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INTRODUCTION The relationship between persistent loneliness and Alzheimer's disease (AD) is unclear. We examined the relationship between different types of mid-life loneliness and the development of dementia and AD. METHODS Loneliness was assessed in cognitively normal adults using one item from the Center for Epidemiologic Studies Depression Scale. We defined loneliness as no loneliness, transient loneliness, incident loneliness,or persistent loneliness, and applied Cox regression models and Kaplan-Meier plots with dementia and AD as outcomes (n = 2880). RESULTS After adjusting for demographics, social network, physical health, and apolipoprotein E e4, persistent loneliness was associated with higher (hazard ratio [HR], 1.91; 95% confidence interval [CI] 1.25-2.90; P

Parkinson's disease (PD) is characterized as a motor disorder, but the majority of individuals with PD also suffer from nonmotor symptoms, including mental health difficulties, such as depression, anxiety, and apathy, as well as decreased cognitive function, daily function, sleep quality, and quality of life. Cognitive behavioral therapy (CBT) is an effective treatment for depression in PD, but motor disability, work schedule, transportation issues, and care partner burden may cause difficulty in attending weekly face-to-face therapy sessions. A promising avenue in the delivery of CBT is telehealth. CBT administered live via videoconference technology may circumvent many of the barriers that prevent those with PD from receiving treatment. This case study evaluates the preliminary efficacy, feasibility, and acceptability of 12-week telehealth CBT for depression in PD. CBT administered via telehealth was feasible, acceptable, and efficacious for a study participant with PD and major depressive disorder. In addition to effectively treating depression, the telehealth intervention improved quality of life and aspects of cognitive functioning, as well as symptoms of anxiety, apathy, and subjective cognitive impairment, all of which are prevalent nonmotor symptoms of PD. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background There is a paucity of longitudinal research investigating the relations between atrial fibrillation (AF) and domain-specific cognitive performance. Objective The purpose of this study was to investigate the association between AF and cognitive performance cross-sectionally and longitudinally. Methods Eligible participants were dementia- and stroke-free at the time of baseline neuropsychological (NP) assessment and underwent at least 1 additional NP assessment with at least 1-year inter-test interval. AF status was examined as a 2-level variable (prevalent AF, no AF) in cross-sectional analyses and then separately as a 3-level variable (prevalent AF, interim AF, no AF) in longitudinal analyses. We examined the association between AF status and cognitive performance with linear regression. We first adjusted models for age and sex and then for vascular risk factors and apolipoprotein e4 (APOE4) status. Results We studied 2682 participants of the Framingham Heart Study original and offspring cohorts. At the baseline NP assessment, 112 participants (4%) had AF (mean age 72 ± 9 years; 32% women). After adjustment for vascular risk factors and APOE4 status, prevalent AF was significantly associated with poorer attention; sex differences were also noted with men performing worse on tests of abstract reasoning and executive function, while women did better on a measure of executive function. Prevalent AF was significantly associated with longitudinal decline in executive function in the original cohort, and interim AF was significantly associated with longitudinal decline in executive function in the offspring cohort. Conclusion After accounting for vascular risk factor burden and APOE4 status, AF was associated with a vascular profile of change in cognitive function.

Apolipoprotein E4 (ApoE4) is a prominent genetic risk factor for Alzheimer's disease. The purpose of this review is to explore differences in structural brain volume detected by magnetic resonance imaging between cognitively intact ApoE4 carriers and non-carriers across the lifespan (i.e., older adults, middle-aged adults, young adults, children and adolescents, and neonates). Consistent findings are found throughout various developmental stages. This area of research may elucidate the mechanisms by which ApoE4 influences risk of developing Alzheimer's disease. It could also inform potential treatment strategies and interventions for carriers of the ApoE4 allele.

Background Digital Clock Drawing Test (dCDT) technology enables the examination of detailed neurocognitive behavior as behavior unfolds in real time; a capability that cannot be obtained using a traditional pen and paper testing format. Objective Parameters obtained from the dCDT were used to investigate neurocognitive constructs related to higher-order neurocognitive decision making and information processing speed. The current research sought to determine the effect of age as related to combined motor and non-motor components of drawing, and higher-order decision making latencies. Methods A large group of stroke- and dementia- free Framingham Heart Study participants were administered the dCDT to command and copy with hands set for "10 after 11". Six age groups (age range 28-98) were constructed. Results Differences between age groups were found for total time to completion, total pen stroke count, and higher-order decision making latencies in both command and copy test conditions. Conclusion Longer age-related decision making latencies may reflect a greater need for working memory and increased self-monitoring in older subjects. These latency measures have potential to serve as neurocognitive biomarkers of Alzheimer's disease and other insidious neurodegenerative disorders.

Background The increased risk of stroke and cognitive impairment associated with atrial fibrillation (AF) is well documented. However, there is a paucity of research investigating the relations between AF and brain morphology. Objective The purpose of this study was to investigate the association between AF and brain volume measures on magnetic resonance imaging (MRI). Methods The study sample included stroke- and dementia-free participants who attended the Framingham Heart Study offspring cohort 7th examination cycle (1999–2005) and underwent contemporaneous MRI. We examined the association between prevalent AF and brain volume measures (total cerebral volume, frontal lobe volume, temporal lobe volume, temporal horn volume, hippocampal volume, and white matter hyperintensity volume) with linear regression. We first adjusted models for age and sex, and then for vascular risk factors and APOE4. Results We studied 2144 individuals (mean age 61.8 ± 9.3 years; 54% women); 73 participants (3.4%) had prevalent AF at the time of MRI. In age- and sex-adjusted models, AF was inversely associated with total cerebral brain volume, frontal brain volume, and temporal brain volume. After further adjustment for vascular risk factors and APOE4, AF remained associated with frontal brain volume. Conclusion After accounting for vascular risk factor burden, prevalent AF was associated with lobar indexes of vascular brain aging but not with expected white matter changes.

Discrepancies in mental representations between self-aspects and significant others are associated with depression, personality disorders, emotional reactivity, and interpersonal distress. The Computerized Implicit Representation Test (CIRT) is a novel measure developed to assess discrepancies in mental representations. Inpatient participants (N = 165) enrolled in a longitudinal study completed baseline CIRT ratings of similarity between self-aspects (actual-self, ideal-self, and ought-self) and between actual-self and significant others (mother, father, liked others, and disliked others). Based on the similarity ratings, multidimensional scaling was utilized to generate distances between key self- and other representations in three-dimensional space. Results of univariate linear regression analyses demonstrated that discrepancies (distances) between self-aspects, actual-self to others, and actual-self to mother were significantly associated with impulsive and self-destructive behaviors and/or lifetime anxiety disorders. Multivariate hierarchical linear regression models further indicated that three CIRT variables provided incremental validity above and beyond age, gender, and/or borderline personality disorder.

Objective This article elucidates how the Boston process approach (BPA) can amplify the role of neuropsychology in the study of preclinical and clinical dementia, particularly Alzheimer's disease (AD), and how advancements in technology expand BPA capacity objectively and exponentially. Method The BPA is based on a conceptualization of cognition as being comprised of multiple processes, the nature of which could not possibly be captured by a single score on a test or battery of tests. Identification of these processes is only possible with careful observation of an individual during the entire testing process to determine how, when, and why a person fails, which helps to reveal the integrity of the cognitive processes underlying the behavior. Results BPA use within the Framingham Heart Study is described, including how digital technology has been incorporated to enhance the sensitivity of BPA to detect insidious onset changes even earlier than had been previously possible. The digital technology movement will dramatically alter the means by which cognitive function is assessed going forward. Conclusions Technological advances will catalyze groundbreaking discoveries for effective treatments of neurodegenerative cognitive disorders, such as AD, and inform novel strategies for dementia prevention and sustained lifelong cognitive health. (PsycINFO Database Record

The financial burden of caring for 5.2 million people with Alzheimer's disease (AD) is $214 billion. This number will rise to $1.2 trillion by 2050 if the projected tripling to 16 million cases does occur. Importantly, these estimates are likely to be conservative, given the numerous causes of dementia, underscoring the imperative for treatment. Furthermore, these numbers do not account for the emotional costs to patients and their families. Unfortunately, to date, there are no disease-modifying medications. The presumption of failed clinical trial studies is that intervention may be too late in the course of the disease [1]. Thus, current research on AD includes significant effort to identify biomarkers decades before the threshold for clinical diagnosis is met [2]. Most current biomarker studies focus on measures of β amyloid (Aβ) detected by positron emission tomography (PET) imaging or measured from cerebrospinal fluid [3], [4], [5]. However, nearly 75% of cognitively normal individuals aged 70–79 years are free of significant amyloid on PET imaging [6]. Furthermore, studies of younger individuals show differences in brain structure and cognitive ability related to APOE genotype status [7] or vascular risk factors [8] at a time when pathologic and in vivo measures of AD pathology are virtually absent. These data suggest that factors other than cerebral amyloidosis during early life may result in increased risk for later-life dementia. There is mounting evidence suggesting a more variable profile in which indices of the neurodegenerative processes (as indicated by changes in cognitive and brain structure) may precede amyloidosis [9]. Despite results that challenge the Aβ model for AD pathogenesis, most clinical trial studies remain centered around amyloid as the primary target for drug development [10], [11]. We propose that the reason clinical trial studies have largely failed is because the pharmaceutical and AD research communities assume AD is a single disease. In fact, it has been well documented that sporadic AD is a heterogeneous disease [12]. Decades ago, the variability of the AD profile and its implication were more widely considered [13], [14], [15], but once the NINCDS-ADRDA diagnostic criteria was put into widespread practice, it was largely abandoned. This may be because the definite diagnosis of dementia depends on autopsy data, requiring widespread distribution of amyloid plaques and neurofibrillary tangles for diagnosis [16]. Neuropathologic studies, however, suggest that other pathologies often co-occur and at times may lead to antemortem diagnosis of AD, even when neuropathologic criteria are not met [12]. Consider now cancer as a model for rethinking the treatment strategy for AD. Like AD, cancer at its end stages is widespread and etiology is difficult to determine. Today, the diagnosis of cancer itself is uninformative. Rather research has determined that there are over 100 different types of cancers, identified in part by symptom variability. As a result of recognizing multiple forms of the disease, drug treatments target each type. Currently, a cancer diagnosis requires additional testing to pinpoint subtype and stage. Depending on the answer, different treatment options are considered. For the diagnosis of leukemia alone, there are over 70 treatment options. For AD, many different drug discovery studies are ongoing but there is no overt strategy of identifying the “types of AD” as potential targets for different drug treatment. Our analogy to cancer is not a clean one. Cancer is a different disease in which biopsy can differentiate between cancer cells and normal ones. The current work on AD biomarkers, however, is an equivalent attempt to find the earliest indicator of disease, similar to detecting preclinical cancer cells. Through biomarker research, the evidence suggests that there are people who are symptomatic for AD that have amyloid and those who do not. Furthermore, there are people without cognitive impairment who have amyloid and those who do not. On commonly used assessment methods, cognitive impairment profiles include those that are predominantly amnestic and those that are not. In fact, for almost every positive study in favor of a particular AD risk factor or biomarker, there are contradictory negative findings. We submit that the primary question we should collectively seek to answer is whether the path to effective AD treatment lies in identifying ADs, potentially resulting in multiple drug targets rather than one. It is likely that the data needed to support this hypothesis have already been generated. A shift from the presumption of a single disease to multiple diseases would reframe the drug development strategy for AD. Although there have been and continue to be clinical trial studies of unique drug compounds, they all are based on the same premise of seeking a cure for a single disease which has been well documented as heterogeneous in nature. Current research has presumed that the failure of past studies stems from intervention that has occurred too late in the disease process and thus much money and effort is being spent on trying to target the disease at its earliest stages. Doing so has resulted in trying to identify people at risk for disease based on specific clinical profiles, including still uncertain expensive biomarkers that require procedures that can be invasive and thus lead to inherently biased study samples. The difference between what we are proposing and what is currently being done is we contend that AD is not a heterogeneous disease, it is multiple diseases, and each type is expressing itself, even at the asymptomatic stages, through these varying clinical profiles. Once each type is identified, the opportunity exists for finding its unique drug target. In summary, the focus of future Alzheimer's research should be on: 1. Identifying AD subpopulations 2. Understanding the structure of each population based on the molecular data 3. Building stratification model(s) (for disease subtypes, drug response, and prognosis) 4. Identifying new therapeutic targets

Background/Study Context: To provide baseline normative data on tests of verbal memory and executive function for nondemented younger- and middle-aged adults.Methods: The Consortium to Establish a Registry for Alzheimer’s Disease word list memory task (CERAD-WL) and Victoria Stroop Test (VST) were administered to 3362 Framingham Heart Study (FHS) volunteer participants aged 24–78 years. Analyses of the effects of age, gender, and education were conducted. Normative data on traditional measures and error responses are reported for each test.Results: Traditional measures were significantly associated with both age and education in this cohort. Error responses also evidenced significant age and education effects.Conclusion: These data provide a normative comparison for assessment of verbal memory and executive functioning capabilities in younger- and middle-aged adults and may be utilized as a tool for preclinical studies of disease in this population.