for women, at least in persons older than 65 years [7]. Although some studies suggest that high cholesterol and LDL increase the risk of developing AD and cognitive impairment [8 –11], there is evidence that increasing LDL may have differential effects on AD risk in those with or without at least one APOE4 allele [2, 3] and in relation to age and sex [12]. Statins, a class of drugs used to inhibit the process of cholesterol production and in effect lower LDL, reduce the risk of atherosclerosis development and coronary heart disease, but there are conflicting findings regarding the use of statins on cognition [13, 14].

The current study sought to examine the effects of LDL levels and statin use on cognition by APOE4 status, specifically with respect to verbal learning and memory, in a sample of cognitively unimpaired, older adults at risk for AD. Women have an increased risk of AD compared to men [15], but there are mixed results as to how being female affects AD risk based on APOE4 status [16]. Therefore, as a post-hoc analysis, this study also sought to look within women as to whether the effects of LDL and statins on cognition may be more detrimental in women who are APOE4 carriers than women who are non-carriers.

MATERIALS AND METHODS

Study population

Neuropsychological, LDL, statin use, and APOE4 data were utilized from an ongoing longitudinal study at the Banner Alzheimer’s Institute in Arizona [17]. All participants were cognitively unimpaired based on Mini-Mental State Examination [18] scores within a normal range (i.e., ≥26), aged 47–75, with a family history of probable AD in at least one first-degree relative. This study examined cross-sectional data extracted from participants’ initial visit.

Verbal learning and memory measure

The Rey Auditory Verbal Learning Test (RAVLT) [19] is a measure composed of 15 unrelated words that are repeated over five learning trials. After an interference task of another 15 unrelated words, the individual being tested is asked to recall both immediately after the interference task and 30 min later. Since verbal learning and memory impairments are associated with AD, three RAVLT measures were included as outcome variables: 1) verbal learning (potential range from 0–75), 2) immediate verbal memory (potential range from 0–15), and 3) delayed verbal memory scores (potential range from 0–15).

APOE4 status

APOE4 status was defined by the presence of at least one APOE4 allele.

Statin use

Statin use was defined by whether the study subject was taking a cholesterol lowering drug, including atorvastatin, fluvastatin, lovastatin, pravastatin, pitavastatin, simvastatin, rosuvastatin, lescol, mevacor, altocor, livalo, and zocor, at study enrollment.

Statistical analyses

Statistical analyses on clinical, demographic, and neuropsychological data were performed using SPSS software version 26.0 (SPSS Inc., Chicago, IL). Descriptive statistics and chi-square analyses were utilized to evaluate sex, APOE4 status, and statin use data. T-tests were conducted between sexes on demographic, metabolic, and neuropsychological data.

Linear regression analyses were conducted to predict each of three outcome variables using LDL as the primary exposure variable. Age, education, sex, body mass index (BMI), APOE4 status, and statin use were included as model covariates.

Additional linear regression analyses were then conducted with the addition of the following interaction terms: 1) APOE4 status by LDL and 2) APOE4 status by statin use. Because of the differences in sample size (there were three times the number of women than men), similar regression post-hoc analyses were conducted within groups of women separately.

RESULTS

The study sample included 205 participants consisting of 56 males (27.3%) and 149 females (72.7%). Age and metabolic data are presented in Table 1. Of the 205 participants, 128 (62.4%) had total cholesterol levels at or above 180 and 125 (61%) had LDL levels at or above 100 (Table 1). There were no significant differences in any demographic, metabolic, or cognitive variables between those with (N = 98) or without (N = 106) at least one APOE4 allele. Chi-square analysis also did not show significant differences in distribution between APOE4 status and statin use (χ²(1) = 0.069, p = 0.79); 23/76 participants with at least one APOE4 allele used statins and 23/106 participants without at least one APOE4 allele used statins. However, there were significant differences in statin use by age and LDL levels. Those who used statins were older and had lower LDL levels (Table 3). Among the 46 statin users, 14 (30.4%) had total cholesterol levels at or above 180 and 11 (23.9%) had LDL levels at or above 100. There were no significant differences in statin use for education, BMI, or any cognitive variables.

No significant sex differences were found in age, LDL, or triglyceride levels, but there were differences in BMI, total cholesterol, HDL-cholesterol, and blood glucose (Table 2). Significant sex differences were found in verbal learning, immediate verbal memory, and delayed verbal memory (Table 2). Chi-square analysis showed no significant differences in distribution between sex and APOE4 status (χ²(1) = 0.107, p = 0.74). Twenty-six men and 73 women had at least one APOE4 allele. Chi-square analysis revealed a significant difference in distribution between sex and statin use (χ²(1) = 5.84, p = 0.02). Nineteen men and 27 women used statins.

Table 1

Whole group demographic and clinical data

	N	Mean	Range	SD
Age	205	60.30	47–75	6.10
Education (y)	205	16.23	12–26	2.15
BMI	205	27.04	18.09–40.99	4.89
Cholesterol (mg/dL)	205	191.16	102–284	35.54
Triglycerides (mg/dL)	205	117.05	34–374	66.02
HDL Cholesterol (mg/dL)	204	60.19	25–112	16.85
LDL Cholesterol (mg/dL)	205	109.98	43–207	31.30
Blood Glucose (mg/dL)	161	93.84	74–131	10.72
MMSE	205	29.72	26–30	0.61
Verbal learning	205	49.96	29–75	9.22
Immediate verbal memory	205	10.10	2–15	2.84
Delayed verbal memory	205	09.70	1–15	3.26

BMI, body mass index; MMSE, Mini-Mental State Examination.

Table 2

Sex differences in demographic, metabolic, and cognitive variables

	Sex	N	Mean	SD	t	p
Age	Male	56	60.64	5.921	0.48	0.63
	Female	149	60.17	6.185
Education	Male	56	16.68	1.790	1.84	0.07
	Female	149	16.06	2.255
BMI	Male	56	28.43	3.84	2.88	0.01
	Female	149	26.52	5.14
Total Cholesterol (mg/dL)	Male	56	181.07	37.89	–2.52	0.01
	Female	149	194.95	33.97
Triglycerides (mg/dL)	Male	56	117.68	73.88	0.08	0.93
	Female	149	116.82	63.08
HDL Cholesterol (mg/dL)	Male	56	50.45	11.82	–6.36	<0.01
	Female	148	63.87	17.04
LDL Cholesterol (mg/dL)	Male	56	110.50	31.64	0.15	0.89
	Female	149	109.79	31.27
Blood Glucose (mg/dL)	Male	51	96.49	12.32	2.16	0.03
	Female	110	92.62	9.71
MMSE	Male	56	29.66	0.61	–0.89	0.38
	Female	149	29.74	0.61
Verbal learning	Male	56	47.79	8.93	–4.13	<0.01
	Female	149	51.52	8.85
Immediate verbal memory	Male	56	09.02	3.06	–3.34	<0.01
	Female	149	10.51	2.77
Delayed verbal memory	Male	56	08.41	3.47	–3.58	<0.01
	Female	149	10.19	3.05

BMI, body mass index; MMSE, Mini-Mental State Examination.

Table 3

Statin use differences in demographic and metabolic variables

	Statin use		No Statin use
	(N = 46)		(N = 159)
	Mean	SD	Mean	SD	t	p
Age	62.94	4.98	59.53	6.20	–3.86	<0.01
Education	16.37	1.94	16.19	2.21	–0.50	0.62
BMI	28.14	4.78	26.72	4.89	–1.74	0.08
Total Cholesterol (mg/dL)	164.65	30.97	198.83	33.07	6.26	<0.01
HDL Cholesterol (mg/dL)	53.80	13.46	62.04	17.32	3.41	<0.01
LDL Cholesterol (mg/dL)	87.33	26.49	116.53	29.53	6.04	<0.01
Triglycerides (mg/dL)	02.64	1.72	02.14	1.71	–1.74	0.08
Blood Glucose (mg/dL)	94.33	10.00	93.70	10.93	–0.31	0.76

BMI, body mass index.

Whole sample

In the sample as a whole, higher LDL was not significantly associated with verbal learning, immediate verbal memory, or delayed verbal memory. A significant interaction between APOE4 carriership and LDL was found in immediate verbal memory (Table 4). In APOE4 non-carriers, for every ten-unit increase in LDL there was a 0.2-drop in immediate verbal memory scores. In carriers, there was a slight 0.1-increase in immediate verbal memory scores for every 10-unit increase in LDL; however, having at least one APOE4 allele was the significant main effect associated with lower immediate verbal memory. Although these findings were statistically significant, they do not appear to be clinically significant. No interactions were found between LDL and APOE4 carriership for verbal learning or delayed verbal memory.

Table 4

Interaction between APOE4 and LDL in whole sample

	B	SE B	β	t	p
Verbal learning
APOE4 carrier	–6.66	4.58	–0.36	–1.45	0.15
LDL	–0.04	0.03	–0.13	–1.24	0.22
APOE4×LDL	0.07	0.04	0.43	1.64	0.10
Immediate verbal memory
APOE4 carrier	–3.25	1.45	–0.56	–2.24	0.03
LDL	–0.02	0.01	–0.22	–2.06	0.04
APOE4×LDL	0.03	0.01	0.59	2.25	0.03
Delayed verbal memory
APOE4 carrier	–1.83	1.65	–0.28	–1.11	0.27
LDL	–0.01	0.01	–0.13	–1.14	0.26
APOE4×LDL	0.02	0.01	0.29	1.07	0.29

APOE4 carrier, carrier for the apolipoprotein epsilon 4 allele; LDL, low-density lipoprotein.

A significant interaction between APOE4 carriership and statin use was found in verbal learning (Table 5). Statin use in APOE4 non-carriers was associated with a 5-point increase in verbal learning scores whereas in APOE4 carriers, statin use was not associated with verbal learning scores (Fig. 1).

Table 5

Interaction between APOE4 and statin use in whole sample

	B	SE B	β	t	p
Verbal learning
APOE4 carrier	2.09	1.39	0.11	1.50	0.14
Statin Use	5.13	2.21	0.23	2.32	0.02
APOE4×Statin use	–6.93	2.93	–0.24	–2.36	0.02
Immediate verbal memory
APOE4 carrier	0.20	0.45	0.03	0.45	0.66
Statin Use	0.70	0.71	0.10	0.98	0.33
APOE4×Statin use	–1.37	0.94	–0.15	–1.45	0.15
Delayed verbal memory
APOE4 carrier	0.26	0.50	0.04	0.51	0.61
Statin Use	0.81	0.80	0.10	1.01	0.31
APOE4×Statin use	–1.79	1.06	–0.17	–1.69	0.09

APOE4 carrier, carrier for the apolipoprotein epsilon 4 allele.

Fig. 1

Effect of statin use on RAVLT verbal learning by APOE4 status in whole sample.

Women only

Among women, we found a significant interaction between LDL and APOE4 carriership for verbal learning but not for immediate or delayed verbal memory (Table 6 and Fig. 2). In APOE4 non-carriers, for every 1-unit increase in LDL there was a 0.08-point drop in verbal learning scores, whereas in APOE4 carriers, there was a 10.8-point drop in verbal learning scores for every 1-unit increase in LDL (Table 6). We also found a significant interaction between APOE4 carriership and statin use for verbal learning, immediate verbal memory, and delayed verbal memory (Table 7 and Figs. 3 –5). Statin use in APOE4 non-carriers was associated with a 6-point increase in verbal learning score whereas in APOE4 carriers, statin use was associated with a 2-point decrease in verbal learning score (Table 7). In APOE4 non-carriers, statin use was associated with a 1-point increase in immediate verbal memory scores whereas in APOE4 carriers, statin use was associated with a 1-point drop in immediate verbal memory scores (Table 7). In APOE4 non-carriers, statin use was associated with a 1-point increase in delayed verbal memory scores whereas in APOE4 carriers, statin use was associated with a 2-point drop in delayed verbal memory scores (Table 7).

Fig. 2

Effect of LDL on RAVLT verbal learning by APOE4 genotype in women only.

Fig. 3

Effect of statin use on RAVLT verbal learning by APOE4 genotype in women only.

Fig. 4

Effect of statin use on RAVLT immediate verbal memory by APOE4 genotype in women only.

Fig. 5

Effect of statin use on RAVLT delayed verbal memory by APOE4 genotype in women only.

Table 6

Interaction between APOE4 and LDL in women only

	B	SE B	β	t	p
Verbal learning
APOE4 carrier	–10.81	5.36	–0.61	–2.02	0.05
LDL	–0.08	0.04	–0.28	–2.13	0.04
APOE4×LDL	00.09	0.05	0.64	1.95	0.05
Immediate verbal memory
APOE4 carrier	–3.57	1.62	–0.65	–2.20	0.03
LDL	–0.02	0.01	–0.20	–1.61	0.11
APOE4×LDL	0.03	0.01	0.57	1.79	0.08
Delayed verbal memory
APOE4 carrier	–2.56	1.83	–0.42	–1.40	0.17
LDL	–0.02	0.01	–0.16	–1.28	0.21
APOE4×LDL	0.02	0.02	0.33	1.03	0.31

APOE4 carrier, carrier for the apolipoprotein epsilon 4 allele.

Table 7

Interaction between APOE4 and statin use in women only

	B	SE B	β	t	p
Verbal learning
APOE4 carrier	0.71	1.58	0.04	0.45	0.65
Statin Use	5.89	2.76	0.26	2.14	0.03
APOE4×Statin use	–8.53	3.72	–0.27	–2.29	0.02
Immediate verbal memory
APOE4 carrier	–0.39	0.48	–0.07	–0.81	0.42
Statin Use	1.32	0.84	0.19	1.58	0.12
APOE4×Statin use	–2.22	1.13	–0.23	–1.97	0.05
Delayed verbal memory
APOE4 carrier	–0.25	0.54	–0.04	–0.47	0.64
Statin Use	1.44	0.94	0.18	1.53	0.13
APOE4×Statin use	–2.89	1.26	–0.27	–2.29	0.02

APOE4 carrier, carrier for the apolipoprotein epsilon 4 allele.

DISCUSSION

Our study examined the effects of LDL and statin use in a cognitively unimpaired sample with risk for AD to assess for differential early risk manifestations of LDL and statin use. Since studies regarding LDL and statin use are mixed [2–5 , 14], our goal was to help clarify these discrepant findings, specifically in relation to genetic risk of AD. Because declines in verbal learning and memory are among the first indication of cognitive decline in relation to AD [20], we purposely focused on verbal learning and memory. Interestingly, we found significant effects for verbal learning and immediate verbal memory in the whole sample, suggesting that poor performance on early input of information might be sensitive to early changes in cognition associated with AD and/or vascular neurocognitive disorder. It is well documented that having at least one APOE4 allele is associated with risk for late onset AD [21]. It is also well documented that women are at an increased risk for developing AD compared to men [15]. Consistent with previous findings [22], women in our sample had higher scores on the verbal tasks compared to men. The potential effects of APOE4 carriership and female status on AD and mild cognitive impairment (MCI) risk motivated our interest in specifically looking at women to examine whether LDL or statin use modifies this risk.

Our findings suggested a differential effect on immediate verbal memory associated with APOE4 carriership and LDL level in our whole sample of men and women. Higher LDL was associated with worse immediate verbal memory in the APOE4 non-carriers, which supports this notion that LDL could function as an independent risk factor for AD outside of APOE4 genotype, as suggested by Wingo et al. [23]. In our study, LDL did not affect immediate verbal memory in the APOE4 carriers. We hypothesize that the presence of at least one APOE4 allele was the predominate risk for lower immediate verbal memory in this latter group, thus potentially masking any possible negative effects of LDL.

The majority of studies that evaluated LDL in relation to APOE4 utilized AD or MCI prevalence as the outcome measure with mixed findings. Elevated LDL has been shown to be associated with early-onset AD and increased risk for AD with [2, 24] and without relationship [3, 23] to APOE4 status. In the studies that did show a relationship with APOE4 status, high LDL posed an increased risk of AD but only in non-carriers. Hyperlipidemia, as measured by plasma cholesterol, was also found to be associated with non-AD type dementias but again, only in the APOE4 non-carriers [25]. In APOE4 carriers, lower cholesterol may actually have a negative impact on global cognition with advancing age [26] due to cholesterol’s role in regulating amyloid-β clearance [27].

However, our findings did show that in APOE4 non-carriers, statin use was associated with better verbal learning but there was no effect in APOE4 carriers in the whole sample containing men and women. This is in contrast to findings from Geifman et al., which found the biggest improvement in cognitive functioning among statin users who were also APOE4 carriers [28]. Interestingly, we found differential effects of statin use in women APOE4 carriers versus non-carriers. Statin use in women APOE4 non-carriers was associated with better verbal learning and memory but worse performances on these tasks in APOE4 carriers. Given this sample was unimpaired but at risk of AD, our findings were consistent with a study that showed that women APOE4 carriers with MCI may decline in verbal learning prior to the declines in delayed verbal memory that are seen in AD [29]. Further, a 4-month randomized clinical trial of statin use versus placebo in a population of cognitively unimpaired adult children of late onset AD patients, statin use improved delayed verbal memory, verbal fluency, and working memory regardless of APOE4 status [30]; however, the majority (approximately 80%) of the study population were men. Our findings in conjunction with the findings from these studies suggest that APOE4 status and sex may be important factors in consideration of statin use. Because of the large group size differences between men and women in our study and the small statin group sizes, we were unable to adequately assess for sex differences and future studies are warranted to help clarify these relationships.

Despite the mixed findings that show a benefit of statin use on AD risk, statins may have differing cognitive effects based on dosage and treatment initiation [14], lending support to the need for clinical trials with cognitively unimpaired populations at risk for AD in the hopes of reducing incident MCI or any dementia. While some studies suggest that statins may provide cognitive benefits [14], it is worth noting potential adverse effects associated with statin use, such as recent findings of elevated HbA1c levels in those without diabetes as well as increased risk of new-onset diabetes [31], an established risk factor for cognitive decline [32], thus complicating the cognitive findings regarding statin use even further. In addition to potentially affecting blood glucose levels, other studies have shown that statin use can adversely affect liver and muscle tissue, increase the risk of hemorrhagic stroke, and negatively impact sleep [33]. Thus, these possible side effects highlight the need for careful consideration in weighing the risks versus the benefits when prescribing statins, especially when treating women who are APOE4 carriers. Currently, standard practice is for the physician to prescribe statins to target hyperlipidemia typically with positive results and clearly, future studies are necessary to determine whether genotyping should be a consideration. The findings from this current study raise the possibility that sex status and genotype may play important roles in terms of the beneficial effects of statins.

Limitations

This study was a secondary analysis based on data from an ongoing study; therefore, interpretation of any associations is limited. Randomized controlled clinical trials are needed to substantiate findings as well as to assess for any causal factors. The use of a MMSE cut-off of 26 has limited diagnostic accuracy to determine unimpaired cognition and may have skewed our findings; however, this was established in the original study as part of recruitment. Because these were secondary analyses of an existing database, to obtain adequate power, we utilized the complete database of individuals within a wide age range. Mid-life high cholesterol and LDL are shown to have greater negative effects on cognition than these elevations in older adults; however, these were individuals that were considered unimpaired with risk for AD. In addition, we covaried for age in our statistical models.

We did not have enough power to analyze the specific types of statin use and information on length of statin use was not available, thus limiting our ability to generalize our findings. However, total cholesterol and its fractions do not change in a short period of time. Therefore, we assumed that statin users were on statins for at least 6 months because statin users had lower LDL than statin non-users. As these were secondary analyses, we strongly support further studies that could support or refute our findings given the widely known benefits of statin use. Although the sex specific findings were based on post-hoc analyses, they were very intriguing and will be addressed further in an ongoing prospective study that is currently underway.

Conclusion

LDL and statin use may have differential effects on early input of verbal information depending on genetic risk for AD. Women appear to be particularly vulnerable to statin use depending on their APOE4 status. Our findings support the trend towards personalized medicine rather than a one-size-fits-all approach.

Footnotes

ACKNOWLEDGMENTS

This work was supported by the grant “Sex Specific Interactions of Modifiable & Non-modifiable Risk Factors of AD” awarded to Natalie Rasgon, MD, PhD, from the Alzheimer’s Association.

Authors’ disclosures available online ().

References

Imamura

, Doi

, Arima

, Yonemoto

, Hata

, Tanizaki

, Ibayashi

, Iida

, Kiyohara

(2009) LDL cholesterol and the development of stroke subtypes and coronary heart disease in a general Japanese population: The Hisayama study. Stroke 40, 382–388.

Hall

, Murrell

, Ogunniyi

, Deeg

, Baiyewu

, Gao

, Gureje

, Dickens

, Evans

, Smith-Gamble

, Unverzagt

, Shen

, Hendrie

(2006) Cholesterol, APOE genotype, and Alzheimer disease: An epidemiologic study of Nigerian Yoruba. Neurology 66, 223–227.

Schilling

, Tzourio

, Soumare

, Kaffashian

, Dartigues

, Ancelin

, Samieri

, Dufouil

, Debette

(2017) Differential associations of plasma lipids with incident dementia and dementia subtypes in the 3C Study: A longitudinal, population-based prospective cohort study. PLoS Med 14, e1002265.

Reitz

, Tang

, Luchsinger

, Mayeux

(2004) Relation of plasma lipids to Alzheimer disease and vascular dementia. Arch Neurol 61, 705–714.

Anstey

, Lipnicki

, Low

(2008) Cholesterol as a risk factor for dementia and cognitive decline: A systematic review of prospective studies with meta-analysis. Am J Geriatr Psychiatry 16, 343–354.

Ancelin

, Ripoche

, Dupuy

, Barberger-Gateau

, Auriacombe

, Rouaud

, Berr

, Carriere

, Ritchie

(2013) Sex differences in the associations between lipid levels and incident dementia. J Alzheimers Dis 34, 519–528.

Molero

, Pino-Ramirez

, Maestre

(2001) Modulation by age and gender of risk for Alzheimer’s disease and vascular dementia associated with the apolipoprotein E-epsilon4 allele in Latin Americans: Findings from the Maracaibo Aging Study. Neurosci Lett 307, 5–8.

Helzner

, Luchsinger

, Scarmeas

, Cosentino

, Brickman

, Glymour

, Stern

(2009) Contribution of vascular risk factors to the progression in Alzheimer disease. Arch Neurol 66, 343–348.

Kivipelto

, Helkala

, Laakso

, Hanninen

, Hallikainen

, Alhainen

, Iivonen

, Mannermaa

, Tuomilehto

, Nissinen

, Soininen

(2002) Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med 137, 149–155.

10.

Shepardson

, Shankar

, Selkoe

(2011) Cholesterol level and statin use in Alzheimer disease: II. Review of human trials and recommendations. Arch Neurol 68, 1385–1392.

11.

Yaffe

, Barrett-Connor

, Lin

, Grady

(2002) Serum lipoprotein levels, statin use, and cognitive function in older women. Arch Neurol 59, 378–384.

12.

Jarvik

, Wijsman

, Kukull

, Schellenberg

, Yu

, Larson

(1995) Interactions of apolipoprotein E genotype, total cholesterol level, age, and sex in prediction of Alzheimer’s disease: A case-control study. Neurology 45, 1092–1096.

13.

Sano

, Bell

, Galasko

, Galvin

, Thomas

, van Dyck

, Aisen

(2011) A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology 77, 556–563.

14.

Schultz

, Patten

, Berlau

(2018) The role of statins in both cognitive impairment and protection against dementia: A tale of two mechanisms. Transl Neurodegener 7, 5.

15.

, Singh

(2014) Sex differences in cognitive impairment and Alzheimer’s disease. Front Neuroendocrinol 35, 385–403.

16.

Neu

, Pa

, Kukull

, Beekly

, Kuzma

, Gangadharan

, Wang

, Romero

, Arneric

, Redolfi

, Orlandi

, Frisoni

, Au

, Devine

, Auerbach

, Espinosa

, Boada

, Ruiz

, Johnson

, Koscik

, Wang

, Hsu

, Chen

, Toga

(2017) Apolipoprotein E genotype and sex risk factors for Alzheimer disease: A meta-analysis. JAMA Neurol 74, 1178–1189.

17.

Reiman

, Caselli

, Yun

, Chen

, Bandy

, Minoshima

, Thibodeau

, Osborne

(1996) Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med 334, 752–758.

18.

Folstein

, Folstein

, McHugh

(1975) “Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12, 189–198.

19.

Schmidt

(1996) Rey Auditory Verbal Learning Test: A Handbook, Western Psychological Services, Los Angeles.

20.

Estevez-Gonzalez

, Kulisevsky

, Boltes

, Otermin

, Garcia-Sanchez

(2003) Rey verbal learning test is a useful tool for differential diagnosis in the preclinical phase of Alzheimer’s disease: Comparison with mild cognitive impairment and normal aging. Int J Geriatr Psychiatry 18, 1021–1028.

21.

Di Battista

, Heinsinger

, Rebeck

(2016) Alzheimer’s disease genetic risk factor APOE-epsilon4 also affects normal brain function. Curr Alzheimer Res 13, 1200–1207.

22.

Kramer

, Delis

, Daniel

(1988) Sex differences in verbal learning. J Clin Psychol 44, 907–915.

23.

Wingo

, Cutler

, Wingo

, Le

, Rabinovici

, Miller

, Lah

, Levey

(2019) Association of early-onset Alzheimer disease with elevated low-density lipoprotein cholesterol levels and rare genetic coding variants of APOB. JAMA Neurol 76, 809–817.

24.

Evans

, Emsley

, Gao

, Sahota

, Hall

, Farlow

, Hendrie

(2000) Serum cholesterol, APOE genotype, and the risk of Alzheimer’s disease: A population-based study of African Americans. Neurology 54, 240–242.

25.

Dufouil

, Richard

, Fievet

, Dartigues

, Ritchie

, Tzourio

, Amouyel

, Alperovitch

(2005) APOE genotype, cholesterol level, lipid-lowering treatment, and dementia: The Three-City Study. Neurology 64, 1531–1538.

26.

van den Kommer

, Dik

, Comijs

, Fassbender

, Lutjohann

, Jonker

(2009) Total cholesterol and oxysterols: Early markers for cognitive decline in elderly?. Neurobiol Aging 30, 534–545.

27.

Dong

, Gim

, Yeo

, Kim

(2017) Integrated late onset Alzheimer’s disease (LOAD) susceptibility genes: Cholesterol metabolism and trafficking perspectives. Gene 597, 10–16.

28.

Geifman

, Brinton

, Kennedy

, Schneider

, Butte

(2017) Evidence for benefit of statins to modify cognitive decline and risk in Alzheimer’s disease. Alzheimers Res Ther 9, 10.

29.

Wang

, Zhou

, Ye

, Lin

, Zhang

, for Alzheimer’s Disease Neuroimaging Initiative (2019) Sex difference in the association of APOE4 with memory decline in mild cognitive impairment. J Alzheimers Dis 69, 1161–1169.

30.

Carlsson

, Gleason

, Hess

, Moreland

, Blazel

, Koscik

, Schreiber

, Johnson

, Atwood

, Puglielli

, Hermann

, McBride

, Stein

, Sager

, Asthana

(2008) Effects of simvastatin on cerebrospinal fluid biomarkers and cognition in middle-aged adults at risk for Alzheimer’s disease. J Alzheimers Dis 13, 187–197.

31.

Zigmont

, Shoben

, Lu

, Kaye

, Clinton

, Harris

, Olivo-Marston

(2019) Statin users have an elevated risk of dysglycemia and new-onset-diabetes. Diabetes Metab Res Rev 35, e3189.

32.

Milne

, Bucks

, Davis

TME

, Pierson

, Starkstein

, Bruce

(2018) Hippocampal atrophy, asymmetry, and cognition in type 2 diabetes mellitus. Brain Behav 8, e00741.

33.

Golomb

, Evansp

(2008) Statin adverse effects: A review of the literature and evidence for a mitochondrial mechanism. Am J Cardiovasc Drugs 8, 373–418.