Adjudicating Mild Cognitive Impairment Due to Alzheimer's Disease as a Novel Endpoint Event in the TOMMORROW Prevention Clinical Trial.

BACKGROUND: The onset of mild cognitive impairment (MCI) is an essential outcome in Alzheimer's disease (AD) prevention trials and a compelling milestone for clinically meaningful change. Determining MCI, however, may be variable and subject to disagreement. Adjudication procedures may improve the reliability of these determinations. We report the performance of an adjudication committee for an AD prevention trial. METHODS: The TOMMORROW prevention trial selected cognitively normal participants at increased genetic risk for AD and randomized them to low-dose pioglitazone or placebo treatment. When adjudication criteria were triggered, a participant's clinical information was randomly assigned to a three-member panel of a six-member independent adjudication committee. Determination of whether or not a participant reached MCI due to AD or AD dementia proceeded through up to three review stages - independent review, collaborative review, and full committee review - requiring a unanimous decision and ratification by the chair. RESULTS: Of 3494 participants randomized, the committee adjudicated on 648 cases from 386 participants, resulting in 96 primary endpoint events. Most participants had cases that were adjudicated once (n = 235, 60.9%); the rest had cases that were adjudicated multiple times. Cases were evenly distributed among the eight possible three-member panels. Most adjudicated cases (485/648, 74.8%) were decided within the independent review (stage 1); 14.0% required broader collaborative review (stage 2), and 11.1% needed full committee discussion (stage 3). The primary endpoint event decision rate was 39/485 (8.0%) for stage 1, 29/91 (31.9%) for stage 2, and 28/72 (38.9%) for stage 3. Agreement between the primary event outcomes supported by investigators' clinical diagnoses and the decisions of the adjudication committee increased from 50% to approximately 93% (after around 100 cases) before settling at 80-90% for the remainder of the study. CONCLUSIONS: The adjudication process was designed to provide independent, consistent determinations of the trial endpoints. These outcomes demonstrated the extent of uncertainty among trial investigators and agreement between adjudicators when the transition to MCI due to AD was prospectively assessed. These methods may inform clinical endpoint determination in future AD secondary prevention studies. Reliable, accurate assessment of clinical events is critical for prevention trials and may mean the difference between success and failure.

Revisiting the Cholinergic Hypothesis in Alzheimer's Disease: Emerging Evidence from Translational and Clinical Research.

Scientific evidence collected over the past 4 decades suggests that a loss of cholinergic innervation in the cerebral cortex of patients with Alzheimer's disease is an early pathogenic event correlated with cognitive impairment. This evidence led to the formulation of the "Cholinergic Hypothesis of AD" and the development of cholinesterase inhibitor therapies. Although approved only as symptomatic therapies, recent studies suggest that long-term use of these drugs may also have disease-modifying benefits. A Cholinergic System Workgroup reassessed the role of the cholinergic system on AD pathogenesis in light of recent data, including neuroimaging data charting the progression of neurodegeneration in the cholinergic system and suggesting that cholinergic therapy may slow brain atrophy. Other pathways that contribute to cholinergic synaptic loss and their effect on cognitive impairment in AD were also reviewed. These studies indicate that the cholinergic system as one of several interacting systems failures that contribute to AD pathogenesis.

FASTKD2 is associated with memory and hippocampal structure in older adults.

Memory impairment is the cardinal early feature of Alzheimer's disease, a highly prevalent disorder whose causes remain only partially understood. To identify novel genetic predictors, we used an integrative genomics approach to perform the largest study to date of human memory (n=14 781). Using a genome-wide screen, we discovered a novel association of a polymorphism in the pro-apoptotic gene FASTKD2 (fas-activated serine/threonine kinase domains 2; rs7594645-G) with better memory performance and replicated this finding in independent samples. Consistent with a neuroprotective effect, rs7594645-G carriers exhibited increased hippocampal volume and gray matter density and decreased cerebrospinal fluid levels of apoptotic mediators. The MTOR (mechanistic target of rapamycin) gene and pathways related to endocytosis, cholinergic neurotransmission, epidermal growth factor receptor signaling and immune regulation, among others, also displayed association with memory. These findings nominate FASTKD2 as a target for modulating neurodegeneration and suggest potential mechanisms for therapies to combat memory loss in normal cognitive aging and dementia.

Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment.

Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ε4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ε3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ε3/ε3 group (N=315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ε3/ε3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ε3/ε3 individuals (N=923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.

Phenotypic variability in three families with valosin-containing protein mutation.

BACKGROUND AND PURPOSE: The phenotype of IBMPFD [inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia (FTD)] associated with valosin-containing protein (VCP) mutation is described in three families. METHODS: Probands were identified based on a pathological diagnosis of frontotemporal lobar degeneration with TDP-43-positive inclusions type IV. VCP sequencing was carried out. Clinical data on affected family members were reviewed. RESULTS: Ohio family: four subjects presented muscle weakness and wasting. (One subject had both neuropathic and myopathic findings and another subject showed only evidence of myopathy. The etiology of weakness could not be ascertained in the remaining two subjects.) Two individuals also showed Parkinsonism (with associated FTD in one of the two). The proband's brain displayed FTLD-TDP type IV and Braak stage five Parkinson's disease (PD). A VCP R191Q mutation was found. Pennsylvania family: 11 subjects developed IBMPFD. Parkinsonism was noted in two mutation carriers, whilst another subject presented with primary progressive aphasia (PPA). A novel VCP T262A mutation was found. Indiana family: three subjects developed IBMPFD. FTD was diagnosed in two individuals and suspected in the third one who also displayed muscle weakness. A VCP R159C mutation was found. CONCLUSIONS: We identified three families with IBMPFD associated with VCP mutations. Clinical and pathological PD was documented for the first time in members of two families. A novel T262A mutation was found. One individual had PPA: an uncommon presentation of IBMPFD.

Genotype patterns at PICALM, CR1, BIN1, CLU, and APOE genes are associated with episodic memory.

OBJECTIVE: Several genome-wide association studies (GWAS) have associated variants in late-onset Alzheimer disease (LOAD) susceptibility genes; however, these single nucleotide polymorphisms (SNPs) have very modest effects, suggesting that single SNP approaches may be inadequate to identify genetic risks. An alternative approach is the use of multilocus genotype patterns (MLGPs) that combine SNPs at different susceptibility genes. METHODS: Using data from 1,365 subjects in the National Institute on Aging Late-Onset Alzheimer's Disease Family Study, we conducted a family-based association study in which we tabulated MLGPs for SNPs at CR1, BIN1, CLU, PICALM, and APOE. We used generalized estimating equations to model episodic memory as the dependent endophenotype of LOAD and the MLGPs as predictors while adjusting for sex, age, and education. RESULTS: Several genotype patterns influenced episodic memory performance. A pattern that included PICALM and CLU was the strongest genotypic profile for lower memory performance (ß = -0.32, SE = 0.19, p = 0.021). The effect was stronger after addition of APOE (p = 0.016). Two additional patterns involving PICALM, CR1, and APOE and another pattern involving PICALM, BIN1, and APOE were also associated with significantly poorer memory performance (ß = -0.44, SE = 0.09, p = 0.009 and ß = -0.29, SE = 0.07, p = 0.012) even after exclusion of patients with LOAD. We also identified genotype pattern involving variants in PICALM, CLU, and APOE as a predictor of better memory performance (ß = 0.26, SE = 0.10, p = 0.010). CONCLUSIONS: MLGPs provide an alternative analytical approach to predict an individual's genetic risk for episodic memory performance, a surrogate indicator of LOAD. Identifying genotypic patterns contributing to the decline of an individual's cognitive performance may be a critical step along the road to preclinical detection of Alzheimer disease.

Caffeic acid phenethyl ester extends survival of a mouse model of amyotrophic lateral sclerosis.

There is currently very limited effective pharmacological treatment for amyotrophic lateral sclerosis. Recent evidence suggests that caffeic acid phenethyl ester has strong anti-inflammatory, anti-oxidative, and anti-neuronal death properties; thus, the present study tested the effects of caffeic acid phenethyl ester in mice expressing a mutant superoxide dismutase (SOD1(G93A)) linked to human amyotrophic lateral sclerosis. Administration of caffeic acid phenethyl ester after symptom onset significantly increased the post-onset survival and lifespan of SOD1(G93A) mice. Moreover, immunohistochemical analysis detected less activation of microglia and astrocytes and higher motor neuron counts at an early symptomatic stage (7 days following onset) in the spinal cords of SOD1(G93A) mice given caffeic acid phenethyl ester treatment. Additionally, lower levels of phosphorylated p38, a mitogen-activated protein kinase that is involved in both inflammation and neuronal death, were observed in the spinal cords of SOD1(G93A) mice treated with caffeic acid phenethyl ester for 7 days. These results indicate that caffeic acid phenethyl ester may represent a novel and effective therapeutic for the treatment of amyotrophic lateral sclerosis, and these significant neuroprotective effects observed in a commonly used amyotrophic lateral sclerosis mouse model validate the therapeutic potential of caffeic acid phenethyl ester for slowing disease progression by attenuating the neuroinflammation and motor neuron cell death associated with clinical amyotrophic lateral sclerosis pathology.

The effect of vascular risk factors on the efficacy of rivastigmine patch and capsule treatment in Alzheimer's disease.

BACKGROUND: Vascular risk factors (VRF) may influence response to rivastigmine in Alzheimer's disease (AD). METHODS: AD patients who participated in a randomized, double-blind, placebo-controlled trial of rivastigmine patch and capsule treatment were stratified by baseline VRF status. Treatment response was evaluated using the AD Assessment Scale-cognitive subscale (ADAS-cog), AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) and the AD Cooperative Study-Activities of Daily Living (ADCS-ADL) scale. RESULTS: ADAS-cog scores significantly improved in all rivastigmine-treated patients (p < 0.05 vs. placebo), except 9.5 mg/24 h patch-treated patients with VRF, and were significantly affected by VRF status in the study population as a whole. Significant benefits were seen on the ADCS-ADL in 9.5 mg/24 h patch- and capsule-treated patients with, but not without, VRF. The ADCS-CGIC significantly improved in capsule-treated patients with, and patch-treated patients without VRF. Although non-significant, patients without VRF showed an apparent faster rate of placebo decline. CONCLUSION: VRF may influence AD progression and response to rivastigmine.

Caffeic acid phenethyl ester prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurodegeneration.

Parkinson's disease is associated with the loss of dopaminergic neurons in the substantia nigra and decreased striatal dopamine levels. We now report that caffeic acid phenethyl ester (CAPE), an active component of propolis, attenuated dopaminergic neurodegeneration and dopamine loss in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease. The neuroprotective effect of CAPE was associated with marked reductions in inducible nitric oxide synthase (iNOS) and caspase 1 expression. Additionally, CAPE inhibited MPP+-induced neurotoxicity in vitro and directly inhibited MPP+-induced release of cytochrome c and apoptosis inducing factor (AIF) from mitochondria. Thus, CAPE may have beneficial effects in slowing or preventing the progression of Parkinson's disease and other neurodegenerative disorders.

Amyloid precursor protein (APP) processing genes and cerebrospinal fluid APP cleavage product levels in Alzheimer's disease.

The aim of this exploratory investigation was to determine if genetic variation within amyloid precursor protein (APP) or its processing enzymes correlates with APP cleavage product levels: APPα, APPß or Aß42, in cerebrospinal fluid (CSF) of cognitively normal subjects or Alzheimer's disease (AD) patients. Cognitively normal control subjects (n = 170) and AD patients (n = 92) were genotyped for 19 putative regulatory tagging SNPs within 9 genes (APP, ADAM10, BACE1, BACE2, PSEN1, PSEN2, PEN2, NCSTN and APH1B) involved in the APP processing pathway. SNP genotypes were tested for their association with CSF APPα, APPß, and Aß42, AD risk and age-at-onset while taking into account age, gender, race and APOE ε4. After adjusting for multiple comparisons, a significant association was found between ADAM10 SNP rs514049 and APPα levels. In controls, the rs514049 CC genotype had higher APPα levels than the CA, AA collapsed genotype, whereas the opposite effect was seen in AD patients. These results suggest that genetic variation within ADAM10, an APP processing gene, influences CSF APPα levels in an AD specific manner.

Safety and tolerability of rivastigmine transdermal patch compared with rivastigmine capsules in patients switched from donepezil: data from three clinical trials.

OBJECTIVES: To compare the safety and tolerability of switching patients with mild-to-moderate Alzheimer's disease from donepezil to either rivastigmine capsule or transdermal patch. METHODS: Three studies investigated the switch from donepezil to rivastigmine; study US13 was a 26-week, single-arm, immediate-switch study; US18 was a 26-week, sequential cohort study (both studies evaluated rivastigmine capsules 3-12 mg/day); study US38 was a 25-week, randomised, parallel-group, open-label study which investigated switch (immediate or after 7 days' withdrawal) from donepezil to rivastigmine transdermal patch (4.6 mg/24 hr). Safety outcomes included adverse events (AEs), discontinuations caused by AEs and serious AEs (SAEs). RESULTS: Patient groups receiving rivastigmine patch (n = 261) or capsules (n = 331) had mean +/- SD ages of 77.3 +/- 8.0 and 78.1 +/- 7.8 years, dementia durations of 3.9 +/- 2.6 and 3.6 +/- 2.2 years and Mini-Mental State Examination scores of 18.3 +/- 4.00 and 17.9 +/- 4.4 respectively. Overall, 184 (70.5%) and 276 (83.4%) patients experienced at least one AE, and 23 (8.8%) and 55 (16.6%) patients experienced an SAE with the rivastigmine patch and capsules respectively. Of the patients who experienced an AE, 10 (3.8%) and 109 (32.9%) experienced nausea, and 11 (4.2%) and 80 (24.1%) experienced vomiting with the rivastigmine patch and capsules respectively. Discontinuations because of AEs occurred in 64 (19.3%) patients receiving capsules and 38 (14.6%) patients in the transdermal patch group. The most common reasons for discontinuation with the transdermal patch were application site reaction and disease progression, and nausea and vomiting with the capsules. CONCLUSIONS: The rivastigmine transdermal patch appears to have better tolerability than rivastigmine capsules, with fewer gastrointestinal AEs and discontinuations because of these AEs. Simple daily rotation of patch location will likely reduce the frequency of skin reactions. This post hoc analysis was carried out by Novartis Pharmaceuticals Corporation. Data for the analysis were collected from the US13 study (CENA713B US13), the US18 study (CENA713B US18) and the US38 study (CENA713D US38).

Treatment of mild cognitive impairment (MCI).

Mild cognitive impairment (MCI), an intermediate stage between normalcy and dementia, is characterized by fewer symptoms and less functional decline than dementia with less established biological disease processes and is an attractive target for both symptomatic and disease progression therapies. It is always desirable to treat symptoms or slow disease at a stage where the individual is still largely functional. Therapeutic studies in MCI have either been symptomatic, usually of shorter duration or of longer multiyear terms to demonstrate whether disease progression is delayed. Symptomatic agents tested to date include donepezil, SGS-742, and Piracetam. No symptomatic drug study has demonstrated clinically convincing differences between placebo and the study medication. Disease progression trials in MCI investigations of 2 to 4 year durations have included donepezil, vitamin E, rivastigmine, galantamine and rofecoxib. None have demonstrated convincing effects in delaying longer term disease progression or conversion to dementia. Problems that may have undermined these trials; i) disease heterogeneity, ii) slow early progression of the disease, and iii) insensitive cognitive and functional instruments. Future MCI studies may benefit from the use of biomarkers such as apolipoprotein E (APOE4), cerebrospinal fluid amyloid-beta1-42 and Tau levels and PIB positivity on brain PET scans as well as more sensitive neuropsychological test measures may also more accurately reflect clinical changes related to drug effects.

Adipose stromal cells-secreted neuroprotective media against neuronal apoptosis.

Transplantation of pluripotent adipose stem/stromal cells (ASC) alleviates tissue damage and improves functional deficits in both stroke and cardiovascular disease animal models. Recent studies indicate that the primary mechanism of ASC-induced repair may not be directly related to tissue regeneration through differentiation, but rather through paracrine mechanisms provided by secreted pro-survival and repair-inducing trophic factors. In this study, we have found that ASC-conditioned medium (ASC-CM) potently protected cerebellar granule neurons (CGN) from apoptosis induced by serum and potassium deprivation. Neural cell protection was mostly attributable to activated caspase-3 and Akt-mediated neuroprotective pathway signaling. Specific neutralization of neurotrophic factor activity demonstrated that serum and potassium deprivation-induced Akt-mediated neuroprotection and caspase-3-dependent apoptosis were mainly modulated by IGF-1. These data suggest that of the many neuroprotective factors secreted by ASC, IGF-1 is the major factor that mediates protection against serum and potassium deprivation-induced CGN apoptosis. This study establishes a mechanistic basis supporting the therapeutic application of ASC for neurological disorders, specifically through paracrine support provided by trophic factor secretion.

Caffeic acid phenethyl ester prevents cerebellar granule neurons (CGNs) against glutamate-induced neurotoxicity.

Caffeic acid phenethyl ester (CAPE) is an active component of propolis obtained from honeybee hives and is found to have the following properties: anti-mitogenic, anti-carcinogenic, anti-inflammatory, immunomodulatory, and antioxidant. Recent reports suggest that CAPE also has a neuronal protective property against ischemic injury. Since excitotoxicity may play an important role in ischemia, in this study, we investigated whether CAPE could directly protect neurons against excitotoxic insult. We treated cultured rat cerebellar granule neurons (CGNs) with excitotoxic concentrations of glutamate in the presence or absence of CAPE and found that CAPE markedly protected neurons against glutamate-induced neuronal death in a concentration-dependent fashion. Glutamate-induced CGNs death is associated with time-dependent activation of caspase-3 and phosphorylation of p38, both events of which can be blocked by CAPE. Treating CGNs with specific inhibitors of these two enzymes together exerts a synergistic neuroprotective effect, similar to the neuroprotective effect of CAPE exposure. These results suggest that CAPE is able to block glutamate-induced excitotoxicity by inhibiting phosphorylation of p38 and caspase-3 activation. This finding may further help understanding of the mechanism of glutamate-induced neuronal death and CAPE-induced neuroprotection against excitotoxicity.

Association of statin use with cognitive decline in elderly African Americans.

BACKGROUND: Previously reported associations between statin use and incident dementia or cognitive decline have been inconsistent. We report the results from a 3-year prospective study on the association of statin use on cognitive decline and incident dementia in elderly African Americans. METHODS: A community-based cohort of 1,146 African Americans aged 70 and older living in Indianapolis, Indiana, was evaluated in 2001 and 2004. The instrument used for cognitive assessment was the Community Screening Interview for Dementia (CSI-D). Cognitive decline was defined as CSI-D scores measured at 2001 minus scores at 2004. Measurements of low-density lipoprotein cholesterol (LDL-C) and C-reactive protein (CRP) were obtained from baseline blood samples. RESULTS: Adjusting for age at baseline, gender, education, and the possession of ApoE epsilon 4 allele, baseline statin use was associated with less cognitive decline (p = 0.0177). There were no significant interactions of statin use when LDL-C and CRP were included. Logistic regression with the four independent variables showed that statin use may be associated with a reduction in incident dementia (OR = 0.32; p = 0.0673). Association with cognitive decline was less clear when investigating statin use over time. Significance remained only for those who discontinued prior to follow-up compared to continuous users or users who started after baseline. CONCLUSIONS: The relationship between statin use and cognitive decline is complex and subjected to unknown confounders. This effect may not be associated with the cholesterol lowering or anti-inflammatory action of statins.

Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease.

LY450139 dihydrate, a gamma-secretase inhibitor, was studied in a randomized, controlled trial of 70 patients with Alzheimer disease. Subjects were given 30 mg for 1 week followed by 40 mg for 5 weeks. Treatment was well tolerated. Abeta(1-40) in plasma decreased by 38.2%; in CSF, Abeta(1-40) decreased by 4.42 +/- 9.55% (p = not significant). Higher drug doses may result in additional decreases in plasma Abeta concentrations and a measurable decrease in CSF Abeta.

Minocycline prevents gentamicin-induced ototoxicity by inhibiting p38 MAP kinase phosphorylation and caspase 3 activation.

Aminoglycosides are commonly used antibiotics that often induce ototoxicity leading to permanent hair cell loss and hearing impairment. We hereby examined whether minocycline protects hair cells from gentamicin-induced hair cell damage. Two millimolar gentamicin significantly induced outer hair cell damage and the addition of minocycline to gentamicin-treated explants significantly increased hair cell survival in a dose-dependent manner. Additionally, we demonstrated that gentamicin induced p38 MAPK phosphorylation, cytochrome c release, and caspase 3 activation in these cells and these remarkable changes were blocked by minocycline treatments. Furthermore, we showed that the inhibitor of p38 MAPK or the inhibitor of caspase 3 only partially blocked gentamicin-induced hair cell damage, and the pretreatment of explants with the inhibitor of p38 MAPK and the inhibitor of caspase 3 together exerted a synergic protective effect against gentamicin-induced hair cell damage. Our results suggest that minocycline blocks gentamicin-induced hair cell loss possibly by inhibition of three mechanisms: p38 MAPK phosphorylation, cytochrome c release, and caspase 3 activation. This finding may explain why minocycline has protective activity in a variety of apoptotic models. Therapeutic intervention by using minocycline or related drugs may be a novel means for preventing inner ear injury following the use of aminoglycoside.

Impact of APOE in mild cognitive impairment.

OBJECTIVE: The authors aimed to use baseline data of an ongoing large, prospective study in subjects with mild cognitive impairment (MCI) to investigate the impact of APOE genotype on the symptom profile of the condition. METHODS: Cognitive assessments included the AD Assessment Scale cognitive subscale (ADAS-cog), the Mini-Mental State Examination (MMSE), and a cognitive battery for assessment of memory, attention, and executive function. Behavioral assessments included the Neuropsychiatric Inventory and Beck Depression Inventory. Activities of daily living were assessed by the AD Cooperative Study Activities of Daily Living (ADCS-ADL) scale. Hippocampal volumes were measured with MRI. RESULTS: A total of 494 of 1,018 study subjects provided APOE data. Approximately 40% of the subjects were APOE epsilon4 carriers. APOE epsilon4 carriers had lower MMSE (p = 0.01) and higher ADAS-cog (p < 0.0001) scores than noncarriers, indicating worse cognitive impairment. APOE epsilon4 carriers also had greater deficits on New York University delayed paragraph recall and Buschke free and cued selective reminding tests, and on the ADCS-ADL scale (p < 0.001). They also had smaller hippocampal volumes (p = 0.002). Behavioral scores were similar across the subgroups. CONCLUSION: MCI subjects carrying the APOE epsilon4 allele showed distinct cognitive and imaging profiles, which appeared to resemble those of early Alzheimer patients. APOE epsilon4 genotype was associated with greater impairments in memory and functional activities as well as hippocampal atrophy.

Cholesterol and APOE genotype interact to influence Alzheimer disease progression.

In this retrospective analysis of 443 Alzheimer disease (AD) patients from a 30-week tacrine trial, change in Alzheimer's Disease Assessment Scale score from baseline to final value was significantly associated with a total serum cholesterol/APOE genotype interaction. Disease progression in the no-APOE epsilon4 allele/high-cholesterol subgroup was greater than in the normal-cholesterol subgroups with or without epsilon4. Cholesterol levels and APOE genotype may interact to affect AD progression. The results are consistent with preclinical data on cholesterol's effects in AD.