Diabetes mellitus and risk of incident dementia in APOE ɛ4 carriers: an updated meta-analysis.

BACKGROUND AND AIM: Diabetes raises the risk of dementia, mortality, and cognitive decline in the elderly, potentially because of hereditary variables such as APOE. In this study, we aim to evaluate Diabetes mellitus and the risk of incident dementia in APOE ɛ4 carriers. METHOD: We thoroughly searched PubMed (Medline), Scopus, and Google Scholar databases for related articles up to September 2023. The titles, abstracts, and full texts of articles were reviewed; data were extracted and analyzed. RESULT: This meta-analysis included nine cohorts and seven cross-sectional articles with a total of 42,390 population. The study found that APOE ɛ4 carriers with type 2 diabetes (T2D) had a 48% higher risk of developing dementia compared to non-diabetic carriers (Hazard Ratio;1.48, 95%CI1.36-1.60). The frequency of dementia was 3 in 10 people (frequency: 0.3; 95%CI (0.15-0.48). No significant heterogeneity was observed. Egger's test, which we performed, revealed no indication of publication bias among the included articles (p = 0.2). CONCLUSION: Overall, diabetes increases the risk of dementia, but further large-scale studies are still required to support the results of current research.

Quantitative electroencephalography (qEEG), apolipoprotein A-I (APOA-I), and apolipoprotein epsilon 4 (APOE ɛ4) alleles for the diagnosis of mild cognitive impairment and Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is the most common type of dementia. Amnestic mild cognitive impairment (aMCI), a pre-dementia stage is an important stage for early diagnosis and intervention. This study aimed to investigate the diagnostic value of qEEG, APOA-I, and APOE ɛ4 allele in aMCI and AD patients and found the correlation between qEEG (Delta + Theta)/(Alpha + Beta) ratio (DTABR) and different cognitive domains. METHODS: All participants were divided into three groups: normal controls (NCs), aMCI, and AD, and all received quantitative electroencephalography (qEEG), neuropsychological scale assessment, apolipoprotein epsilon 4 (APOE ɛ4) alleles, and various blood lipid indicators. Different statistical methods were used for different data. RESULTS: The cognitive domains except executive ability were all negatively correlated with DTABR in different brain regions while executive ability was positively correlated with DTABR in several brain regions, although without statistical significance. The consequences confirmed that the DTABR of each brain area were related to MMSE, MoCA, instantaneous memory, and the language ability (p < 0.05), and the DTABR in the occipital area was relevant to all cognitive domains (p < 0.01) except executive function (p = 0.272). Also, occipital DTABR was most correlated with language domain when tested by VFT with a moderate level (r = 0.596, p < 0.001). There were significant differences in T3, T5, and P3 DTABR between both AD and NC and aMCI and NCs. As for aMCI diagnosis, the maximum AUC was achieved when using T3 combined with APOA-I and APOE ε4 (0.855) and the maximum AUC was achieved when using T5 combined with APOA-I and APOE ε4 (0.889) for AD diagnosis. CONCLUSION: These findings highlight that APOA-I, APOE ɛ4, and qEEG play an important role in aMCI and AD diagnosis. During AD continuum, qEEG DTABR should be taken into consideration for the early detection of AD risk.

Link among apolipoprotein E E4, gait, and cognition in neurodegenerative diseases: ONDRI study.

INTRODUCTION: Apolipoprotein E E4 allele (APOE E4) and slow gait are independently associated with cognitive impairment and dementia. However, it is unknown whether their coexistence is associated with poorer cognitive performance and its underlying mechanism in neurodegenerative diseases. METHODS: Gait speed, APOE E4, cognition, and neuroimaging were assessed in 480 older adults with neurodegeneration. Participants were grouped by APOE E4 presence and slow gait. Mediation analyses were conducted to determine if brain structures could explain the link between these factors and cognitive performance. RESULTS: APOE E4 carriers with slow gait had the lowest global cognitive performance and smaller gray matter volumes compared to non-APOE E4 carriers with normal gait. Coexistence of APOE E4 and slow gait best predicted global and domain-specific poorer cognitive performances, mediated by smaller gray matter volume. DISCUSSION: Gait slowness in APOE E4 carriers with neurodegenerative diseases may indicate extensive gray matter changes associated with poor cognition. HIGHLIGHTS: APOE E4 and slow gait are risk factors for cognitive decline in neurodegenerative diseases. Slow gait and smaller gray matter volumes are associated, independently of APOE E4. Worse cognition in APOE E4 carriers with slow gait is explained by smaller GM volume. Gait slowness in APOE E4 carriers indicates poorer cognition-related brain changes.

Ideal vitamin D and handgrip strength counteracts the risk effect of APOE genotype on dementia: a population-based longitudinal study.

BACKGROUND: Higher vitamin D concentrations and grip strength contribute to lower individual-level risk of dementia, while apolipoprotein 4 (APOE e4) genotype carries increases dementia risk, but whether combination of ideal vitamin D and grip strength counteracts the risk effect of dementia related to APOE e4 genotype remains unclear. We aimed to investigate the interactions between vitamin D/grip strength and APOE e4 genotype and their association with dementia. METHODS: The UK Biobank cohort comprised 165,688 dementia-free participants (aged at least 60 years) for the dementia analysis. Dementia was ascertained using hospital inpatient, mortality, and self-reported data until 2021. Vitamin D and grip strength were collected at baseline and divided into tertiles. APOE genotype was coded as APOE e4 non-carries and APOE e4 carries. Data were analyzed using Cox proportional hazard models and restricted cubic regression splines, with adjusted for known confounders. RESULTS: Over the follow-up (median: 12.0 years), 3917 participants developed dementia. In women and men, respectively, compared with to the lowest tertile of vitamin D, the HRs (95% CIs) of dementia were lower in the middle [0.86 (0.76-0.97)/0.80 (0.72-0.90)] and the highest tertile [0.81 (0.72-0.90)/0.73 (0.66-0.81)]. Tertiles of grip strength showed similar patterns. In women and men, respectively, participants who had both highest tertile of vitamin D and grip strength was associated with a lower risk of dementia compared to those with both lowest tertile of these two exposures among APOE e4 genotype carries (HR = 0.56, 95% CI 0.42-0.76, and HR = 0.48, 95% CI 0.36-0.64) and APOE e4 genotype non-carries (HR = 0.56, 95% CI 0.38-0.81, and HR = 0.34, 95% CI 0.24-0.47). There were significant additive interactions between lower vitamin D/grip strength and APOE e4 genotype on dementia among women and men. CONCLUSIONS: Higher vitamin D and grip strength were associated with a lower risk of dementia, and seemed to halve the adverse effects of APOE e4 genotype on dementia. Our findings suggested that vitamin D and grip strength may be imperative for estimating the risks of dementia, especially among APOE e4 genotype carries.

The long-term effects of a polygenetic predisposition to general cognition on healthy cognitive ageing: evidence from the English Longitudinal Study of Ageing.

BACKGROUND: As an accelerated cognitive decline frequently heralds onset of severe neuropathological disorders, understanding the source of individual differences in withstanding the onslaught of cognitive ageing may highlight how best cognitive abilities may be retained into advanced age. METHODS: Using a population representative sample of 5088 adults aged •50 years from the English Longitudinal Study of Ageing, we investigated relationships of polygenic predisposition to general cognition with a rate of change in cognition during a 10-year follow-up period. Polygenic predisposition was measured with polygenic scores for general cognition (GC-PGS). Cognition was measured employing tests for verbal memory and semantic fluency. RESULTS: The average baseline memory score was 11.1 (s.d. = 2.9) and executive function score was 21.5 (s.d. = 5.8). An increase in GC-PGS by one standard deviation (1-s.d.) was associated with a higher baseline verbal memory by an average 0.27 points (95% CI 0.19-0.34, p < 0.001). Similarly, 1-s.d. increase in GC-PGS was associated with a higher semantic fluency score at baseline in the entire sample (ß = 0.45, 95% CI 0.27-0.64, p < 0.001). These associations were significant for women and men, and all age groups. Nonetheless, 1-s.d. increase in GC-PGS was not associated with decreases in verbal memory nor semantic fluency during follow-up in the entire sample, as well stratified models by sex and age. CONCLUSION: Although common genetic variants associated with general cognition additively are associated with a stable surplus to cognition in adults, a polygenic predisposition to general cognition is not associated with age-related cognitive decline during a 10-year follow-up.

Apolipoprotein E Polymorphism, Cardiac Remodeling, and Heart Failure in the ARIC Study.

BACKGROUND: ß-Amyloid has recently been discovered in the myocardium of patients with Alzheimer's disease (AD). Whether genetic variation in apolipoprotein E (APOE) ɛ4, a common variant associated with Alzheimer's disease, is associated with incident heart failure (HF), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and cardiac structure and function is unknown. METHODS AND RESULTS: We studied 15,064 White and Black participants in the Atherosclerosis Risk in Communities, relating genotype status at visit 1 (1987-1989) to incident HF hospitalization using Cox regression. At visits 2, 4, and 5, we assessed NT-proBNP levels by genotype. At visits 3 and 5, we related Aß peptides to incident HF. At visit 5 (2011-2013, n = 6251), we assessed the relationship of genotype with prevalent HF and echocardiographic parameters. The mean participant age was 54.7 ± 5.8 years, 45% were men, and 73% were White. At visit 5, there was no difference in prevalent HF by genotype. The APOE ε4 carriers did not have increased risk for HF hospitalization. The APOE ε4 genotype was not associated with cardiac structure and function or NT-proBNP levels. The Aß peptides were not associated with incident HF after multivariable adjustment. CONCLUSIONS: A genetic predisposition to Alzheimer's disease through APOE ε4 is not associated with an increased prevalence of HF, HF hospitalization, myocardial remodeling, or biochemical evidence of HF.

Cognitive Functioning of Unaffected First-degree Relatives of Individuals With Late-onset Alzheimer's Disease: A Systematic Literature Review and Meta-analysis.

First-degree relatives of individuals with late-onset Alzheimer's disease (LOAD) are at increased risk for developing dementia, yet the associations between family history of LOAD and cognitive dysfunction remain unclear. In this quantitative review, we provide the first meta-analysis on the cognitive profile of unaffected first-degree blood relatives of LOAD-affected individuals compared to controls without a family history of LOAD. A systematic literature search was conducted in PsycINFO, PubMed /MEDLINE, and Scopus. We fitted a three-level structural equation modeling meta-analysis to control for non-independent effect sizes. Heterogeneity and risk of publication bias were also investigated. Thirty-four studies enabled us to estimate 218 effect sizes across several cognitive domains. Overall, first-degree relatives (n = 4,086, mean age = 57.40, SD = 4.71) showed significantly inferior cognitive performance (Hedges' g = -0.16; 95% CI, -0.25 to -0.08; p < .001) compared to controls (n = 2,388, mean age = 58.43, SD = 5.69). Specifically, controls outperformed first-degree relatives in language, visuospatial and verbal long-term memory, executive functions, verbal short-term memory, and verbal IQ. Among the first-degree relatives, APOE ɛ4 carriership was associated with more significant dysfunction in cognition (g = -0.24; 95% CI, -0.38 to -0.11; p < .001) compared to non-carriers (g = -0.14; 95% CI, -0.28 to -0.01; p = .04). Cognitive test type was significantly associated with between-group differences, accounting for 65% (R23 = .6499) of the effect size heterogeneity in the fitted regression model. No evidence of publication bias was found. The current findings provide support for mild but robust cognitive dysfunction in first-degree relatives of LOAD-affected individuals that appears to be moderated by cognitive domain, cognitive test type, and APOE ɛ4.

The effects of docosahexaenoic acid supplementation on cognition and well-being in mild cognitive impairment: A 12-month randomised controlled trial.

OBJECTIVES: Several recent clinical trials have shown that docosahexaenoic acid (DHA) supplements have a significant effect on cognition in cognitively impaired older adults. This randomised controlled trial aimed to investigate the cognitive effects of a DHA fish oil supplement in older adults with mild cognitive impairment, and to examine the moderating effect of the apolipoprotein E (APOE) ɛ4 allele on cognition and well-being. METHODS/DESIGN: Seventy-two older adults between the ages of 60 and 90 from New Zealand were given a DHA supplement equivalent to 1491 mg DHA + 351 mg eicosapentaenoic acid per day or a placebo for a period of 12 months. Outcome measures included cognition, wellbeing and self-rated quality of life as well as height, weight, blood pressure and APOE genotyping. RESULTS: The final analysis (n = 60) found no evidence of a treatment effect on cognitive measures, although did find a treatment effect on systolic blood pressure (p = 0.03, ƞ2  = 0.08), and a treatment interaction for APOE ɛ4 carriers on depression (p = 0.04, ƞ2  = 0.07) and anxiety (p = 0.02, ƞ2  = 0.09) scores in favour of the DHA supplement. CONCLUSIONS: Despite no effect on cognition, the positive result in APOE ɛ4 carriers on depression and anxiety scores and on systolic blood pressure justifies further DHA trials. It may be a prudent step going forward for more studies to replicate the design elements (dose, duration and cognitive measures) of previous DHA trials to help understand why not all older adults appear to benefit from taking a fish oil supplement.

A Likelihood Ratio Test for Gene-Environment Interaction Based on the Trend Effect of Genotype Under an Additive Risk Model Using the Gene-Environment Independence Assumption.

Several statistical methods have been proposed for testing gene-environment (G-E) interactions under additive risk models using data from genome-wide association studies. However, these approaches have strong assumptions from underlying genetic models, such as dominant or recessive effects that are known to be less robust when the true genetic model is unknown. We aimed to develop a robust trend test employing a likelihood ratio test for detecting G-E interaction under an additive risk model, while incorporating the G-E independence assumption to increase power. We used a constrained likelihood to impose 2 sets of constraints for: 1) the linear trend effect of genotype and 2) the additive joint effects of gene and environment. To incorporate the G-E independence assumption, a retrospective likelihood was used versus a standard prospective likelihood. Numerical investigation suggests that the proposed tests are more powerful than tests assuming dominant, recessive, or general models under various parameter settings and under both likelihoods. Incorporation of the independence assumption enhances efficiency by 2.5-fold. We applied the proposed methods to examine the gene-smoking interaction for lung cancer and gene-apolipoprotein E $\varepsilon$4 interaction for Alzheimer disease, which identified 2 interactions between apolipoprotein E $\varepsilon$4 and loci membrane-spanning 4-domains subfamily A (MS4A) and bridging integrator 1 (BIN1) genes at genome-wide significance that were replicated using independent data.

The Alzheimer's Disease Chronicles: Will Evidence Triumph Over Adversity?

Herpes simplex virus type 1 (HSV1) infects most humans and remains lifelong in the body in latent form within the PNS. The virus can be reactivated by stress, immunosuppression etc, and in some people it then causes cold sores.

An increased rate of longitudinal cognitive decline is observed in Parkinson's disease patients with low CSF Aß42 and an APOE ε4 allele.

OBJECTIVE: Low concentrations of cerebrospinal fluid (CSF) amyloid-beta (Aß-42) are associated with increased risk of cognitive decline in Parkinson's disease (PD). We sought to determine whether APOE genotype modifies the rate of cognitive decline in PD patients with low CSF Aß-42 compared to patients with normal levels. METHODS: The Parkinson's Progression Markers Initiative is a longitudinal, ongoing study of de novo PD participants, which includes APOE genotyping, CSF Aß-42 determinations, and neuropsychological assessments. We used linear mixed effects models in three PD groups (PD participants with low CSF Aß at baseline, PD participants with normal CSF Aß, and both groups combined). Having at least one copy of the APOE ɛ4 allele, time, and the interaction of APOE ɛ4 and time were predictor variables for cognitive change, adjusting for age, gender and education. RESULTS: 423 de novo PD participants were followed up to 5 years with annual cognitive assessments. 103 participants had low baseline CSF Aß-42 (39 APOE ε4+, 64 APOE ε4-). Compared to participants with normal CSF Aß-42, those with low CSF Aß-42 declined faster on most cognitive tests. Within the low CSF Aß-42 group, APOE ε4+ participants had faster rates of decline on the Montreal Cognitive Assessment (primary outcome; 0.57 points annual decline, p = .005; 5-year standardized change of 1.2) and the Symbol Digit Modalities Test (1.4 points annual decline, p = .002; 5-year standardized change of 0.72). DISCUSSION: PD patients with low CSF Aß-42 and APOE ε4+ showed a higher rate of cognitive decline early in the disease. Tests of global cognition (Montreal Cognitive Assessment) and processing speed (Symbol Digit Modalities Test) were the most sensitive to early cognitive decline. Results suggest that CSF Aß-42 and APOE ε4 might interact to promote early cognitive changes in PD patients.

Impacts of apolipoprotein E disclosure on healthy Asian older adults: a cohort study.

BACKGROUND: The apolipoprotein E (APOE) genotype provides information about Alzheimer's disease risk, yet genotype disclosure is discouraged due to concerns about possible distress. This is the first study investigating the psychological and behavioral impacts that genetic susceptibility testing for Alzheimer's disease has in an Asian population. METHODS: From March 2016 to November 2017, we ran a prospective cohort study at Duke-National University of Singapore Medical School. 280 healthy Chinese elderly filled in questionnaires that measured psychological symptoms and health behaviors, 1 week before and 6 weeks after APOE genotype disclosure. Responses from ε4-positive subjects (associated with greater Alzheimer's disease risk) were compared to responses from ε4-negative subjects. RESULTS: ε4 presence was not significantly associated with anxiety (p = 0.09) or depression (p = 0.25). No associations were found for changes to diet (p = 0.36), dietary supplements consumption (p = 0.90), physical activity (p = 0.15), or cognitive activity (p = 0.18). CONCLUSION: There is no evidence to suggest that disclosure of APOE to Asian populations was associated with any short-term adverse psychological or behavioral impacts.

Genetic resilience to Alzheimer's disease in APOE ε4 homozygotes: A systematic review.

INTRODUCTION: Individuals with homozygosity for the apolipoprotein E (APOE) ε4 allele are in the highest risk category for late-onset Alzheimer's disease (LOAD). However, some individuals in this category do not develop LOAD beyond the age of 75 years, despite being at elevated genetic risk. These "resilient" individuals may carry protective genetic factors. METHODS: This study aimed to systematically review any previous studies that involved resilient APOE ε4 homozygotes and to identify possible modifying or protective genetic factors. RESULTS: Fifteen studies met our inclusion criteria and reported genetic factors contributing to reduced risk. We found that only two single nucleotide polymorphisms, CASP7 rs10553596 and SERPINA3 rs4934-A/A, had strong evidence. DISCUSSION: We found a paucity of studies adequately designed to discover protective genetic factors against LOAD. Many studies combined APOE ε4 homozygotes and heterozygotes together because of small sample sizes and used control populations too young to be clearly defined as controls for LOAD.

Functional segregation loss over time is moderated by APOE genotype in healthy elderly.

We investigated the influence of the apolipoprotein E-ɛ4 allele (APOE-ɛ4) on longitudinal age-related changes in brain functional connectivity (FC) and cognition, in view of mixed cross-sectional findings. One hundred and twenty-two healthy older adults (aged 58-79; 25 APOE-ɛ4 carriers) underwent task-free fMRI scans at baseline. Seventy-eight (16 carriers) had at least one follow-up (every 2 years). Changes in intra- and internetwork FCs among the default mode (DMN), executive control (ECN), and salience (SN) networks, as well as cognition, were quantified using linear mixed models. Cross-sectionally, APOE-ɛ4 carriers had lower functional connectivity between the ECN and SN than noncarriers. Carriers also showed a stronger age-dependent decrease in visuospatial memory performance. Longitudinally, carriers had steeper increase in inter-ECN-DMN FC, indicating loss of functional segregation. The longitudinal change in processing speed performance was not moderated by APOE-ɛ4 genotype, but the brain-cognition association was. In younger elderly, faster loss of segregation was correlated with greater decline in processing speed regardless of genotype. In older elderly, such relation remained for noncarriers but reversed for carriers. APOE-ɛ4 may alter aging by accelerating the change in segregation between high-level cognitive systems. Its modulation on the longitudinal brain-cognition relationship was age-dependent.

Regionally specific changes in the hippocampal circuitry accompany progression of cerebrospinal fluid biomarkers in preclinical Alzheimer's disease.

Neuropathological and in vivo brain imaging studies agree that the cornu ammonis 1 and subiculum subfields of the hippocampus are most vulnerable to atrophy in the prodromal phases of Alzheimer's disease (AD). However, there has been limited investigation of the structural integrity of the components of the hippocampal circuit, including subfields and extra-hippocampal white matter structure, in relation to the progression of well-accepted cerebrospinal fluid (CSF) biomarkers of AD, amyloid-ß 1-42 (Aß) and total-tau (tau). We investigated these relationships in 88 aging asymptomatic individuals with a parental or multiple-sibling familial history of AD. Apolipoprotein (APOE) ɛ4 risk allele carriers were identified, and all participants underwent cognitive testing, structural magnetic resonance imaging, and lumbar puncture for CSF assays of tau, phosphorylated-tau (p-tau) and Aß. Individuals with a reduction in CSF Aß levels (an indicator of amyloid accretion into neuritic plaques) as well as evident tau pathology (believed to be linked to neurodegeneration) exhibited lower subiculum volume, lower fornix microstructural integrity, and a trend towards lower cognitive score than individuals who showed only reduction in CSF Aß. In contrast, persons with normal levels of tau showed an increase in structural MR markers in relation to declining levels of CSF Aß. These results suggest that hippocampal subfield volume and extra-hippocampal white matter microstructure demonstrate a complex pattern where an initial volume increase is followed by decline among asymptomatic individuals who, in some instances, may be a decade or more away from onset of cognitive or functional impairment.

Effect of long-term nutraceutical and dietary supplement use on cognition in the elderly: a 10-year systematic review of randomised controlled trials.

Nutraceuticals have generated interest as a way to mitigate the cognitive decline in older adults. The aim of this systematic review was to determine the evidence for these claims from the scientific literature in randomised, double-blinded, controlled trials (duration: ≥1 year; participants: n≥100; age(mean): ≥65 years). Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched four electronic databases (PubMed, Scopus, CINAHL and Web of Science) and identified twenty-five studies published between the 15·June·2006 and 14·June·2016. Interventions included B-vitamins, n-3 fatty acids, antioxidant vitamins and herbs. Of the B-vitamin studies, four found benefits to cognition with supplementation. The first of these B-vitamin studies, in individuals with mild cognitive impairment (n 266; duration=2 years), included benefit to executive function (P=0·015) and improvements in the Mini-Mental State Examination (MMSE) among participants with baseline homocysteine above 11·3 µmol/l (P<0·001). In the same sample, the second study found cognitive benefits of B-vitamins dependent on the higher baseline plasma n-3 fatty acid status. The third B-vitamin study (n 900; duration=2 years) reported improved performance in immediate (P=0·046) and delayed recall (P=0·013), whereas the fourth study (n 856; duration=2 years) reported slower rate of cognitive decline in the MMSE (P=0·05). One study investigating DHA treatment (n 402; duration=1·5 years) revealed the slower rate of cognitive change in apoE e4 non-carriers (P=0·03). As only five included studies revealed notable benefits, presently based on the specific compounds explored here, there is not compelling evidence to support the use nutraceuticals to improve cognition in the elderly. Future long-term trials of nutraceuticals should investigate interactions with lifestyle, blood biomarkers and genetic risk factors.

Precuneus degeneration in nondemented elderly individuals with APOE ɛ4: Evidence from structural and functional MRI analyses.

Neurodegenerative diseases such as Alzheimer's disease (AD) have been recognized to exhibit disease-specific brain vulnerability patterns. Apolipoprotein E (APOE) ɛ4 allele imparts a high genetic risk of developing AD. Whether the APOE ɛ4 allele damages the brain when cognitive functions are still intact is important to understand, especially for possible early detection and intervention. This study aimed to examine the selective degeneration pattern associated with the APOE ɛ4 allele in the brains of cognitively normal elderly subjects. We enrolled 35 cognitively healthy ɛ4 carriers and 40 non-carriers (53 to 81 years old) to evaluate group differences in cortical thickness and brain activation during a memory-encoding task. We also assessed the functional connectivity of the brain regions with both structural and functional damages. The results from the neuropsychological tests showed that the performances of ɛ4 carriers and non-carriers were comparable. Primarily, we found that the precuneus exhibited thinner cortical thickness and decreased deactivation during memory encoding. Furthermore, the connectivity analyses show that carriers exhibited damaged connectivity of the precuneus to several regions in the default mode network and the attention/executive control network. Our study reveals the degeneration pattern of the ɛ4 allele, which could be used as a potential biomarker for early detection for possible interventions and treatments. Hum Brain Mapp 38:271-282, 2017. © 2016 Wiley Periodicals, Inc.

Insulin resistance is associated with poorer verbal fluency performance in women.

AIMS/HYPOTHESIS: Type 2 diabetes is an independent risk factor for cognitive decline. Insulin resistance occurring during midlife may increase the risk of cognitive decline later in life. We hypothesised that insulin resistance is associated with poorer cognitive performance and that sex and APOE*E4 might modulate this association. METHODS: The association of insulin resistance and APOE*E4 genotype on cognitive function was evaluated in a nationwide Finnish population-based study (n = 5,935, mean age 52.5 years, range 30-97 years). HOMA-IR was used to measure insulin resistance. Cognitive function was tested by word-list learning, word-list delayed-recall, categorical verbal fluency and simple and visual-choice reaction-time tests. Linear regression analysis was used to determine the association between HOMA-IR and the results of the cognitive tests. RESULTS: Higher HOMA-IR was associated with poorer verbal fluency in women (p < 0.0001) but not in men (p = 0.56). Higher HOMA-IR was also associated with poorer verbal fluency in APOE*E4 -negative individuals (p = 0.0003), but not in APOE*E4 carriers (p = 0.28). Furthermore, higher HOMA-IR was associated with a slower simple reaction time in the whole study group (p = 0.02). CONCLUSIONS/INTERPRETATION: To our knowledge, this is the first comprehensive, population-based study, including both young and middle-aged adults, to report that female sex impacts the association of HOMA-IR with verbal fluency. Our study was cross-sectional, so causal effects of HOMA-IR on cognition could not be evaluated. However, our results suggest that HOMA-IR could be an early marker for an increased risk of cognitive decline in women.

APOE ɛ4 constrains engagement of encoding-related compensatory networks in amnestic mild cognitive impairment.

People with amnestic mild cognitive impairment (aMCI), compared to healthy older adults (HO), benefit less from semantic congruent cues during episodic encoding. The presence of the apolipoprotein E (APOE) ɛ4 makes this congruency benefit smaller, but the neural correlates of this deficit are unknown. Here, we estimated the source generators of EEG oscillatory activity associated with successful encoding of face-location associations preceded by semantically congruent and incongruent cues in HO (N = 26) and aMCI subjects (N = 34), 16 of which were ɛ4 carriers (ɛ4(+) ) and 18 ɛ4 noncarriers (ɛ4(-) ). Source estimation was performed in those spectrotemporal windows where the power of low-alpha, high-alpha, and beta oscillatory activity differed either between congruent and incongruent faces or between groups. Differences in high-alpha and beta-oscillatory dynamics indicated that aMCI ɛ4(+) are unable to activate lateral regions of the temporal lobe involved in associative memory and congruency benefit in HO. Interestingly, and regardless of APOE genotype, aMCI activated additional regions relative to HO, through alpha oscillations. However, only activation in a distributed fronto-temporo-parietal network in ɛ4 noncarriers was paralleled by enhanced memory. On the contrary, the redundant prefrontal activation shown by aMCI ɛ4(+) did not prevent performance from decreasing. These results indicate that the effect of aMCI-related degeneracy on functional networks is constrained by the presence of APOE ɛ4. Whereas individuals with aMCI ɛ4(-) activate attentional, perceptual and semantic compensatory networks, aMCI ɛ4(+) show reduced processing efficiency and capacity.

Asymmetry and heterogeneity of Alzheimer's and frontotemporal pathology in primary progressive aphasia.

Fifty-eight autopsies of patients with primary progressive aphasia are reported. Twenty-three of these were previously described (Mesulam et al., 2008) but had their neuropathological diagnoses updated to fit current criteria. Thirty-five of the cases are new. Their clinical classification was guided as closely as possible by the 2011 consensus guidelines (Gorno-Tempini et al., 2011). Tissue diagnoses included Alzheimer's disease in 45% and frontotemporal lobar degeneration (FTLD) in the others, with an approximately equal split between TAR DNA binding protein 43 proteinopathies and tauopathies. The most common and distinctive feature for all pathologies associated with primary progressive aphasia was the asymmetric prominence of atrophy, neuronal loss, and disease-specific proteinopathy in the language-dominant (mostly left) hemisphere. The Alzheimer's disease pathology in primary progressive aphasia displayed multiple atypical features. Males tended to predominate, the neurofibrillary pathology was more intense in the language-dominant hemisphere, the Braak pattern of hippocampo-entorhinal prominence was tilted in favour of the neocortex, and the APOE e4 allele was not a risk factor. Mean onset age was under 65 in the FTLD as well as Alzheimer's disease groups. The FTLD-TAR DNA binding protein 43 group had the youngest onset and fastest progression whereas the Alzheimer's disease and FTLD-tau groups did not differ from each other in either onset age or progression rate. Each cellular pathology type had a preferred but not invariant clinical presentation. The most common aphasic manifestation was of the logopenic type for Alzheimer pathology and of the agrammatic type for FTLD-tau. The progressive supranuclear palsy subtype of FTLD-tau consistently caused prominent speech abnormality together with agrammatism whereas FTLD-TAR DNA binding protein 43 of type C consistently led to semantic primary progressive aphasia. The presence of agrammatism made Alzheimer's disease pathology very unlikely whereas the presence of a logopenic aphasia or word comprehension impairment made FTLD-tau unlikely. The association of logopenic primary progressive aphasia with Alzheimer's disease pathology was much more modest than has been implied by results of in vivo amyloid imaging studies. Individual features of the aphasia, such as agrammatism and comprehension impairment, were as informative of underlying pathology as more laborious subtype diagnoses. At the single patient level, no clinical pattern was pathognomonic of a specific neuropathology type, highlighting the critical role of biomarkers for diagnosing the underlying disease. During clinical subtyping, some patients were unclassifiable by the 2011 guidelines whereas others simultaneously fit two subtypes. Revisions of criteria for logopenic primary progressive aphasia are proposed to address these challenges.