Effects of food and drug administration-approved medications for alzheimer's disease on clinical progression

Effects of Food and Drug Administration-approved medications for Alzheimer’s disease on clinical progression Michelle M. MielkeJeannie-Marie Leoutsakos, Chris D. Corcoran, Robert C. Green Maria C. Norton,Kathleen A. W, JoAnn T. Tschanz,, Constantine G. L aDepartment of Psychiatry, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA bDivision of Epidemiologic Studies, Utah State University, Logan, UT, USA cDepartment of Mathematics and Statistics, Utah State University, Logan, UT, USA dDepartments of Neurology, Medicine (Genetics), and Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA, USA eDepartment of Psychology, Utah State University, Logan, UT, USA fDepartment of Family, Consumer and Human Development, Utah State University, Logan, UT, USA gDepartment of Psychiatry and Behavioral Sciences and the Joseph and Kathleen Bryan Alzheimer’s Disease Research Center, Duke University, Background: Observational studies suggest that cholinesterase inhibitors and/or memantine maydelay clinical progression of Alzheimer’s disease (AD) in 40% of individuals taking the medications.
Given this response and existence of side effects, we sought to quantify medication use and benefits ina population-based study of incident AD cases.
Methods: The Cache County Dementia Progression Study enrolled and followed a cohort of 327 in-cident AD cases for a maximum of 9 years. Drug exposure was expressed using a persistency index(PI), calculated as total years of drug use divided by total years of observation. Linear mixed-effectsmodels examined PI, and interactions with sex and apolipoprotein E (APOE) as predictors of clinicalprogression on the Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes.
Results: A total of 69 participants (21.1%) reported having ever used cholinesterase inhibitors or mem-antine. There was a strong three-way interaction between PI, sex, and time. Among women, a higher PI(i.e., greater duration of use) of cholinesterase inhibitors was associated with slower progression on theMini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes, particularly among thosewith an APOE 34 allele. In contrast, higher PI was associated with faster progression in males.
Conclusion: A low percentage of individuals with AD in the community are taking cholinesterase inhib-itors or memantine. This study suggests that women, particularly those with an APOE 34 allele, may benefitthe most from these medications. With the newly approved increased dose of donepezil, it will be imper-ative to determine whether a higher dose is needed in men or whether other factors warrant consideration.
Ó 2012 The Alzheimer’s Association. All rights reserved.
Cholinesterase inhibitor; Memantine; Incident Alzheimer’s disease; Population-based; Disease progression;Sex; APOE J.T.T. and C.G.L. are co-last authors.
All other authors have no disclosures.
The corresponding author had full access to all the data in the study and had final responsibility of the decision to submit for publication.
The authors had access to the data at all times and retain the data. Funding was obtained from NIH grants. All participants provided informed consent and the study was approved by the Johns Hopkins University, Utah State University, and Duke University Institutional Review Boards.
Constantine Lyketsos: Grant support (research or CME)—NIMH, NIA, Associated Jewish Federation of Baltimore, Weinberg Foundation, Forest, Glaxo-Smith-Kline, Eisai, Pfizer, Astra-Zeneca, Lilly, Ortho-McNeil, Bristol-Myers, Novartis; Consultant/Advisor—Astra-Zeneca, Glaxo-Smith Kline,Eisai, Novartis, Forest, Supernus, Adlyfe, Takeda, Wyeth, Lundbeck, Merz, Lilly, Genentech; Honorarium or travel support—Pfizer, Forest,Glaxo-Smith Kline, Health Monitor.
*Corresponding author. Tel.: 443-326-5174; Fax: 410-550-1407.
E-mail address: 1552-5260/$ - see front matter Ó 2012 The Alzheimer’s Association. All rights reserved.
M.M. Mielke et al. / Alzheimer’s & Dementia 8 (2012) 180–187 including APOE 34 genotype, sex, and onset age, affect re-sponse to these medications in this cohort.
Although there is currently no cure for Alzheimer’s dis- ease (AD), current therapeutic strategies with the aim totreat disease symptoms and delay cognitive and functional decline include the use of second-generation cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and theN-methyl-D-aspartate The design and sampling methods of the study have pre- Studies conducted in specialized clinical settings and nurs- viously been described in detail . The DPS originated ing homes suggest a high prevalence of dementia medica- from the longitudinal, population-based Cache County tion use among patients with AD . However, this is Study on Memory in Aging (CCSMA), which has examined likely an overestimate of use because many persons with the prevalence, incidence, and risk factors of dementia in AD in the United States do not seek specialized a U.S. county recognized for the longevity of its residents.
treatment and thus are not diagnosed . A study of In its first wave, CCSMA enrolled 90% of the 5677 county community-dwelling Medicare beneficiaries reported that residents aged 65 years. Three triennial incidence waves only 26% of persons with dementia were prescribed a were subsequently completed, as described previously cholinesterase inhibitor or memantine between 2001 and Briefly, using state-of-the-art diagnostic assess- 2003 Although claims data include information on pre- ments involving cognitive screening and in-home evaluation scription medications, they lack clinical information and by a trained team, a study geropsychiatrist and neuropsy- are subject to misclassification biases due to diagnostic chologist reviewed data from each participant at each errors, especially underdiagnosis. A population-based study CCSMA wave and assigned preliminary diagnoses of de- of well-characterized participants with incident AD is pre- mentia according to Diagnostic and Statistical Manual ferred to characterize patterns of medication use among AD (DSM)-III-R criteria Neuroimaging and laboratory studies were used as part of the diagnostic work-up to further Cholinesterase inhibitors and memantine are regarded as define dementia type. The age of dementia onset was the age having very moderate symptomatic benefits on cognition when the participant unambiguously met DSM-III-R criteria and functioning, but are not disease modifying. Observa- for dementia. Dementia severity was rated on the Clinical tional studies suggest that these drugs may have symptom- Dementia Rating (CDR) and health status according atic effects that delay cognitive progression for up to to the General Medical Health Rating A panel of ex- a year and may delay the time to nursing home placement perts consisting of neurologists, geropsychiatrists, neuro- . However, only 40% are thought to be improved psychologists, and a cognitive neuroscientist reviewed Given this low response and the existence of side all available clinical and neuropathological data, and effects, it is important to quantify their benefits in real possible and probable AD was diagnosed according to world settings and to identify predictors of treatment National Institutes of Neurological Diseases and Stroke– response. Although several clinical trials and clinical Alzheimer’s Disease and Related Disorders Association cri- observational studies have examined such predictors, these teria All study procedures were approved by the insti- have not been examined in a population-based study of tutional review boards of Utah State, Duke, and the Johns well-characterized incident dementia cases. Clinical studies and randomized trials have more stringent criteria for inclu- All participants and their caregivers/proxy informants sion and findings may therefore not be generalizable to the surviving as of 2002 were recruited to participate in the vast majority of individuals with AD.
DPS, a longitudinal study of dementia progression. Partici- The Cache County Dementia Progression Study (DPS) pants and their caregivers/proxy informants were visited has enrolled and followed a population-based cohort of semiannually by a nurse and psychometric technician. Par- incident dementia cases for more than 9 years. Participants ticipants completed a battery of neuropsychological tests in- were originally diagnosed from the population-based Cache cluding the MMSE, and underwent a brief physical County Study on Memory and Aging. The aims of the examination including height and weight check and stan- present analyses were to (1) describe patterns of use for dardized measurement of blood pressure. A CDR was ad- Food and Drug Administration (FDA)-approved AD demen- ministered to participants and caregivers. Caregivers were tia medications (cholinesterase inhibitors and memantine) in also interviewed regarding the functional status of the this unique population-based sample of incident dementia care-recipient, and they provided updated information re- cases; (2) determine whether persistency of medication use lated to the participant’s health history, psychiatric symp- (defined later) is associated with slower dementia progres- toms, family history of memory problems, medications, sion, as assessed by the Mini-Mental State Examination quality of life, and use of formal and informal services.
(MMSE) and Clinical Dementia Rating-Sum of Boxes Of the original 581 individuals diagnosed with incident (CDR-Sum); and (3) examine whether specific participant dementia in the CCSMA, 358 had at least one follow-up visit characteristics previously reported in clinical studies, either through procedures of the CCMSA or the DPS. The M.M. Mielke et al. / Alzheimer’s & Dementia 8 (2012) 180–187 DPS enrolled 88% of the surviving cases of dementia was taking it only over half the study duration. Because the (n 5 337) and has followed them semiannually over the DPS sample is an incident sample, all participants with AD past 8 years. Attrition has been primarily because of death, had been assessed before the onset of dementia. The use of with ,5% of subjects refusing follow-up. Participants diag- these medications was first assessed at the visit when demen- nosed with possible or probable AD were included in the tia was diagnosed. Time in the study was from the initial baseline visit (e.g., from the visit of the dementia diagnosis)onward, and in multivariate models, we adjusted for the du- ration of dementia at the time of the diagnostic visit that wasdetermined by the age of onset estimated at the consensus Outcomes reflecting progression of AD dementia were conference. A PI was calculated for any dementia medica- tion use and just for cholinesterase inhibitors (excluding par- a global measure of cognition that is widely used in clinical ticipants ever taking memantine). We did not calculate a PI trials that assess potential treatments on AD progression for memantine-only users because of insufficient numbers.
. Similar to methods previously used in DPS , Because we did not have information on medication use a sensory/motor MMSE-adjusted score was calculated by between visits, if a person was taking a medication at con- discarding items missed due to sensory/motor impairment secutive visits, we assumed she/he was taking it over the en- (e.g., severe vision or hearing loss, motor weakness, tremor, tire period between these visits. If an individual was taking etc.), calculating the percent correct, and rescaling the final the medication at one visit but not at the next consecutive visit, we estimated that the time of drug use was half the The CDR examines functioning in six domains: time between visits. This method was supported by our ob- memory, orientation, judgment/problem solving, commu- servation in this study that no individuals went on drug, nity affairs, home/hobbies, and personal care. The CDR is off drug, and then back on drug over three consecutive visits.
assessed with a semistructured interview and has excellent Hence, once they started a dementia medication, they tended reliability and validity . Scores include a composite to stay on a dementia medication, although they may have score (CDR-composite) and Sum of Boxes (CDR-Sum), changed to a different cholinesterase inhibitor or memantine which is the sum of ratings in each of the six domains with a range of 0 (no impairment) to 30 (maximum impair-ment in all domains). CDR-Sum was chosen as the principal outcome here, instead of the composite, because of itsgreater range, and demonstrated sensitivity to change in Differences in baseline demographic and health-related mild cognitive impairment and AD as demonstrated characteristics between those who ever regularly used a de-mentia medication versus irregular (,4 times/week) ornever users were examined using Fisher’s exact test for cat- 2.3. Medication ascertainment and calculation of egorical variables and Student’s t test for continuous vari- ables. Similarly, these same tests were used to estimate Ascertainment of medications in this study has been pre- differences between those with only a baseline visit and viously described and relied on visual inspection of all those with one or more follow-up visits.
available medication vials at each follow-up. When partici- To model nonlinear effects of medication use (PI) on de- pants were institutionalized, this information was obtained mentia progression, we examined average change in MMSE from nursing home records. We classified current dementia and CDR-sum from the visit at which dementia was first medication use as regular if a medication was being used diagnosed, using mixed-effects models, treating subject- 4 times per week. We focused on FDA-approved medica- specific intercepts and linear change with time as random ef- tions: cholinesterase inhibitors (donepezil, rivastigmine, and fects. This approach, used previously in DPS allows us galantamine) and the N-methyl-D-aspartate receptor antago- to assess the effects of key fixed factors, such as age, on nist, memantine. As the various cholinesterase inhibitors average rate of change, while accounting for the dependence have been shown to have similar efficacy despite different between within-subject repeated measures and for nonlinear pharmacological properties, we examined this drug category change with respect to time. Because our analysis revealed significant nonlinear time effects for both the MMSE and Because accumulation of exposure to AD dementia med- CDR-sum, and as we have done before in similar analyses, ications may be important to progression, drug exposure was we included a time-squared term and appropriate time- estimated using the persistency index (PI) The PI was squared terms in all examined interactions.
calculated as the total years of drug use divided by the total Some variables have previously been found to be associ- years of observation since AD diagnosis by the study inves- ated with progression in MMSE and CDR-sum in this pop- tigators, and ranged from 0 to 1. A PI of 1 indicates that the ulation of AD participants Therefore, they were person has been taking an AD medication over the entire included as covariates in the current models; these variable study duration, whereas a PI of 0.5 would indicate the person include baseline age, sex, education, duration of dementia M.M. Mielke et al. / Alzheimer’s & Dementia 8 (2012) 180–187 at the time from the age of onset to the age when diagnosis tine during the study and the 258 who did not are shown in was made, and presence of one or two APOE 34 alleles.
. Those who ever took an FDA-approved AD medica- Education, sex, and APOE genotype were determined at tion were younger (81.2 vs 87.1, P , .001), had more years wave 1 of the CCSMA. APOE genotype was determined of education (14.0 vs 13.0, P 5 .014), and were more likely from buccal DNA, using standard protocol . In addition, to be APOE 34 allele carriers (68.1% vs 39.1%, P , .001), we also examined three-way interactions between the PI, compared with those who never regularly used a cholinester- time, and sex. The interaction terms were retained in the ase inhibitor and/or memantine. There were no differences models if the comparison between likelihood ratio (LR) in baseline MMSE or CDR-Sum scores, dementia duration, test statistics between models with and without the interac- or other health-related characteristics, including medical tion terms was significant (P , .05). All analyses were con- ducted using STATA Version 10.0 (StataCorp, College Of the 327 participants at baseline, 216 had at least one follow-up visit and could be analyzed longitudinally; 191were included in the calculation of the cholinesteraseinhibitor-only PI after excluding those ever taking meman- tine. Of the total, 111 (33.9%) individuals lacked any follow-up, the majority (n 5 88, 79.3%) because of death.
As previously reported these individuals were older The current analyses included 327 participants diagnosed and had a lower MMSE at diagnosis compared with those with incident AD and who had information on medication with follow-up data. Of the 216 participants with follow- use. The majority were female (65.8%), Caucasian (99.1%), up data, average time in the study was 3.3 years and had mild impairment (mean global CDR 5 1.1, standard (SD 5 2.2; maximum 5 9.9 years) with 4.2 study visits deviation [SD] 5 0.6) at the time of diagnosis. At baseline, (SD 5 2.4; maximum 5 11 visits). The mean (SD) of the 36 (11.0%) were regularly taking a cholinesterase inhibitor overall PI among the 62 persons in the longitudinal sample and/or memantine: 32 (9.8%) were regularly only taking taking any FDA-approved AD medication was 0.64 a cholinesterase inhibitor. Over the course of the follow-up, (SD 5 0.31, range: 0.07–1.0), which means that they were an additional 26 (8.0%) individuals initiated regular cholines- taking such a medication for 64% of the time under observa- terase use and 7 (2.1%) initiated regular memantine use tion. For the 37 participants only taking a cholinesterase in- for cross-sectional use of dementia medications at hibitor (excluding anyone taking memantine), the mean PI each follow-up visit and at which visit each drug was first was 0.63 (SD 5 0.31, range 5 0.07–1).
taken). For persons who took dementia medications at multi-ple visits, all visits were consecutive (i.e., no person was on a drug at one time point, off at another time point, thenback on the medication again at the next time point).
For individuals taking any FDA-approved AD medication Sixty-nine participants (21.1%) ever used a cholinesterase or for those taking cholinesterase inhibitors only, a higher PI inhibitor or memantine from the time of diagnosis to the last (i.e., use of one of these medications for longer periods under follow-up. Differences in baseline demographic and other observation) was not associated with better performance health-related characteristics between the 69 persons who over time on either the MMSE or CDR-Sum ). How- ever regularly took a cholinesterase inhibitor and/or meman- ever, there was a strong three-way interaction between PI, Table 1Regular use and starting visit of cholinesterase inhibitors and memantine over the DPS follow-up 33 (15.3%) 27 (19.3%) 22 (20.0%) 14 (16.7%) 36 (11.0%) 38 (17.6%) 37 (27.2%) 32 (29.0%) 25 (29.8%) 17 (28.3%) 7 (20.6%) 3 (13.6%) 3 (18.8%) 2 (18.2%) 1 (33.3%) Abbreviation: DPS, Dementia Progression Study.
M.M. Mielke et al. / Alzheimer’s & Dementia 8 (2012) 180–187 Table 2Baseline characteristics of regular dementia medication users at any examination over the follow-up and nonusers Abbreviations: APOE, apolipoprotein E; CABG, coronary artery bypass surgery; MI, myocardial infarction; GMHR, General Medical Health Rating scale; MMSE, Mini-Mental State Examination; CDR-Sum, Clinical Dementia Rating Scale—Sum of boxscores; SD, standard deviation.
sex, and time, particularly when examining cholinesterase of progression on both the MMSE and CDR-Sum at 1, 3, inhibitor use only (MMSE LR: c2 5 9.26, 2 df, P , .01; and 5 years after baseline. For example, after 5 years, women CDR-Sum LR: c2 5 6.40, 2 df, P , .05), for which there with a PI of 1 and an APOE 34 allele had a 2.6-point decline was more power, because of the greater number of individ- (95% confidence interval: 29.11, 3.96) on the MMSE, uals taking these medications as compared with memantine which was significantly less than the 20.9-point decline ). Women with a PI of 1 compared with PI of 0 did among women with a PI of 1 and without an APOE 34 allele.
better on the MMSE and CDR-Sum over time. In contrast, Similarly, after 5 years, men with a PI of 1 and an APOE 34 men with a PI of 1 compared with PI of 0 did worse over allele had a 19.7-point MMSE decline (95% confidence in- terval: 228.87, 210.22), which was significantly more We further explored the effect of the APOE 34 allele on than the 6.4-point decline among men with a PI of 1 and the three-way interaction, stratifying the earlier models by the presence of any versus none 34 alleles. Although theresults are based on a small sample number (19 females and 10 males) with a PI . 0 and an 34 allele, the relationshipbetween cholinesterase inhibitor use and MMSE and CDR In this population-based study of an incident cohort of in- trajectories appeared to be limited to 34 carriers for each dividuals with AD we found that: (1) only 21.1% of persons sex, such that women with a high PI did better over time if diagnosed with AD ever regularly used a cholinesterase in- they had an 34 allele while men did worse. shows hibitor or memantine; (2) participants who used these med- this association in greater detail and displays the amount ications tended to be younger, were more highly educated, Table 3Examination of the dementia medication PI as a predictor of progression on the MMSE and CDR-Sum Abbreviations: PI, persistency index; CI, confidence interval.
*Using mixed-effects regression, all models adjusted for time, time2, baseline age, sex, education, dementia duration at baseline, and any APOE 34 allele.
yA positive coefficient for MMSE represent a better performance whereas a negative coefficient for CDR-Sum represents a better performance.
M.M. Mielke et al. / Alzheimer’s & Dementia 8 (2012) 180–187 Table 4Examination of an interaction between the dementia medication persistency index (PI) and sex as a predictor of progression on the MMSE and CDR-Sum *Using mixed-effects regression, all models adjusted for time, time2, baseline age, sex, education, dementia duration at baseline, and any APOE 34 allele.
yA positive coefficient for MMSE represent a better performance whereas a negative coefficient for CDR-Sum represents a better performance.
and were more likely to have an APOE 34 allele, but they Some studies from clinical settings have reported a high were no more or less likely to have medical comorbidities; prevalence of dementia medication use For example, (3) among all participants, a higher PI was not significantly Zhu et al reported that almost 80% of persons in the pre- associated with progression in the MMSE or CDR-Sum.
dictors 2 cohort used cholinesterase inhibitors or meman- However, among women, longer periods of cholinesterase tine. In contrast, in this population-based cohort of inhibitor use were associated with slower progression on incident AD, just over 21% of participants used one of these both the MMSE and CDR-Sum, particularly among those FDA-approved AD medications. Our finding is similar to women with an APOE 34 allele. In contrast, among men, a study of Medicare beneficiaries, which reported that 26% longer periods of cholinesterase inhibitor use were associ- of individuals with an AD diagnosis had filled prescriptions ated with a faster progression, particularly among those for either type of medication Because claims data often underestimate the prevalence of dementia, the percentage of Table 5Amount of progression on the MMSE and CDR-SB at 1, 3, and 5 years after baseline by sex, 34 status, and PI M.M. Mielke et al. / Alzheimer’s & Dementia 8 (2012) 180–187 persons with dementia who were taking a dementia medica- only subgroups of the population may be benefiting from tion is likely lower than 26%. Thus, there is a large discrep- these drugs at the currently approved doses. Given that ancy between the prevalence of use in clinical observational some side effects do exist, it is important to further studies and use at the population level. Notably, the study of determine the people who might most benefit from these Medicare beneficiaries described usage between 2001 and medications, in additional population-based studies.
2003, and the DPS began enrolling incident dementia cases Although reasons for the slower decline among women in 2002. Thus, it is possible that the low frequency could be with a higher PI are not exactly known, this sex-specific attributable to the timing of the medication assessments be- benefit of these medications has been reported in some clin- cause rivastigmine and galantamine were only approved in ical trials , but not others In animal studies, sex 2000 and 2001, respectively. However, as the Predictors 2 differences have been found for nearly all cholinergic mark- cohort recruited the majority of participants before 2002, ers including acetylcholinesterase activity, acetylcholine, and median follow-up was 4 years, this timing cannot com- and acetylcholine-receptor distribution . Further, pletely explain the differences in percentages.
testosterone may interfere with the effects of cholinesterase Although reasons for this discrepancy are not readily inhibitors by decreasing the amount of drug that reaches clear, it is not surprising that persons who are younger and the brain or by modifying the interaction of the more educated are more likely to be on a medication. How- cholinesterase inhibitor with cholinesterase . Thus, it ever, because APOE 34 status obtained in the Cache County is possible that men either have less benefit overall or Study was not released to any community physician or par- would need a higher dose to have the same benefit from the ticipant at any point in the study, and information on medications as women. In light of recent approval of a APOE 34 status was not included in the clinical consensus higher dose of donepezil by the FDA, it would be diagnosis of dementia type, it is surprising that individuals interesting to find out whether there are sex differences in with an APOE 34 allele were almost twice as likely to tolerability and efficacy. It is also notable that women only have taken a dementia medication. It is possible 34 allele car- taking cholinesterase inhibitors benefitted, compared with riers were more clear-cut cases of AD and, thus, easier for physicians to recognize. However, there were no differences Limitations in this study warrant consideration. First, we between 34 allele carriers and noncarriers in the prevalence did not have information on pharmacy claims to directly as- of vascular factors and other comorbidities at baseline, which certain whether an individual was a regular user and contin- may complicate the diagnosis of AD. Although African uously refilled their prescription. Thus, we may have either Americans and Hispanics have a lower prevalence of demen- overestimated or underestimated the medication use if it tia medication use , this factor cannot explain the was started and stopped between waves. Second, we did finding in this study because 99% of participants were not have information on dose. However, it is unlikely that Caucasian. Thus, additional research examining factors doses for women would have been higher than men, and associated with use of dementia medications in community thus explain the beneficial effect in women on this basis; if at all, we might expect women to be on lower doses due to We used the PI to quantify exposure to FDA- less tolerability of higher doses because of smaller body approved AD medications during the study. The PI is the size. Third, the number of women and men who were total years of drug use divided by the total years of observa- APOE 34 carriers and taking cholinesterase inhibitors was tion. The advantage of using this index was twofold—it quite small and necessitates the need for replication in allowed for the quantification of the medication duration a larger study of incident AD cases. Finally, the Cache of exposure and accounted for variations in the period of ob- County population is primarily Caucasian and of northern servation because of the high rate of mortality-related attri- European descent. Thus, these results may not generalize tion. Rountree et al previously reported that higher PIs to populations with different ethnic representation. Strengths were associated with better performance on cognitive and of the study include its population base, its focus on incident functional outcomes. In this study, we did not find an associ- cases, the extended follow-up after dementia onset, and the ation between PI and decline among the entire sample. How- high participation rates observed in dementia ascertainment ever, there was a strong sex interaction such that women with a higher PI had a slower decline compared with women not In conclusion, a low percentage of individuals with AD taking these medications, particularly women carrying an in the community are taking cholinesterase inhibitors or APOE 34 allele. This is interesting in light of the fact that memantine for treatment. As these drugs may benefit a women with AD have been found to have a faster decline subset of AD patients it is important to further than men when cholinesterase use is not considered ascertain the reasons for the low prevalence of use. Finally, . In contrast, men with a high PI and an APOE 34 this study suggests that women on dementia medications allele did significantly worse compared with men with have a slower decline compared with men. With the newly a low PI or with men, regardless of PI, with no APOE 34 approved increased dose of donepezil, it will be imperative allele. This explains our lack of finding when a gender to determine whether a higher dose is needed in men or interaction was not included. Further, this suggests that whether other factors warrant consideration.
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