The neuropsychology of normal aging and preclinical Alzheimer's disease

ObjectiveA National Institute on Aging–sponsored work group on preclinical Alzheimer's disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD.MethodsSeventy-one apolipoprotein E (APOE) ε4 homozygotes, 194 ε3/ε4 heterozygotes, and 356 ε4 noncarriers age 21 to 87 years who were cognitively healthy underwent neuropsychological testing every 2 years. Longitudinal trajectories of test scores were compared between APOE subgroups.ResultsThere was a significant effect of age on all cognitive domains in both APOE ε4 carriers and noncarriers. A significant effect of APOE ε4 gene dose was confined to the memory domain and the Dementia Rating Scale. Cross-sectional comparisons did not discriminate the groups.ConclusionsAlthough cognitive aging patterns are similar in APOE ε4 carriers and noncarriers, preclinical AD is characterized by a significant ε4 gene dose effect that impacts memory and is detectable longitudinally. Preclinical neuropsychological testing strategies should emphasize memory-sensitive measures and longitudinal design.     

The ε4 genotype of apolipoprotein E and white matter integrity in Alzheimer's disease

BackgroundIn this multicenter study, we investigated a possible association between the APOE ε4 allele and white matter (WM) integrity in Alzheimer's disease (AD) using diffusion tensor imaging (DTI).MethodsWe analyzed fractional anisotropy (FA) and mean diffusivity (MD) as indices of WM integrity in 70 AD patients (35 APOE ε4 carriers, 35 noncarriers) and 56 healthy control (HC) subjects (28 APOE ε4 carriers, 28 noncarriers). APOE ε4 carriers and noncarriers were matched for age and gender within each diagnostic group.ResultsWe found significant effects of diagnosis (P_corrected < .05 [FWE]; i.e., smaller FA values and larger MD values in AD patients compared with HCs) and significant effects (P < .001) of APOE ε4 carrier status on MD in HCs but not in AD subjects.ConclusionsThe results indicate that APOE ε4 has a moderate effect on WM integrity in HCs, but no effect on WM integrity in manifest AD.     

Effect of APOE genotype status on targeted clinical trials outcomes and efficiency in dementia and mild cognitive impairment resulting from Alzheimer's disease

BackgroundThe apolipoprotein E (APOE) ε4 genotype has been recommended as a potential inclusion or exclusion criterion in targeted clinical trials for Alzheimer's disease (AD) and mild cognitive impairment (MCI) resulting from AD, and has been implemented in trials of immunotherapeutic agents.MethodsWe tested this recommendation with clinical trial simulations using participants from a meta-database of 19 studies to create trial samples with APOE ε4 proportions ranging from 0% (all noncarriers) to 100% (all carriers). For each percentage of APOE ε4 carriers, we resampled the database randomly for 1000 trials for each trial scenario, planning for 18- or 24-month trials with samples from 50 to 400 patients per treatment or placebo group, up to 40% dropouts, and outcomes on the Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS-cog) with effect sizes from 0.15 to 0.75, and calculated statistical power.ResultsEnrichment of clinical trial participants based on APOE ε4 carrier status resulted in minimal increases in power compared with enrolling participants with the APOE ε3 genotype only or enrolling patients without regard to APOE genotype. Increased screening requirements to enhance the sample would offset gains in power.ConclusionsAlthough samples enriched for APOE ε4 carriers in AD or MCI clinical trials showed slightly more cognitive impairment and greater decline using the number APOE ε4 alleles as an inclusion criterion most likely would not result in more efficient trials, and trials would take longer because fewer patients would be available. The APOE ε4/εX (where X = 2, 3 or 4) genotype could be useful, however, as an explanatory variable or covariate if warranted by a drug's action.     

Cerebrospinal fluid biomarkers of neurodegeneration,synaptic integrity,and astroglial activation across the clinical Alzheimer's disease spectrum

IntroductionWe investigated relations between amyloid-β (Aβ) status, apolipoprotein E (APOE) ε4, and cognition, with cerebrospinal fluid markers of neurogranin (Ng), neurofilament light (NFL), YKL-40, and total tau (T-tau).MethodsWe included 770 individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD)-type dementia from the EMIF-AD Multimodal Biomarker Discovery study. We tested the association of Ng, NFL, YKL-40, and T-tau with Aβ status (Aβ− vs. Aβ+), clinical diagnosis APOE ε4 carriership, baseline cognition, and change in cognition.ResultsNg and T-tau distinguished between Aβ+ from Aβ− individuals in each clinical group, whereas NFL and YKL-40 were associated with Aβ+ in nondemented individuals only. APOE ε4 carriership did not influence NFL, Ng, and YKL-40 in Aβ+ individuals. NFL was the best predictor of cognitive decline in Aβ+ individuals across the cognitive spectrum.DiscussionAxonal degeneration, synaptic dysfunction, astroglial activation, and altered tau metabolism are involved already in preclinical AD. NFL may be a useful prognostic marker.     

Influence of apolipoprotein E ɛ4 on rates of cognitive and functional decline in mild cognitive impairment

BackgroundApolipoprotein E ?4 (APOE ?4) allele carrier status has been well established as a risk factor for developing Alzheimer's disease. However, the specific influence of APOE ?4 allele status on cognitive and functional rates of decline in mild cognitive impairment (MCI) is poorly understood. We examine the prospective association of APOE ?4 allele status on measures of cognitive and functional decline in subjects with amnestic MCI (aMCI).MethodsA total of 516 aMCI participants aged 55–90 years who received placebo or vitamin E from the Alzheimer's Disease Cooperative Study's MCI treatment trial were evaluated. During the 36-month study period, neurocognitive and functional measures were collected. These measures were assessed over time for change and association with APOE ?4 status. Generalized Estimating Equations were performed to model each outcome measure over the study period.ResultsAPOE ?4 status had a significant impact on cognitive and functional decline on multiple measures; those who were APOE ?4 positive had significantly more rapid decline in performance on all cognitive and functional measures except Number Cancellation and Maze tracing (P < .05). The greatest decline was seen in global measures of cognition and function including the Clinical Diagnostic Rating scale, followed by the Mini-Mental State Examination, Global Deterioration scale, and the Alzheimer's Disease Assessment Scale-Cognitive Subscale.ConclusionsThese findings demonstrate that APOE ?4 genotype is predictive of increased general rates of decline with global measures of cognition and function most affected. With accelerated declines in common clinical trial primary efficacy measures, APOE ?4 status needs to be accounted for in treatment trials of MCI.     

Cerebral atrophy,apolipoprotein E ɛ4, and rate of decline in everyday function among patients with amnestic mild cognitive impairment

BackgroundPatients with amnestic mild cognitive impairment (MCI) demonstrate decline in everyday function. In this study, we investigated whether whole brain atrophy and apolipoprotein E (APOE) genotype are associated with the rate of functional decline in MCI.MethodsParticipants were 164 healthy controls, 258 MCI patients, and 103 patients with mild Alzheimer's disease (AD), enrolled in the Alzheimer's Disease Neuroimaging Initiative. They underwent brain MRI scans, APOE genotyping, and completed up to six biannual Functional Activities Questionnaire (FAQ) assessments. Random effects regressions were used to examine trajectories of decline in FAQ across diagnostic groups, and to test the effects of ventricle-to-brain ratio (VBR) and APOE genotype on FAQ decline among MCI patients.ResultsRate of decline in FAQ among MCI patients was intermediate between that of controls and mild AD patients. Patients with MCI who converted to mild AD declined faster than those who remained stable. Among MCI patients, increased VBR and possession of any APOE ?4 allele were associated with faster rate of decline in FAQ. In addition, there was a significant VBR by APOE ?4 interaction such that patients who were APOE ?4 positive and had increased atrophy experienced the fastest decline in FAQ.ConclusionsFunctional decline occurs in MCI, particularly among patients who progress to mild AD. Brain atrophy and APOE ?4 positivity are associated with such declines, and patients who have elevated brain atrophy and are APOE ?4 positive are at greatest risk of functional degradation. These findings highlight the value of genetic and volumetric MRI information as predictors of functional decline, and thus disease progression, in MCI.     

Differential default mode network trajectories in asymptomatic individuals at risk for Alzheimer's disease

IntroductionThe longitudinal trajectories of functional brain dynamics and the impact of genetic risk factors in individuals at risk for Alzheimer's disease are poorly understood.MethodsIn a large-scale monocentric cohort of 224 amyloid stratified individuals at risk for Alzheimer's disease, default mode network (DMN) resting state functional connectivity (FC) was investigated between two serial time points across 2 years.ResultsWidespread DMN FC changes were shown in frontal and posterior areas, as well as in the right hippocampus. There were no cross-sectional differences, however, apolipoprotein E ε4 (APOE ε4) carriers demonstrated slower increase in FC in frontal lobes. There was no impact of individual brain amyloid load status.DiscussionFor the first time, we demonstrated that the pleiotropic biological effect of the APOE ε4 allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkers may become useful surrogate outcomes for the development of preclinical targeted therapeutic interventions.     

Influence of APOE genotype and the presence of Alzheimer's pathology on synaptic membrane lipids of human brains

The APOE genotype is the major risk factor for Alzheimer's disease (AD); however, it remains unclarified how the ε4 allele accelerates whereas the ε2 allele suppresses AD development, compared with the more common ε3 allele. On the basis of the previous finding that the assembly of the amyloid‐β protein (Aβ) into fibrils in the brain, an early and invariable pathological feature of AD, depends on the lipid environment, we determined the levels of synaptic membrane lipids in aged individuals of different APOE genotypes. In the comparison between amyloid‐free ε2/ε3 and ε3/ε3 brains, the presence of the ε2 allele significantly decreased the level of cholesterol. Alternatively, in the comparison among ε3/ε3 brains, the presence of AD pathology substantially decreased the levels of cholesterol. This study suggests that the ε2 allele suppresses the initiation of AD development by lowering the cholesterol levels in synaptic membranes. © 2014 Wiley Periodicals, Inc.     

Head circumference,apolipoprotein E genotype and cognition in the Bavarian School Sisters Study

BackgroundThe apolipoprotein E (APOE) ?4 allele is correlated with an earlier onset of Alzheimer's disease symptoms; larger head circumference has been associated with an individual resilience against cognitive impairment.MethodsWe explored if larger head circumference attenuates the effect of the APOE ?4 allele on cognition in 380 Catholic sisters covering the spectrum from normal cognitive performance to severe dementia.ResultsLinear regression analysis, adjusting for risk factors for cognitive decline, revealed that APOE ?4 was correlated with worse cognition and that larger head circumference attenuated the negative effect of the ?4 allele on cognitive performance.ConclusionLarger head circumference (i.e. larger brain size) seems to be associated with greater resilience against genetic determinants of cognitive impairment, possibly due to enhanced brain or cognitive reserve.     

Effects of APOE ε2 allele on basal forebrain functional connectivity in mild cognitive impairment

Background

Basal forebrain cholinergic system (BFCS) dysfunction is associated with cognitive decline in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Apolipoprotein E (APOE) ε2 is a protective genetic factor in AD and MCI, and cholinergic sprouting depends on APOE.

Objective

We investigated the effect of the APOE ε2 allele on BFCS functional connectivity (FC) in cognitively normal (CN) subjects and MCI patients.

Method

We included 60 MCI patients with APOE ε3/ε3, 18 MCI patients with APOE ε2/ε3, 73 CN subjects with APOE ε3/ε3, and 36 CN subjects with APOE ε2/ε3 genotypes who had resting-state functional magnetic resonance imaging data from the Alzheimer's disease Neuroimaging Initiative. We used BFCS subregions (Ch1-3 and Ch4) as seeds and calculated the FC with other brain areas. Using a mixed-effect analysis, we explored the interaction effects of APOE ε2 allele × cognitive status on BFCS-FC. Furthermore, we examined the relationships between imaging metrics, cognitive abilities, and AD pathology markers, controlling for sex, age, and education as covariates.

Results

An interaction effect on functional connectivity was found between the right Ch4 (RCh4) and left insula (p < 0.05, corrected), and between the RCh4 and left Rolandic operculum (p < 0.05, corrected). Among all subjects and APOE ε2 carriers, RCh4-left Insula FC was associated with early tau deposition. Furthermore, no correlation was found between imaging metrics and amyloid burden. Among all subjects and APOE ε2 carriers, FC metrics were associated with cognitive performance.

Conclusion

The APOE ε2 genotype may play a protective role during BFCS degeneration in MCI.     

APOE ε4 influences β-amyloid deposition in primary progressive aphasia and speech apraxia

BackgroundApolipoprotein E ε4 (APOE ε4) is a risk factor for β-amyloid deposition in Alzheimer's disease dementia. Its influence on β-amyloid deposition in speech and language disorders, including primary progressive aphasia (PPA), is unclear.MethodsOne hundred thirty subjects with PPA or progressive speech apraxia underwent APOE genotyping and Pittsburgh compound B (PiB) PET scanning. The relationship between APOE ε4 and PiB status, as well as severity and regional distribution of PiB, was assessed.ResultsForty-five subjects had an APOE ε4 allele and 60 subjects were PiB-positive. The odds ratio for a subject with APOE ε4 being PiB-positive compared with a subject without APOE ε4 being PiB-positive was 10.2 (95% confidence interval, 4.4–25.5; P < .0001). The APOE ε4 allele did not influence regional PiB distribution or severity.ConclusionAPOE ε4 increases the risk of β-amyloid deposition in PPA and progressive speech apraxia but does not influence regional β-amyloid distribution or severity.     

Duration of preclinical,prodromal, and dementia stages of Alzheimer's disease in relation to age,sex, and APOE genotype

IntroductionWe estimated the age-specific duration of the preclinical, prodromal, and dementia stages of Alzheimer's disease (AD) and the influence of sex, setting, apolipoprotein E (APOE) genotype, and cerebrospinal fluid tau on disease duration.MethodsWe performed multistate modeling in a combined sample of 6 cohorts (n = 3268) with death as the end stage and estimated the preclinical, prodromal, and dementia stage duration.ResultsThe overall AD duration varied between 24 years (age 60) and 15 years (age 80). For individuals presenting with preclinical AD, age 70, the estimated preclinical AD duration was 10 years, prodromal AD 4 years, and dementia 6 years. Male sex, clinical setting, APOE ε4 allele carriership, and abnormal cerebrospinal fluid tau were associated with a shorter duration, and these effects depended on disease stage.DiscussionEstimates of AD disease duration become more accurate if age, sex, setting, APOE, and cerebrospinal fluid tau are taken into account. This will be relevant for clinical practice and trial design.     

Temporal lobe functional activity and connectivity in young adult APOE ɛ4 carriers

BackgroundWe sought to determine if the APOE ε4 allele influences both the functional activation and connectivity of the medial temporal lobes (MTLs) during successful memory encoding in young adults.MethodsTwenty-four healthy young adults, i.e., 12 carriers and 12 noncarriers of the APOE ε4 allele, were scanned in a subsequent-memory paradigm, using event-related functional magnetic resonance imaging. The neuroanatomic correlates of successful encoding were measured as greater neural activity for subsequently remembered versus forgotten task items, or in short, encoding success activity (ESA). Group differences in ESA within the MTLs, as well as whole-brain functional connectivity with the MTLs, were assessed.ResultsIn the absence of demographic or performance differences, APOE ε4 allele carriers exhibited greater bilateral MTL activity relative to noncarriers while accomplishing the same encoding task. Moreover, whereas ε4 carriers demonstrated a greater functional connectivity of ESA-related MTL activity with the posterior cingulate and other peri-limbic regions, reductions in overall connectivity were found across the anterior and posterior cortices.ConclusionsThese results suggest that the APOE ?4 allele may influence not only functional activations within the MTL, but functional connectivity of the MTLs to other regions implicated in memory encoding. Enhanced functional connectivity of the MTLs with the posterior cingulate in young adult ε4 carriers suggests that APOE may be expressed early in brain regions known to be involved in Alzheimer's disease, long before late-onset dementia is a practical risk or consideration. These functional connectivity differences may also reflect pleiotropic effects of APOE during early development.     

Impact of the apolipoprotein E ε4 allele on early Parkinson's disease progression

ObjectiveEmerging evidence shows that apolipoprotein E (APOE) ε4 exacerbates alpha-synuclein pathology. We aimed to investigate whether the APOE ε4 allele contributes to early Parkinson's disease (PD) progression.MethodsThis cohort study included 361 early PD patients who were classified as APOE ε4 carriers (n = 90) and noncarriers (n = 271). The patients underwent yearly motor and nonmotor assessments covering neuropsychiatric, sleep-related, and autonomic symptoms over 5 years of follow-up. Dopamine transporter (DAT) imaging was conducted at baseline and the 1-, 2-, and 4-year follow-up visits.ResultsThe APOE ε4 carriers had steeper declines in the Montreal Cognitive Assessment score (p=0.005) and the semantic fluency test score (p=0.012) than the noncarriers. No significant between-group differences in the longitudinal changes in motor, other nonmotor, and DAT imaging variables were observed.ConclusionsOur exploratory analyses show that only cognitive performance was negatively affected by the APOE ε4 allele in the progression of early PD. More specifically, this allele was associated with poorer performance in semantic verbal fluency among cognitive domains.     

Comparing test-specific distress of susceptibility versus deterministic genetic testing for Alzheimer's disease

BackgroundGenetic risk for Alzheimer's disease (AD) can be conferred by the susceptibility polymorphism apolipoprotein E (APOE), where the ε4 allele increases the risk of developing late-onset AD but is not a definitive predictor of the disease, or by autosomal dominant mutations (eg, the presenilins), which almost inevitably result in early-onset familial AD. The purpose of this study was to compare the psychological impact of using these two different types of genetic information to disclose genetic risk for AD to family members of affected patients.MethodsData were compared from two separate protocols. The Risk Evaluation and Education for Alzheimer's Disease (REVEAL) Study is a randomized, multi-site clinical trial that evaluated the impact of susceptibility testing for AD with APOE in 101 adult children of AD patients. A separate study, conducted at the University of Washington, assessed the impact of deterministic genetic testing by disclosing presenilin-1, presenilin-2, or TAU genotype to 22 individuals at risk for familial AD or frontotemporal dementia. In both protocols, participants received genetic counseling and completed the impact of event scale (IES), a measure of test-specific distress. Scores were analyzed at the time point closest to 1 year after disclosure at which IES data were available. The role of genetic test result (positive vs negative) and type of genetic testing (deterministic vs susceptibility) in predicting log-transformed IES scores were assessed with linear regression, controlling for age, gender, and time from disclosure.ResultsSubjects from the REVEAL Study who learned that they were positive for the susceptibility gene APOE ε4+ experienced similar, low levels of test-specific distress compared with those who received positive results of deterministic testing in the University of Washington study (P = .78). APOE ε4+ individuals in the susceptibility protocol experienced more test-specific distress than those who tested ε4– in the same study (P = .04); however, among those receiving deterministic test disclosure, the subjects who received positive results did not experience significantly higher levels of distress when compared with those who received negative results (P = .88).ConclusionsThe findings of this preliminary study, with limited sample size, suggest that the test-related distress experienced by those receiving positive results for a deterministic mutation is similar to the distress experienced by those receiving positive results from genetic susceptibility testing, and that the majority of participants receiving genotype disclosure do not experience clinically significant distress as indicated by IES scores 1 year after learning of their test results.     

More than just risk for Alzheimer’s disease: APOE ε4's impact on the aging brain

The apolipoprotein ε4 (APOE ε4) allele is most commonly associated with increased risk for late-onset Alzheimer’s disease (AD). However, recent longitudinal studies suggest that these risks are overestimated; most ε4 carriers will not develop dementia in their lifetime. In this article, we review new evidence regarding the impact of APOE ε4 on cognition among healthy older adults. We discuss emerging work from animal models suggesting that ε4 impacts brain structure and function in multiple ways that may lead to age-related cognitive impairment, independent from AD pathology. We discuss the importance of taking an individualized approach in future studies by incorporating biomarkers and neuroimaging methods that may better disentangle the phenotypic influences of APOE ε4 on the aging brain from prodromal AD pathology.     

APOE ε4 and risk for Alzheimer's disease: Do regionally distributed white matter hyperintensities play a role?

BackgroundWe previously demonstrated that parietal lobe white matter hyperintensities (WMH) increase the risk for Alzheimer's disease (AD). Here, we examined whether individuals with apolipoprotein E gene (APOE ε4) have increased parietal WMH volume.MethodsParticipants were from the Washington Heights-Inwood Columbia Aging Project (WHICAP; n = 694, 47 with dementia) in northern Manhattan and the Etude Santé Psychologique Prévalence Risques et Traitement study (ESPRIT; n = 539, 8 with dementia) in Montpellier. The association between regional WMH and APOE ε4 was examined separately in each group and then in a combined analysis.ResultsIn WHICAP, ε4 carriers had higher WMH volume particularly in parietal and occipital lobes. In ESPRIT, ε4 carriers had elevated WMH particularly in parietal and temporal lobes. In the combined analysis, ε4 carriers had higher WMH in parietal and occipital lobes. Increased WMH volume was associated with increased frequency of dementia irrespective of APOE ε4 status; those with the ε4 were more likely to have dementia if they also had increased parietal WMH.ConclusionsAPOE ε4 is associated with increased parietal lobe WMH.     

Apolipoprotein E ε4 genotype and risk of freezing of gait in Parkinson's disease

ObjectiveTo investigate the association between Apolipoprotein E (APOE) genotype and freezing of gait (FOG) in Parkinson's disease (PD).MethodsThis cohort study included 339 early PD patients who were divided into APOE ε4-positive (n = 88) and ε4-negative (n = 251) groups. They were followed-up for up to 6 years to identify the development of FOG. To investigate the influence of CSF β-amyloid 1–42 (Aβ₄₂) on the association between APOE ε4 and FOG, the patients were additionally dichotomized into “high-level” and “low-level” groups using three different cutoff values for the CSF Aβ₄₂ levels.ResultsAt baseline, the APOE ε4-positive group had lower CSF Aβ₄₂ levels than the APOE ε4-negative group. During a median follow-up of 5.0 years, the APOE ε4-positive group had a higher incidence of FOG than the APOE ε4-negative group. In the multivariable Cox model excluding CSF Aβ₄₂, APOE ε4 was a significant predictor of FOG. However, after adding CSF Aβ₄₂ in the model, APOE ε4 did not survive, whereas lower CSF Aβ₄₂ levels were associated with FOG. In the subgroup analyses, the effect of the APOE ε4 allele was not found in the “low-level” group. However, in the “high-level” group, the APOE ε4 allele independently increased the risk of FOG, and this association was stronger than the association with CSF Aβ₄₂.ConclusionThe APOE ε4 allele may be a novel genetic risk factor for FOG in PD. This association seemed to be mainly mediated by Aβ-dependent pathways, but its Aβ-independent effects might also contribute to the development of FOG.     

APOE ε4 is a high-risk factor for Alzheimer's disease in the Mongolian population

To determine the relationship between apolipoprotein E (APOE) ε4 and sporadic Alzheimer's disease (SAD) in the Mongolian population in China, we examined 106 Mongolian SAD patients in China and 100 Mongolian healthy controls. All subjects were genotyped for APOE.The odds ratio (OR) for developing SAD was significantly increased in carriers of the APOE ε4 allele compared with APOE ε4 non-carriers (χ² = 5.59, df = 1, P = 0.018, OR = 1.84, 95% CI 1.02–3.31).Our findings suggested that APOE ε4 is a high-risk factor for AD in the Mongolian population in China. The present study is the first to establish the relationship between APOE ε4 and SAD in the Mongolian population.     

APOE ε4: The most prevalent yet understudied risk factor for Alzheimer's disease

Brain pathology of Alzheimer's diseases (AD) and the genetics of autosomal dominant familial AD have been the “lamp posts” under which the AD field has been looking for therapeutic targets. Although this approach still remains valid, none of the compounds tested to date have produced clinically meaningful results. This calls for developing complementary therapeutic approaches and AD targets. The allele ε4 of apolipoprotein E4 (APOE ε4), is the most prevalent genetic risk factor for sporadic AD, and is expressed in more than half of the AD patients. However, in spite of its genetic prominence, the allele APOE ε4 and its corresponding protein product apoE4 have been understudied. We presently briefly discuss the reasons underlying this situation and review newly developed AD therapeutic approaches that target apoE4 and which pave the way for future studies.