Objective This study investigated how cognitive function changes with age and whether rates of decline vary by sex or education in a large, homogenous longitudinal cohort characterized by high participation rates, long-duration of follow-up, and minimal loss to follow-up. Design/Setting/Participants Between 1988–2016, 2,225 community-dwelling participants of the Rancho Bernardo Study, aged 31–99 at their initial cognitive assessment, completed neuropsychological testing approximately every four years, over a maximum 27-year follow-up. Measurements Linear mixed effects regression models defined sex-specific cognitive trajectories, adjusting for education and retest effects. Results Significant decline across all cognitive domains began around age 65 and accelerated after age 80. Patterns of decline were generally similar between sexes, although men declined more rapidly than women on the global function test. Higher education was associated with slower decline on the tests of executive and global functions. After excluding 517 participants with evidence of cognitive impairment, accelerating decline with age remained for all tests, and women declined more rapidly than men on the executive function test. Conclusions Accelerating decline with advancing age occurs across multiple cognitive domains in community-dwelling older adults, with few differences in rates of decline between men and women. Higher education may provide some protection against executive and global function decline with age. These findings better characterize normal cognitive aging, a critical prerequisite for identifying individuals at risk for cognitive impairment, and lay the groundwork for future studies of health and behavioral factors that affect age-related decline in this cohort.

Abstract Background Hearing impairment is prevalent among older adults and has been identified as a risk factor for cognitive impairment and dementia. We evaluated the association of hearing impairment with long-term cognitive decline among community-dwelling older adults. Methods A population-based longitudinal study of adults not using hearing aids who had hearing acuity and cognitive function assessed in 1992–1996, and were followed for a maximum of 24 years with up to five additional cognitive assessments. Hearing acuity was categorized based on pure-tone average (PTA) thresholds: normal (PTA ≤ 25 dB), mild impairment (PTA > 25–40 dB), moderate/severe impairment (PTA > 40 dB). Results Of 1,164 participants (mean age 73.5 years, 64% women), 580 (49.8%) had mild hearing impairment and 196 (16.8%) had moderate/severe hearing impairment. In fully adjusted models, hearing impairment was associated with steeper decline on the Mini-Mental State Examination (MMSE) (mild impairment β = −0.04, p = .01; moderate/severe impairment β = −0.08, p = .002) and Trails B (mild impairment β = 1.21, p = .003; moderate/severe impairment β = 2.16, p = .003). Associations did not differ by sex or apolipoprotein E (APOE) ϵ4 status and were not influenced by social engagement. The MMSE-hearing association was modified by education: mild hearing impairment was associated with steeper decline on the MMSE among participants without college education but not among those with college education. Moderate/severe hearing impairment was associated with steeper MMSE decline regardless of education level. Conclusions Hearing impairment is associated with accelerated cognitive decline with age, and should be screened for routinely. Higher education may provide sufficient cognitive reserve to counter effects of mild, but not more severe, hearing impairment.

Methylphenidate (MPH), introduced more than 60 years ago, accounts for two-thirds of current prescriptions for attention deficit hyperactivity disorder (ADHD). Although many studies have modeled MPH's effect on executive function, almost none have directly modeled its effect on long-term memory (LTM), even though improvement in LTM is a critical target of therapeutic intervention in ADHD. We examined the effects of a wide range of doses of MPH (0.01 -10 mg/kg, i.p.) on Pavlovian fear learning, a leading model of memory. MPH's effects were then compared to those of atomoxetine (0.1 -10 mg/kg, i.p.), bupropion (0.5 -20 mg/kg, i.p.), and citalopram (0.01 -10 mg/kg, i.p.). At low, clinically relevant doses, MPH enhanced fear memory; at high doses it impaired memory. MPH's memory-enhancing effects were not confounded by its effects on locomotion or anxiety. Further, MPH-induced memory enhancement seemed to require both dopamine and norepinephrine transporter inhibition. Finally, the addictive potential of MPH (1 mg/kg and 10 mg/kg) was compared to those of two other psychostimulants, amphetamine (0.005 mg/kg and 1.5 mg/kg) and cocaine (0.15 mg/kg and 15 mg/ kg), using a conditioned place preference and behavioral sensitization paradigm. We found that memory-enhancing effects of psychostimulants observed at low doses are readily dissociable from their reinforcing and locomotor activating effects at high doses. Together, our data suggest that fear conditioning will be an especially fruitful platform for modeling the effects of psychostimulants on LTM in drug development.

Objective: The apolipoprotein E (APOE) gene is an established risk factor for sporadic Alzheimer’s disease, with elevated risk for ε4-carriers and reduced risk for ε2-carriers. However, it is unclear whether APOE modifies risk for cognitive decline in normal aging. The objective of this study was to determine whether ε2 and ε4 are associated with rates of normal cognitive aging, and whether associations of ε4 with cognitive decline are modified by sex, education or health behaviors (exercise, alcohol consumption, smoking). Method: A community-based sample of 1,393 older adults were genotyped for APOE and underwent cognitive assessment up to seven times over a maximum of period of 27 years. Results: ε2-carriers showed slower executive function decline with age relative to ε3 homozygotes or ε4-carriers, whereas ε4-carriers demonstrated more rapid executive function and verbal fluency decline. Accelerated executive function decline was particularly pronounced in ε4-carriers with lower education. After excluding individuals with cognitive impairment, faster executive function decline was still apparent in ε4-carriers, and the effect of ε4 on episodic memory interacted with alcohol consumption, such that only ε4-carriers who did not drink showed more rapid memory decline than ε4 non-carriers. The influence of ε4 on cognitive aging did not differ by sex, nor was it modified by smoking or exercise. Conclusions: These findings indicate that the ε2 and ε4 alleles have differential effects on cognitive aging, and that negative effects of ε4 may be partly mitigated by behavioral choices.

BackgroundDiffusion imaging has demonstrated sensitivity to structural brain changes in Alzheimer’s disease (AD). However, there remains a need for a more complete characterization of microstructural alterations occurring at the earliest disease stages, and how these changes relate to underlying neuropathology. This study evaluated the sensitivity of restriction spectrum imaging (RSI), an advanced diffusion magnetic resonance imaging (MRI) technique, to microstructural brain changes in mild cognitive impairment (MCI) and AD.MethodsMRI and neuropsychological test data were acquired from 31 healthy controls, 12 individuals with MCI, and 13 individuals with mild AD, aged 63–93 years. Cerebrospinal fluid amyloid-β levels were measured in a subset (n = 38) of participants. RSI measures of neurite density (ND) and isotropic free water (IF) were computed in fiber tracts and in hippocampal and entorhinal cortex gray matter, respectively. Analyses evaluated whether these measures predicted memory performance, correlated with amyloid-β levels, and distinguished impaired individuals from controls. For comparison, analyses were repeated with standard diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA) and mean diffusivity.ResultsBoth RSI and DTI measures correlated with episodic memory and disease severity. RSI, but not DTI, measures correlated with amyloid-β42 levels. ND and FA in the arcuate fasciculus and entorhinal cortex IF most strongly predicted recall performance. RSI measures of arcuate fasciculus ND and entorhinal cortex IF best discriminated memory impaired participants from healthy participants.ConclusionsRSI is highly sensitive to microstructural changes in the early stages of AD, and is associated with biochemical markers of AD pathology. Reduced ND in cortical association fibers and increased medial temporal lobe free-water diffusion predicted episodic memory, distinguished cognitively impaired from healthy individuals, and correlated with amyloid-β. Although further research is needed to assess the sensitivity of RSI to preclinical AD and disease progression, these results suggest that RSI may be a promising tool to better understand neuroanatomical changes in AD and their association with neuropathology.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-017-0281-7) contains supplementary material, which is available to authorized users.