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Regional tau pathology and loneliness in cognitively normal older adults.

ABSTRACT: Loneliness is a perception of social and emotional isolation that increases in prevalence among older adults during the eighth decade of life. Loneliness has been associated with higher brain amyloid-? deposition, a biologic marker of Alzheimer's disease, in cognitively normal older adults, suggesting a link with preclinical Alzheimer's disease pathophysiology. This study examined whether greater loneliness was associated with tau pathology, the other defining feature of Alzheimer's disease, in 117 cognitively normal older adults. Using flortaucipir positron emission tomography, we measured tau pathology in the entorhinal cortex, a region of initial accumulation in aging adults with or without elevated amyloid-?, and in the inferior temporal cortex, a region of early accumulation typically associated with elevated amyloid-? and memory impairment. Loneliness was measured by self-report using the 3-item UCLA-loneliness scale. We found that higher tau pathology in the right entorhinal cortex was associated with greater loneliness, controlling for age, sex, and apolipoprotein E ?4, the Alzheimer's disease genetic risk marker. This association remained significant after further adjustment for socioeconomic status, social network, depression and anxiety scores, and memory performance. There was no association of inferior temporal cortical or left entorhinal tau pathology with loneliness. Exploratory whole-brain surface maps supported these findings and identified additional clusters correlating loneliness and tau in the right fusiform gyrus. These results provide further support for loneliness as a socioemotional symptom in preclinical Alzheimer's disease.

SUBMITTER: d'Oleire Uquillas F

PROVIDER: S-EPMC6299114 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Regional tau pathology and loneliness in cognitively normal older adults.

d'Oleire Uquillas Federico F Jacobs Heidi I L HIL Biddle Kelsey D KD Properzi Michael M Hanseeuw Bernard B Schultz Aaron P AP Rentz Dorene M DM Johnson Keith A KA Sperling Reisa A RA Donovan Nancy J NJ

Translational psychiatry 20181218 1

Loneliness is a perception of social and emotional isolation that increases in prevalence among older adults during the eighth decade of life. Loneliness has been associated with higher brain amyloid-β deposition, a biologic marker of Alzheimer's disease, in cognitively normal older adults, suggesting a link with preclinical Alzheimer's disease pathophysiology. This study examined whether greater loneliness was associated with tau pathology, the other defining feature of Alzheimer's disease, in ...[more]

PMID: 30563962

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Project description:ImportanceEmotional and behavioral symptoms in cognitively normal older people may be direct manifestations of Alzheimer disease (AD) pathophysiology at the preclinical stage, prior to the onset of mild cognitive impairment. Loneliness is a perceived state of social and emotional isolation that has been associated with cognitive and functional decline and an increased risk of incident AD dementia. We hypothesized that loneliness might occur in association with elevated cortical amyloid burden, an in vivo research biomarker of AD.ObjectiveTo determine whether cortical amyloid burden is associated with greater loneliness in cognitively normal older adults.Design, setting, and participantsCross-sectional analyses using data from the Harvard Aging Brain Study of 79 cognitively normal, community-dwelling participants. A continuous, aggregate measure of cortical amyloid burden, determined by Pittsburgh Compound B-positron emission tomography (PiB-PET), was examined in association with loneliness in linear regression models adjusting for age, sex, apolipoprotein E ε4 (APOEε4), socioeconomic status, depression, anxiety, and social network (without and with the interaction of amyloid and APOEε4). We also quantified the association of high amyloid burden (amyloid-positive group) to loneliness (lonely group) using logistic regression, controlling for the same covariates, with the amyloid-positive group and the lonely group, each composing 32% of the sample (n = 25).Main outcomes and measuresLoneliness, as determined by the 3-item UCLA Loneliness Scale (possible range, 3-12, with higher score indicating greater loneliness).ResultsThe 79 participants included 43 women and 36 men with a mean (SD) age of 76.4 (6.2) years. Mean (SD) cortical amyloid burden via PiB-PET was 1.230 (0.209), and the mean (SD) UCLA-3 loneliness score was 5.3 (1.8). Twenty-two (28%) had positive APOEε4 carrier status, and 25 (32%) were in the amyloid-positive group with cortical PiB distribution volume ratio greater than 1.2. Controlling for age, sex, APOEε4, socioeconomic status, depression, anxiety, and social network, we found that higher amyloid burden was significantly associated with greater loneliness: compared with individuals in the amyloid-negative group, those in the amyloid-positive group were 7.5-fold (95% CI, 1.7-fold to 34.0-fold) more likely to be classified as lonely than nonlonely (β = 3.3, partial r = 0.4, P = .002). Furthermore, the association of high amyloid burden and loneliness was stronger in APOEε4 carriers than in noncarriers.Conclusions and relevanceWe report a novel association of loneliness with cortical amyloid burden in cognitively normal older adults, suggesting that loneliness is a neuropsychiatric symptom relevant to preclinical AD. This work will inform new research into the neural underpinnings and disease mechanisms involved in loneliness and may enhance early detection and intervention research in AD.

Project description:To improve the ability to develop treatments that prevent incipient Alzheimer disease (AD) from progressing to overt AD, it is important to understand the molecular basis of the earliest pathophysiological abnormalities and to determine how amyloid-? (A?) is involved very early in its pathogenesis.To investigate 2 specific A? oligomers, A? trimers and A?*56, in human cerebrospinal fluid (CSF); evaluate the effects of aging and AD; and obtain support for the hypothesis that they may be pathogenic by determining their relationships to CSF tau.A CSF sampling study.The University of Minnesota Medical School in Minneapolis, Minnesota, and the Salhgrenska University Hospital, Sweden.Forty-eight older adults with mild cognitive impairment or AD (impaired group); 49 age-matched cognitively intact control subjects (unimpaired group); and 10 younger, normal control subjects.Measurements of CSF A? trimers, A?*56, the 42-amino acid A? isoform (A?1-42), total tau (T-tau), and phospho-tau 181 (p-tau(181)). The hypothesis being tested was formulated after data collection. RESULTS We observed that A? trimers and A?*56 levels increased with age; within the unimpaired group, they were elevated in subjects with T-tau/A?1-42 ratios greater than a cutoff that distinguished the unimpaired group from subjects with AD. In the unimpaired group, T-tau and p-tau(181) were found to correlate strongly with A? trimers and A?*56 (r > 0.63), but not with A?1-42 (-0.10 < r < -0.01). The strong correlations were found to be attenuated in the impaired group.In cognitively intact older adults, CSF A? trimers and A?*56 were elevated in individuals at risk for AD, and they showed stronger relationships with tau than did A?1-42, a surrogate for A? fibril deposition. These findings suggest that prior to overt symptoms, 1 or both of the A? oligomers, but not fibrillar A?, is coupled to tau; however, this coupling is weakened or broken when AD advances to symptomatic stages. The uncoupling is interesting in light of the failure of experimental A? therapies to improve mild cognitive impairment/AD, which has prompted a shift in the timing of A? therapies to asymptomatic subjects. Knowing which A? species to target in asymptomatic subjects may enhance the success of future treatments for AD.

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Regional tau pathology and loneliness in cognitively normal older adults.

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Regional tau pathology and loneliness in cognitively normal older adults.

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