Insulin resistance predicts brain amyloid deposition in late middle-aged adults.

BACKGROUND: Insulin resistance (IR) increases Alzheimer's disease (AD) risk. IR is related to greater amyloid burden post-mortem and increased deposition within areas affected by early AD. No studies have examined if IR is associated with an in vivo index of amyloid in the human brain in late middle-aged participants at risk for AD. METHODS: Asymptomatic, late middle-aged adults (N = 186) from the Wisconsin Registry for Alzheimer's Prevention underwent [C-11]Pittsburgh compound B (PiB) positron emission tomography. The cross-sectional design tested the interaction between insulin resistance and glycemic status on PiB distribution volume ratio in three regions of interest (frontal, parietal, and temporal). RESULTS: In participants with normoglycemia but not hyperglycemia, higher insulin resistance corresponded to higher PiB uptake in frontal and temporal areas, reflecting increased amyloid deposition. CONCLUSIONS: This is the first human study to demonstrate that insulin resistance may contribute to amyloid deposition in brain regions affected by AD.

Emergence of mild cognitive impairment in late middle-aged adults in the wisconsin registry for Alzheimer's prevention.

AIM: It is difficult to reliably detect the earliest signs of Alzheimer's disease (AD)-associated cognitive impairment. Our aim was to compare 3 psychometric methods of identifying amnestic mild cognitive impairment (aMCI) in a middle-aged longitudinal cohort enriched for AD risk. METHODS: Wisconsin Registry for Alzheimer's Prevention (WRAP) participants with 3 waves of cognitive assessment over approximately 6 years were coded as meeting each of 3 psychometric aMCI definitions: (a) 'aMCI standard-baseline' used published norms to establish cutoffs for baseline performance; (b) 'aMCI robust-baseline' applied WRAP-specific robust norms to baseline, and (c) 'aMCI robust-multiwave' applied these robust norms across 3 waves of assessment. Each group was compared to a cognitively healthy subset. RESULTS: Half the aMCI standard-baseline and one third of the aMCI robust-baseline group reverted to normal ranges at follow-up. Only the aMCI robust-multiwave method had an aMCI × age interaction showing significantly worse age-related memory declines in the aMCI group compared to the cognitively healthy group over 6 years of follow-up. CONCLUSION: Both cross-sectional methods showed instability over time, with many reverting to normal performance after baseline. The multiwave approach identified a group who showed progressive memory declines over 3 visits. Being able to detect progressive decline in late middle age is a critical step in improving prevention efforts.

Language-enriched exercise plus socialization for older adults with dementia: translation to rural communities.

Interventions that stimulate and engage individuals with dementia physically, cognitively, and socially offer promise for improving health and well-being and for potentially slowing functional losses with disease progression. We describe a volunteer-based intervention that combines physical exercise, cognitive-linguistic stimulation, and social outings for older persons living with dementia in rural communities. One-year follow-up data, although clearly preliminary (n = 8), suggest stability in global cognition, mood, and aspects of physical fitness. Challenges to implementing dementia interventions in rural areas are discussed.

Machine learning amplifies the effect of parental family history of Alzheimer's disease on list learning strategy.

Identification of preclinical Alzheimer's disease (AD) is an essential first step in developing interventions to prevent or delay disease onset. In this study, we examine the hypothesis that deeper analyses of traditional cognitive tests may be useful in identifying subtle but potentially important learning and memory differences in asymptomatic populations that differ in risk for developing Alzheimer's disease. Subjects included 879 asymptomatic higher-risk persons (middle-aged children of parents with AD) and 355 asymptotic lower-risk persons (middle-aged children of parents without AD). All were administered the Rey Auditory Verbal Learning Test at baseline. Using machine learning approaches, we constructed a new measure that exploited finer differences in memory strategy than previous work focused on serial position and subjective organization. The new measure, based on stochastic gradient descent, provides a greater degree of statistical separation (p = 1.44 × 10-5) than previously observed for asymptomatic family history and non-family history groups, while controlling for apolipoprotein epsilon 4, age, gender, and education level. The results of our machine learning approach support analyzing memory strategy in detail to probe potential disease onset. Such distinct differences may be exploited in asymptomatic middle-aged persons as a potential risk factor for AD.

The effect of TOMM40 poly-T length on gray matter volume and cognition in middle-aged persons with APOE ε3/ε3 genotype.

OBJECTIVE: Apolipoprotein E (APOE) genotypes are associated with variable risk of developing late-onset Alzheimer's disease (LOAD), with APOE epsilon 4 (APOE ε4) having higher risk. A variable poly-T length polymorphism at rs10524523, within intron 6 of the translocase of the outer mitochondrial membrane (TOMM40) gene, has been shown to influence age of onset in LOAD, with very long (VL) poly-T length associated with earlier disease onset, and short poly-T length associated with later onset. In this study, we tested the hypothesis that brain and cognitive changes suggestive of presymptomatic LOAD may be associated with this TOMM40 polymorphism. METHODS: Among healthy APOE ε3 homozygous adults (N = 117; mean age, 55 years), we compared those who were homozygous for VL/VL (n = 35) TOMM40 poly-T lengths (who were presumably at higher risk) with those homozygous for short (S/S; n = 38) poly-T lengths, as well as those with heterozygous (S/VL; n = 44) poly-T length polymorphisms, on measures of learning and memory and on structural brain imaging. RESULTS: The VL/VL group showed lower performance than the S/S TOMM40 group on primacy retrieval from a verbal list learning task, a finding which is also seen in early Alzheimer's disease. A dose-dependent increase in the VL TOMM40 polymorphism (from no VL alleles, to S/VL heterozygous, to VL/VL homozygous) was associated with decreasing gray matter volume in the ventral posterior cingulate and medial ventral precuneus, a region of the brain affected early in LOAD. CONCLUSIONS: These findings among APOE ε3/ε3 late middle-aged adults suggest that a subgroup with VL TOMM40 poly-T lengths may be experiencing incipient LOAD-related cognitive and brain changes.

Effect of parental family history of Alzheimer's disease on serial position profiles.

BACKGROUND: An exaggerated recency effect (ie, disproportionate recall of last-presented items) has been consistently observed in the word list learning of patients with Alzheimer's disease (AD). Our study sought to determine whether there were similar alterations in serial position learning among asymptomatic persons at risk for AD as a result of parental family history. METHODS: Subjects included 623 asymptomatic middle-aged children of patients with AD (median, 53 years) and 157 control participants whose parents survived to at least age 70 without AD or other memory disorders. All participants were administered the Rey Auditory Verbal Learning Test, which requires learning and recall of 15 unrelated nouns. RESULTS: There was no significant difference in total words recalled between the AD children and control groups. However, compared with controls, AD children exhibited a significantly greater tendency to recall words from the end (recency) versus beginning (primacy) of the list. Serial position effects were unrelated to apolipoprotein allele epsilon 4 or depressive symptoms. CONCLUSIONS: Asymptomatic persons at risk for AD by virtue of family history do not show a difference in total words recalled compared with controls, but they exhibit a distinctly different serial position curve, suggesting greater reliance on immediate as opposed to episodic memory. This is the same serial position pattern observed in mild AD, seen here in reduced severity. Longitudinal follow-up is planned to determine whether changes in serial position patterns are a meaningful marker for preclinical detection of AD.

Screening for dementia in community-based memory clinics.

PROBLEM: Dementia is a significant public health problem that is underrecognized in primary care settings. This study examined the usefulness of 3 brief screening tests in detecting dementia and mild cognitive impairment (MCI) in persons seeking consultation for memory complaints within a network of memory diagnostic clinics in Wisconsin. METHODS: This prospective study of consecutive referrals for memory diagnostic evaluation analyzed data for 364 patients > or = 50 years. Scores on 3 cognitive screening measures-the Mini-Mental State Examination (MMSE), Clock Drawing, and Animal Naming--were compared to clinical diagnosis of normal cognitive aging, MCI, or dementia. RESULTS: Using the standard cut score of <24, the MMSE identified only 60% of persons diagnosed with dementia. By contrast, using a recommended cut score of <14 words per minute, Animal Naming identified 85% of persons with dementia with a relatively low (12%) false positive rate. Clock Drawing was intermediate to the other 2 measures in screening effectiveness. CONCLUSIONS: Animal Naming was moderately to highly effective in identifying dementia. The naming procedure is easy to administer and may have value as a brief initial dementia screen in busy practice settings. More demanding cognitive measures may be needed to improve screening accuracy for MCI.

Middle-aged children of persons with Alzheimer's disease: APOE genotypes and cognitive function in the Wisconsin Registry for Alzheimer's Prevention.

Adult children of persons with Alzheimer's disease are at increased risk of developing Alzheimer's disease because of hereditary, environmental, and health risk factors shared with affected parents. The Wisconsin Registry for Alzheimer's Prevention (WRAP) has completed baseline assessments on 452 middle-aged persons (mean = 53 years) who have at least 1 parent with AD. Forty-five percent had 1 or more apolipoprotein (APOE) epsilon4 alleles. There were few significant differences between epsilon4 carriers and noncarriers in demographics, health, and lifestyle measures or in neuropsychological performance. The high percentage of WRAP participants who are carriers of APOE epsilon4 underscores their increased risk for developing Alzheimer's disease, but the absence of differences related to APOE status and high mean scores on cognitive tests suggests that the APOE epsilon4 gene has yet to have a clinical impact on cognitive functioning. The WRAP cohort may be a valuable group to follow prospectively to characterize the nature of cognitive change in relation to risk factors and to identify underlying preclinical neurobiological changes.

Apolipoprotein E epsilon4 and change in cognitive functioning in community-dwelling older adults.

The relationship between apolipoprotein E (APOE) epsilon4 and change in cognition was examined in older men (n = 247; age = 75.0 +/- 3.5 years) and women (n = 79; age = 70.8 +/- 4.9 years) free of history of stroke. Participants were examined again 4.0 +/- 0.5 years later. Exclusion criteria were (1) initial scores on the Mini-Mental State Examination of 23 or less or (2) the presence of the APOE 2/4 genotype. Men with epsilon4 showed greater decline in some measures of executive function and verbal memory compared to those without epsilon4; women with epsilon4 showed greater decline in Trail Making test performance relative to women without the allele. A significant gender x APOE epsilon4 interaction was seen for change in performance on short delay cued recall. These results suggest that APOE epsilon4 is associated with cognitive decline differently in older adult men and women.

Middle-aged children of Alzheimer parents, a pilot study: stable neurocognitive performance at 20-year follow-up.

The objective of this pilot study on a convenience sample of 25 offspring of Alzheimer patients (mean age 61.5 +/- 8.8 years; range, 50-82) was the early detection of neurocognitive decline. This preliminary report appears to be the first one dealing with 20-year follow-up of neurocognitive data of Alzheimer's disease (AD) children. Digit symbol (Wechsler Adult Intelligence Scale) was the only of 11 neurocognitive measures with a significant decline. And that decline between first and last testing (mean = 19.98 +/- 0.30 years) was on raw scores, not scaled scores. Neither parents' age at onset of AD nor autopsy confirmation or offspring APOE-e4 status influenced neurocognitive results. More robust data than currently available are needed to confirm the findings of this first pilot study and to determine both the trajectory of neurocognitive decline in AD and the risks of developing AD faced by children whose parent had the disease.

Intervention of multi-modal activities for older adults with dementia translation to rural communities.

A Language-Enriched Exercise Plus Socialization (LEEPS) Program for older adults with Alzheimer's disease and related disorders (ADRD) was implemented in rural Wisconsin communities. Patterned after a university-based research intervention, (1) the LEEPS protocol entailed ongoing weekly to biweekly sessions with a trained volunteer and an individual with dementia, with exercise and language stimulation sessions interspersed with social or volunteer outings. Of 64 persons with ADRD who enrolled, 29 completed an initial follow-up assessment at an average of 10.65 months, and 8 completed a second follow-up at an average of 20.55 months. Results generally show stability in cognition, mood, and physical performance. Improvement was noted at the initial retest on 1 of the 3 physical fitness measures (arm curls; t = 2.61, P = .015), but self-rated quality of life declined slightly from baseline to the first retest (t = -2.09, P = .048). Change in the Mini-Mental State Examination at the first and second follow-ups (mean = +0.18 and -1.0, respectively) was negligible. The maintenance of function observed with LEEPS is an encouraging outcome, given the progressive nature of ADRD, but controlled investigations are needed to establish the efficacy of LEEPS. Barriers to implementation of an intensive activities-focused intervention in rural communities are discussed.

Heritability of cognitive traits among siblings with a parental history of Alzheimer's disease.

Cognitive decline is one of the hallmark features of Alzheimer's disease, but many studies struggle to find strong associations between cognitive function and genetic variants. In order to identify which aspects of cognition are more likely to have a strong genetic component, we assessed the heritability of various cognitive functions related to Alzheimer's disease in 303 initially asymptomatic middle-aged adult siblings with a parental history of Alzheimer's disease from the Wisconsin Registry for Alzheimer's Prevention. Participants underwent extensive cognitive testing, and six cognitive factors were identified via factor analysis. Working Memory and Visual Learning & Memory had the highest heritability (52% and 41%, respectively). Inclusion of APOE allele counts did not notably change heritability estimates, indicating that there are likely additional genetic variants contributing to cognition. These findings suggest that future genetic studies should focus on the cognitive domains of Working Memory and Visual Learning & Memory.

Aging, Practice Effects, and Genetic Risk in the Wisconsin Registry for Alzheimer's Prevention.

BACKGROUND: In the last five years, a consensus has developed that Alzheimer's disease (AD) may begin years before overt cognitive impairment. Accordingly, the focus has shifted to identifying preclinical disease in order to match treatments to those most likely to benefit. Subtle cognitive changes, including reduced benefit from practice, may be one such preclinical sign. In this study, we explore cognitive aging trajectories within a large cohort of clinically intact late middle-aged adults. METHOD: Longitudinal cognitive data were analyzed from 594 participants in the Wisconsin Registry for Alzheimer's Prevention. Mixed models were used to examine trajectories, adjusting for prior exposure, and the moderation thereof by markers of dementia risk, APOE-ε4 status, and family history of AD. RESULTS: Practice effects were observed for Verbal Learning & Memory, Working Memory, Speed & Flexibility, and Visual Learning. However, for Working Memory and Speed & Flexibility, these effects were attenuated for FH + subjects. CONCLUSION: Reduced practice effects have previously been observed in clinical groups. These results in middle-aged adults suggest that they may also indicate preclinical changes on the path to AD.

Association of Insulin Resistance With Cerebral Glucose Uptake in Late Middle-Aged Adults at Risk for Alzheimer Disease.

IMPORTANCE: Converging evidence suggests that Alzheimer disease (AD) involves insulin signaling impairment. Patients with AD and individuals at risk for AD show reduced glucose metabolism, as indexed by fludeoxyglucose F 18-labeled positron emission tomography (FDG-PET). OBJECTIVES: To determine whether insulin resistance predicts AD-like global and regional glucose metabolism deficits in late middle-aged participants at risk for AD and to examine whether insulin resistance-predicted variation in regional glucose metabolism is associated with worse cognitive performance. DESIGN, SETTING, AND PARTICIPANTS: This population-based, cross-sectional study included 150 cognitively normal, late middle-aged (mean [SD] age, 60.7 [5.8] years) adults from the Wisconsin Registry for Alzheimer's Prevention (WRAP) study, a general community sample enriched for AD parental history. Participants underwent cognitive testing, fasting blood draw, and FDG-PET at baseline. We used the homeostatic model assessment of peripheral insulin resistance (HOMA-IR). Regression analysis tested the statistical effect of HOMA-IR on global glucose metabolism. We used a voxelwise analysis to determine whether HOMA-IR predicted regional glucose metabolism. Finally, predicted variation in regional glucose metabolism was regressed against cognitive factors. Covariates included age, sex, body mass index, apolipoprotein E ε4 genotype, AD parental history status, and a reference region used to normalize regional uptake. MAIN OUTCOMES AND MEASURES: Regional glucose uptake determined using FDG-PET and neuropsychological factors. RESULTS: Higher HOMA-IR was associated with lower global glucose metabolism (ß = -0.29; P < .01) and lower regional glucose metabolism across large portions of the frontal, lateral parietal, lateral temporal, and medial temporal lobes (P < .05, familywise error corrected). The association was especially robust in the left medial temporal lobe (R2 = 0.178). Lower glucose metabolism in the left medial temporal lobe predicted by HOMA-IR was significantly related to worse performance on the immediate memory (ß = 0.317; t148 = 4.08; P < .001) and delayed memory (ß = 0.305; t148 = 3.895; P < .001) factor scores. CONCLUSIONS AND RELEVANCE: Our results show that insulin resistance, a prevalent and increasingly common condition in developed countries, is associated with significantly lower regional cerebral glucose metabolism, which in turn may predict worse memory performance. Midlife may be a critical period for initiating treatments to lower peripheral insulin resistance to maintain neural metabolism and cognitive function.

Memory Self-Appraisal and Cerebral Glucose Metabolism in Age-Associated Memory Impairment.

The authors used positron emission tomography to measure cerebral glucose metabolism in 43 people with age-associated memory impairment to determine relationships between memory self-appraisal and brain function. People with lower frontal metabolism during a resting state reported more frequent prior mnemonics usage, a measure of memory self-appraisal. A multiple regression analysis indicated that reported mnemonics usage was the most significant predictor of left (P = 0.0004) and right (P = 0.0014) frontal metabolism. These models indicated that mnemonics usage, along with depression ratings, accounted for 39% of left frontal lobe function and, along with visual spatial memory, accounted for 40% of right frontal metabolism. These results suggest that mnemonics usage may compensate for subtle frontal dysfunction or reflect greater efficiency of memory processing.

Investigation of triggering receptor expressed on myeloid cells 2 variant in the Wisconsin Registry for Alzheimer's Prevention.

Recent studies have found an association between a variant in triggering receptor expressed on myeloid cells 2 (TREM2) (rs75932628-T) and both Alzheimer's disease (AD) and cognitive function in individuals aged 80-100 years. The role of TREM2 in younger, asymptomatic individuals is unknown. We examined this variant in 1148 participants from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of middle-aged adults enriched for a parental history of AD. Thirteen individuals carried the T risk allele. Carriers were more likely to have a parental history of AD (100% of carriers vs. 70% of noncarriers; p = 0.01) and, among the parental history subset, families with a TREM2 carrier had a younger maternal age of AD onset than noncarriers (67.9 vs. 75.6 years; p = 0.03). There was no significant association between TREM2 carrier status and cognitive function or decline. In conclusion, the association between TREM2 and both parental history of AD and younger maternal age of AD onset provide additional support for the role of TREM2 in AD and illustrate the importance of considering family history in AD study design.

Cognitive activities and cognitive performance in middle-aged adults at risk for Alzheimer's disease.

Cognitive activity is thought to provide some protection against dementia, but the mechanism and timing of these effects are unknown. Data for this study were drawn from the Wisconsin Registry for Alzheimer's Prevention (WRAP), an at-risk middle-aged sample (mean age = 54 years) enriched for parental family history of Alzheimer's disease (AD). We had two main aims: (a) to determine the relative contribution of three facets of cognitive activity-education, occupational complexity with data, and cognitive leisure activities-to WRAP participants' cognitive performance; and (b) to assess for interactions between genetic risk factors and cognitive activity in explaining cognitive performance. Results from mixed effects models indicate that some of the variance usually attributed to education may be more closely accounted for by cognitive activities later in life. Overall, our analyses suggest cautious optimism for cognitive activities, especially game playing, as a strategy for preserving cognitive strengths in midlife.

Interaction between two cholesterol metabolism genes influences memory: findings from the Wisconsin Registry for Alzheimer's Prevention.

The strongest genetic factor for late-onset Alzheimer's disease (AD) is APOE; nine additional susceptibility genes have recently been identified. The effect of these genes is often assumed to be additive and polygenic scores are formed as a summary measure of risk. However, interactions between these genes are likely to be important. We sought to examine the role of interactions between the nine recently identified AD susceptibility genes and APOE in cognitive function and decline in 1,153 participants from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of middle-aged adults enriched for a parental history of AD. Participants underwent extensive cognitive testing at baseline and up to two additional visits approximately 4 and 6 years later. The influence of the interaction between APOE and each of 14 single nucleotide polymorphisms (SNPs) in the nine recently identified genes on three cognitive factor scores (Verbal Learning and Memory, Working Memory, and Immediate Memory) was examined using linear mixed models adjusting for age, gender, and ancestry. Interactions between the APOE ε4 allele and both of the genotyped ABCA7 SNPs, rs3764650 and rs3752246, were associated with all three cognitive factor scores (p-values ≤ 0.01). Both of these genes are in the cholesterol metabolism pathway leading to AD. This research supports the importance of considering non-additive effects of AD susceptibility genes.

Insulin resistance, brain atrophy, and cognitive performance in late middle-aged adults.

OBJECTIVE: Insulin resistance dysregulates glucose uptake and other functions in brain areas affected by Alzheimer disease. Insulin resistance may play a role in Alzheimer disease etiopathogenesis. This longitudinal study examined whether insulin resistance among late middle-aged, cognitively healthy individuals was associated with 1) less gray matter in Alzheimer disease-sensitive brain regions and 2) worse cognitive performance. RESEARCH DESIGN AND METHODS: Homeostasis model assessment of insulin resistance, gray matter volume, and the Rey Auditory Verbal Learning Test (RAVLT) were acquired in 372 participants at baseline and a consecutive subset of 121 individuals ~4 years later. Voxel-based morphometry and tensor-based morphometry were used, respectively, to test the association of insulin resistance with baseline brain volume and progressive gray matter atrophy. RESULTS: Higher insulin resistance predicted less gray matter at baseline and 4 years later in medial temporal lobe, prefrontal cortices, precuneus, and other parietal gyri. A region-of-interest analysis, independent of the voxel-wise analyses, confirmed that higher insulin resistance was related to medial temporal lobe atrophy. Atrophy itself corresponded to cognitive deficits in the RAVLT. Temporal lobe atrophy that was predicted by higher insulin resistance significantly mediated worse RAVLT encoding performance. CONCLUSIONS: These results suggest that insulin resistance in an asymptomatic, late middle-aged cohort is associated with progressive atrophy in regions affected by early Alzheimer disease. Insulin resistance may also affect the ability to encode episodic information by negatively influencing gray matter volume in medial temporal lobe.

Healthy brain aging: role of cognitive reserve, cognitive stimulation, and cognitive exercises.

Current knowledge about the roles of cognitively stimulating lifestyles and cognitive training interventions in preserving cognitive function in later life is reviewed. Potential mechanisms for beneficial effects of cognitive stimulation and training are discussed, and key gaps in research identified. Suggestions are provided for advising patients about brain-healthy lifestyles, acknowledging that much remains to be learned in this area of research. More randomized controlled trials, using challenging regimes of training and stimulation and long-term follow-up, are needed, measuring cognitive trajectories in normal aging and relative risk of Alzheimer disease as outcomes.