The ability to make advantageous choices among outcomes that differ in magnitude, probability, and delay until their arrival is critical for optimal survival and well-being across the lifespan. Aged individuals are often characterized as less impulsive in their choices than their young adult counterparts, demonstrating an increased ability to forgo immediate in favor of delayed (and often more beneficial) rewards. Such "wisdom" is usually characterized as a consequence of learning and life experience. However, aging is also associated with prefrontal cortical dysfunction and concomitant impairments in advantageous choice behavior. Animal models afford the opportunity to isolate the effects of biological aging on decision-making from experiential factors. To model one critical component of decision-making, young adult and aged Fischer 344 rats were trained on a two-choice delay discounting task in which one choice provided immediate delivery of a small reward and the other provided a large reward delivered after a variable delay period. Whereas young adult rats showed a characteristic pattern of choice behavior (choosing the large reward at short delays and shifting preference to the small reward as delays increased), aged rats maintained a preference for the large reward at all delays (i.e., attenuated "discounting" of delayed rewards). This increased preference for the large reward in aged rats was not due to perceptual, motor, or motivational factors. The data strongly suggest that, independent of life experience, there are underlying neurobiological factors that contribute to age-related changes in decision-making, and particularly the ability to delay gratification.

Previous literature has focused on predicting a diagnostic label from structural brain imaging. Since subtle changes in the brain precede a cognitive decline in healthy and pathological aging, our study predicts future decline as a continuous trajectory instead. Here, we tested whether baseline multimodal neuroimaging data improve the prediction of future cognitive decline in healthy and pathological aging. Nonbrain data (demographics, clinical, and neuropsychological scores), structural MRI, and functional connectivity data from OASIS-3 (N = 662; age = 46-96 years) were entered into cross-validated multitarget random forest models to predict future cognitive decline (measured by CDR and MMSE), on average 5.8 years into the future. The analysis was preregistered, and all analysis code is publicly available. Combining non-brain with structural data improved the continuous prediction of future cognitive decline (best test-set performance: R2 = 0.42). Cognitive performance, daily functioning, and subcortical volume drove the performance of our model. Including functional connectivity did not improve predictive accuracy. In the future, the prognosis of age-related cognitive decline may enable earlier and more effective individualized cognitive, pharmacological, and behavioral interventions.

Impairments in synaptic connectivity have been linked to cognitive deficits in age-related neurodegenerative disorders and healthy aging. However, the anatomical and structural bases of these impairments have not been identified yet. A hallmark of neural plasticity in young adults is short-term synaptic rearrangement, yet aged animals already display higher synaptic turnover rates at the baseline. Using two-photon excitation (2PE) microscopy, we explored if this elevated turnover alters the aged brain's response to plasticity. Following a sensory-evoked plasticity protocol involving whisker stimulation, aged mice display reduced spine dynamics (gain, loss, and turnover), decreased spine clustering, and lower spine stability when compared to young adult mice. These results suggest a deficiency of the cortical neurons of aged mice to structurally incorporate new sensory experiences, in the form of clustered, long-lasting synapses, into already existing cortical circuits. This research provides the first evidence linking experience-dependent plasticity with in vivo spine dynamics in the aged brain and supports a model of both reduced synaptic plasticity and reduced synaptic tenacity in the aged somatosensory system.

Synaptic dysfunction is one of the key mechanisms associated with cognitive deficits observed in Alzheimer's disease (AD), yet little is known about the presynaptic axonal boutons in AD. Focusing on cortical en passant boutons (EPBs) along axons located in the motor, sensory and prefrontal regions of the cerebral cortex in the APP/PS1 mouse model of AD, we investigated structural properties of EPBs over the lifespan and in response to a midlife environmental enrichment (EE) intervention. At 3, 12, and 18-22 months and following 6 months of midlife EE, we found that EPBs showed remarkable resilience in preserving overall synaptic output, as evidenced by the maintained density of EPBs along the axon shaft across all experimental conditions. Using cranial window imaging to monitor synaptic changes in real time, we report that despite maintaining a stable synaptic density, the dynamic fraction (gains and losses) of EPBs was significantlyreduced at 10-13 months of age in APP/PS1 axons compared to age matched controls.

Although the absence of the age-regulating klotho protein causes klotho-deficient mice to rapidly develop cognitive impairment and increasing klotho enhances hippocampal-dependent memory, the cellular effects of klotho that mediate hippocampal-dependent memory function are unknown. Here, we show premature aging of the klotho-deficient hippocampal neurogenic niche as evidenced by reduced numbers of neural stem cells, decreased proliferation, and impaired maturation of immature neurons. Klotho-deficient neurospheres show reduced proliferation and size that is rescued by supplementation with shed klotho protein. Conversely, 6-month-old klotho-overexpressing mice exhibit increased numbers of neural stem cells, increased proliferation, and more immature neurons with enhanced dendritic arborization. Protection from normal age-related loss of object location memory with klotho overexpression and loss of spatial memory when klotho is reduced by even half suggests direct, local effects of the protein. Together, these data show that klotho is a novel regulator of postnatal neurogenesis affecting neural stem cell proliferation and maturation sufficient to impact hippocampal-dependent spatial memory function.

The production of amyloid β (Aβ) in the brain from Aβ precursor protein (APP) through γ-secretase is important for the pathogenesis of Alzheimer's disease (AD). Our previous studies have demonstrated that autophagy impairment and endoplasmic reticulum stress increase presenilin 1 expression and enhance γ-secretase activity through the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) and the translation of activating transcription factor 4 (ATF4). However, the inhibitory molecules for γ-secretase are largely unknown. Here, we demonstrate that the levels of ATF4 expression are increased in the brain of APP23 AD model mice; furthermore, these levels enhanced in the brain of APP23 mice crossed with obese and diabetic db/db (Lepr(db/db)) mice. A polyhydroxylated flavonoid, quercetin, suppressed presenilin 1 expression and Aβ secretion in autophagy-impaired cells by the induction of growth arrest and DNA damaged-inducible gene (GADD) 34, which mediates eIF2α dephosphorylation, leading to decreased ATF4 expression. GADD34 induction was observed in the brain of wild-type mice, and APP23 mice fed quercetin in their diet. After the long-term feeding of quercetin, deterioration in memory assessed by freezing behavior was delayed in APP23 mice. These results indicate that quercetin may reduce eIF2α phosphorylation and ATF4 expression through GADD34 induction in the brain, leading to the improvement of memory in aged mice and the delay of deterioration in memory at the early stage of AD in AD model mice.

The age-related loss of GABA in the inferior colliculus (IC) likely plays a role in the development of age-related hearing loss. Perineuronal nets (PNs), specialized aggregates of extracellular matrix, increase with age in the IC. PNs, associated with GABAergic neurotransmission, can stabilize synapses and inhibit structural plasticity. We sought to determine whether PN expression increased on GABAergic and non-GABAergic IC cells that project to the medial geniculate body (MG). We used retrograde tract-tracing in combination with immunohistochemistry for glutamic acid decarboxylase and Wisteria floribunda agglutinin across three age groups of Fischer Brown Norway rats. Results demonstrate that PNs increase with age on lemniscal and non-lemniscal IC-MG cells, however two key differences exist. First, PNs increased on non-lemniscal IC-MG cells during middle-age, but not until old age on lemniscal IC-MG cells. Second, increases of PNs on lemniscal IC-MG cells occurred on non-GABAergic cells rather than on GABAergic cells. These results suggest that synaptic stabilization and reduced plasticity likely occur at different ages on a subset of the IC-MG pathway.

The hippocampus is a critical site for alterations that are responsible for age-related changes in memory. Here, we present a relatively novel approach of examining the relationship between memory performance and glutamate-glutamine levels using short echo time magnetic resonance spectroscopy. Specifically, we investigated the relationship between Glx (a composite of glutamate and glutamine) levels in the hippocampus, performance on a word-recall task, and resting-state functional connectivity. While there was no overall difference in Glx intensity between young and aging adults, we identified a positive correlation between delayed word-list recall and Glx, bilaterally in older adults, but not in young adults. Collapsed across age, we also discovered a negative relationship between Glx intensity and resting-state functional connectivity between the anterior hippocampus and regions in the subcallosal gyrus. These findings demonstrate the possible utility of Glx in identifying age-related changes in the brain and behavior and provide encouragement that magnetic resonance spectroscopy can be useful in predicting age-related decline before any physical abnormalities are present.

While aging is generally associated with episodic memory decline, not all older adults exhibit memory loss. Furthermore, emotional memories are not subject to the same extent of forgetting and appear preserved in aging. We conducted high-resolution fMRI during a task involving pattern separation of emotional information in older adults with and without age-related memory impairment (characterized by performance on a word-list learning task: low performers: LP vs. high performers: HP). We found signals consistent with emotional pattern separation in hippocampal dentate (DG)/CA3 in HP but not in LP individuals, suggesting a deficit in emotional pattern separation. During false recognition, we found increased DG/CA3 activity in LP individuals, suggesting that hyperactivity may be associated with overgeneralization. We additionally observed a selective deficit in basolateral amygdala-lateral entorhinal cortex-DG/CA3 functional connectivity in LP individuals during pattern separation of negative information. During negative false recognition, LP individuals showed increased medial temporal lobe functional connectivity, consistent with overgeneralization. Overall, these results suggest a novel mechanistic account of individual differences in emotional memory alterations exhibited in aging.

Age-related cognitive decline preferentially targets long-lasting episodic memories that require intact hippocampal function. Memory traces (or engrams) are believed to be encoded within the neurons activated during learning (neuronal ensembles), and recalled by reactivation of the same population. However, whether engram reactivation dictates memory performance late in life is not known. Here, we labeled neuronal ensembles formed during object location recognition learning in the dentate gyrus, and analyzed the reactivation of this population during long-term memory recall in young adult, cognitively impaired- and unimpaired-aged mice. We found that reactivation of memory-encoding neuronal ensembles at long-term memory recall was disrupted in impaired but not unimpaired-aged mice. Furthermore, we showed that the memory performance in the aged population correlated with the degree of engram reactivation at long-term memory recall. Overall, our data implicates recall-induced engram reactivation as a prediction factor of memory performance in aging. Moreover, our findings suggest impairments in neuronal ensemble stabilization and/or reactivation as an underlying mechanism in age-dependent cognitive decline.

Loss-of-function mutations in the PINK1 gene lead to recessive forms of Parkinson's disease. Animal models with depleted PINK1 expression have failed to reproduce significant nigral dopaminergic neurodegeneration and clear alpha-synuclein pathology, main characteristics of the disease. In this study, we investigated whether alpha-synuclein pathology is altered in the absence of PINK1 in cell culture and in vivo. We observed that downregulation of PINK1 enhanced alpha-synuclein aggregation and apoptosis in a neuronal cell culture model for synucleinopathy. Silencing of PINK1 expression in mouse substantia nigra using recombinant adeno-associated viral vectors did not induce dopaminergic neurodegeneration in a long-term study up to 10 months, nor did it enhance or accelerate dopaminergic neurodegeneration after alpha-synuclein overexpression. However, in PINK1 knockout mice, overexpression of alpha-synuclein in the substantia nigra resulted in enhanced dopaminergic neurodegeneration as well as significantly higher levels of alpha-synuclein phosphorylation at serine 129 at 4 weeks postinjection. In conclusion, our results demonstrate that total loss of PINK1 leads to an increased sensitivity to alpha-synuclein-induced neuropathology and cell death in vivo.

Alzheimer's disease (AD) is a neurodegenerative disorder involving impaired cholinergic neurotransmission and dysregulation of nicotinic acetylcholine receptors (nAChRs). Ly-6/neurotoxin (Lynx) proteins have been shown to modulate cognition and neural plasticity by binding to nAChR subtypes and modulating their function. Hence, changes in nAChR regulatory proteins such as Lynx proteins could underlie the dysregulation of nAChRs in AD. Using Western blotting, we detected bands corresponding to the Lynx proteins prostate stem cell antigen (PSCA) and Lypd6 in human cortex indicating that both proteins are present in the human brain. We further showed that PSCA forms stable complexes with the α4 nAChR subunit and decreases nicotine-induced extracellular-signal regulated kinase phosphorylation in PC12 cells. In addition, we analyzed protein levels of PSCA and Lypd6 in postmortem tissue of medial frontal gyrus from AD patients and found significantly increased PSCA levels (approximately 70%). In contrast, no changes in Lypd6 levels were detected. In concordance with our findings in AD patients, PSCA levels were increased in the frontal cortex of triple transgenic mice with an AD-like pathology harboring human transgenes that cause both age-dependent β-amyloidosis and tauopathy, whereas Tg2576 mice, which display β-amyloidosis only, had unchanged PSCA levels compared to wild-type animals. These findings identify PSCA as a nAChR-binding protein in the human brain that is affected in AD, suggesting that PSCA-nAChR interactions may be involved in the cognitive dysfunction observed in AD.

Temporal precision, a key component of sound and speech processing in the inferior colliculus (IC), depends on a balance of inhibition and excitation, and this balance degrades during aging. The cause of disrupted excitatory-inhibitory balance in aging is unknown, however changes at the synapse are a likely candidate. We sought to determine whether synaptic changes occur in the lateral cortex of the IC (IClc), a multimodal nucleus that processes lemniscal, intrinsic, somatosensory, and descending auditory input. Using electron microscopic techniques across young, middle age and old Fisher Brown Norway rats, our results demonstrate minimal loss of synapses in middle age, but significant (∼28%) loss during old age. However, in middle age, targeting of GABAergic dendrites by GABAergic synapses is increased and the active zones of excitatory synapses (that predominantly target GABA-negative dendrites) are lengthened. These synaptic changes likely result in a net increase of excitation in the IClc during middle age. Thus, disruption of excitatory-inhibitory balance in the aging IClc may be due to synaptic changes that begin in middle age.

We investigated progression and interrelationships of cerebral small vessel disease (cSVD) markers. This population-based cohort study included 325 participants (age ≥ 60 years) who had repeated measures of cSVD markers over 6 years: white-matter hyperintensity (WMH), perivascular spaces (PVS), lacunes, and grey-matter (GM) and ventricular volumes. We found that all cSVD markers, except PVS, progressed faster with increasing age. Regional WMH progressed faster in males and less-educated people (p < 0.05). Each 10-point increment in global WMH score was associated with multi-adjusted hazard ratio of 1.78 (95% CI = 1.50‒2.10) for incident lacunes and multi-adjusted β-coefficients of 0.15 (0.08-0.22), -0.37 (-0.58‒-0.16), and 0.11 (0.03‒0.18) for annual changes of global WMH score, GM volume, and ventricular volume, respectively. The corresponding figures associated with per 10-PVS increment were 1.14 (1.01‒1.28), 0.07 (0.03‒0.11), -0.18 (-0.32‒-0.04), and 0.02 (-0.03‒0.07). Prevalent lacunes were related to multi-adjusted β-coefficients of 0.29 (0.00‒0.58), 0.22 (0.05‒0.38), 0.10 (0.01‒0.18), and -0.93 (-1.83‒-0.03) for annual changes of global, deep, and periventricular WMH scores and GM volume, respectively. These results suggest that cSVD progresses faster in older, male, and less-educated people, and that greater loads of WMH, PVS, and lacunes anticipate faster cSVD progression.

Alzheimer's disease (AD) is associated with disturbances in blood glucose regulation, and type-2 diabetes elevates the risk for dementia. A role for amyloid-β peptide (Aβ) in linking these age-related conditions has been proposed, tested primarily in transgenic mouse lines that overexpress mutated amyloid precursor protein (APP). Because APP has its own impacts on glucose regulation, we examined the BRI-Aβ42 line ("Aβ42-tg"), which produces extracellular Aβ1-42 in the CNS without elevation of APP. We also looked for interactions with diet-induced obesity (DIO) resulting from a high-fat, high-sucrose ("western") diet. Aβ42-tg mice were impaired in both spatial memory and glucose tolerance. Although DIO induced insulin resistance, Aβ1-42 accumulation did not, and the impacts of DIO and Aβ on glucose tolerance were merely additive. Aβ42-tg mice exhibited no significant differences from wild-type in insulin production, body weight, lipidemia, appetite, physical activity, respiratory quotient, an-/orexigenic factors, or inflammatory factors. These negative findings suggested that the phenotype in these mice arose from perturbation of glucose excursion in an insulin-independent tissue. To wit, cerebral cortex of Aβ42-tg mice had reduced glucose utilization, similar to human patients with AD. This was associated with insufficient trafficking of glucose transporter 1 to the plasma membrane in parenchymal brain cells, a finding also documented in human AD tissue. Together, the lower cerebral metabolic rate of glucose and diminished function of parenchymal glucose transporter 1 indicate that aberrant regulation of blood glucose in AD likely reflects a central phenomenon, resulting from the effects of Aβ on cerebral parenchyma, rather than a generalized disruption of hypothalamic or peripheral endocrinology. The involvement of a specific glucose transporter in this deficit provides a new target for the design of AD therapies.

Alzheimer's disease (AD) is the most common form of dementia and has no effective treatment. Besides the well-known pathologic characteristics, this disease also has a vascular component, and substantial evidence shows increased thrombosis as well as a critical role for fibrin(ogen) in AD. This molecule has been implicated in neuroinflammation, neurovascular damage, blood-brain barrier permeability, vascular amyloid deposition, and memory deficits that are observed in AD. Here, we present evidence demonstrating that fibrin deposition increases in the AD brain and correlates with the degree of pathology. Moreover, we show that fibrin(ogen) is present in areas of dystrophic neurites and that a modest decrease in fibrinogen levels improves neuronal health and ameliorates amyloid pathology in the subiculum of AD mice. Our results further characterize the important role of fibrin(ogen) in this disease and support the design of therapeutic strategies aimed at blocking the interaction between fibrinogen and amyloid-β (Aβ) and/or normalizing the increased thrombosis present in AD.

It is well established that mitochondrial fragmentation plays a key role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial fission is mediated by dynamin-related protein 1 (Drp1), which is highly expressed in nervous system and regulated by various posttranslational modifications including phosphorylation. We identified glycogen synthase kinase (GSK)3β-dependent Drp1 phosphorylation at Ser(40) and Ser(44), which increases Drp1 GTPase activity and its mitochondrial distribution and could induce mitochondrial fragmentation. Moreover, neurons transfected with Ser(40)Ser(44) phosphomimic Drp1 showed increased mitochondria fragmentation and were more vulnerable to amyloid-β (Aβ)-induced apoptosis. Therefore, blocking GSK3β-induced Drp1 phosphorylation may be an effective way to protect neurons from Aβ toxicity. To address this, we designed and synthesized an artificial polypeptide named TAT-Drp1-SpS, which could specifically block GSK3β-induced Drp1 phosphorylation. Our results demonstrated that TAT-Drp1-SpS treatment could significantly reduce Aβ-induced neuronal apoptosis in cultured neurons. Notably, TAT-Drp1-SpS administration in hippocampus Cornu Ammonis 1 (CA1) region significantly reduced Aβ burden and rescued the memory deficits in AD transgenic mice. Although Aβ has multiple targets to exert its neurotoxicity, our findings suggested that GSK3β-induced mitochondrial fragmentation was, at least partially, mediated by Aβ toxicity and contribute to the pathogenesis of AD. Taken together, GSK3β-induced Drp1 phosphorylation provides a novel mechanism for mitochondrial fragmentation in AD, and our findings suggested a novel therapeutic strategy for AD.

Anticholinergic drug use is common in older adults and has been related to increased dementia risk. This suggests that users of these drugs may experience accelerated cognitive decline. So far, however, longitudinal data on this topic are absent and the available evidence is inconclusive with respect to effects on specific cognitive domains due to suboptimal control of confounding variables. We investigated whether anticholinergic medication use is associated with cognitive decline over 6 years in a population-based study of older adults (aged 60-90; n = 1473) without dementia. We found that users (n = 29) declined more on episodic memory over 6 years compared to nonusers (n = 1418). These results were independent of age, sex, education, overall drug intake, physical activity, depression, cardiovascular risk burden, and cardiovascular disease. By contrast, anticholinergic drug use was unrelated to performance in processing speed, semantic memory, short-term memory, verbal fluency, and global cognition (the Mini-Mental-State Examination). Our results suggest that effects of anticholinergics may be particularly detrimental to episodic memory in older adults, which supports the assertion that the cholinergic system plays an important role in episodic memory formation.

Heterozygous triggering receptor expressed on myeloid cells (TREM2) mutations are an Alzheimer's disease (AD) risk factor. Nonmutated TREM2 dysregulation occurs in AD brain. Whether TREM2 is altered in prodromal AD remains unknown. Western blotting was used to determine levels of TREM2 (∼25 kDa) and Iba1 in the frontal cortex and TREM2 in the hippocampus from people who died with an ante-mortem clinical diagnosis of non- and mild-cognitive impairment, mild/moderate AD, and severe AD (sAD). Immunohistochemistry defined the relationship between amyloid and Iba1 profiles. Polymerase chain reaction analysis revealed that all subjects did not carry the most common R47H TREM2 variant. TREM2 was significantly upregulated in sAD frontal cortex but stable in hippocampus. Frontal TREM2 mRNA and protein level patterns were similar but not significantly different. Iba1 immunopositive microglia counts increased significantly in frontal cortex containing plaques in sAD. TREM2 and Iba1 levels were not associated with plaques, tangles, neuropathological criteria, or cognitive performance. Frontal cortex TREM2 upregulation is a late event and may not play a major role early in the pathogenesis of the disease.

In this study, we examined the relationship between various β-amyloid (Aβ) oligomer assemblies in autopsy brain with the levels of fibrillar Aβ and cholinergic synaptic function. Brain tissues obtained from the frontal cortex of 14 Alzheimer's disease (AD) patients grouped into early-onset AD (EOAD) and late-onset AD (LOAD) and 12 age-matched control subjects were used to extract and quantify Aβ oligomers in soluble (TBS), detergent soluble (TBST), and insoluble (GuHCl) fractions. The predominant oligomeric Aβ assemblies detected were dodecamers, decamers, and pentamers, and different patterns of expression were observed between EOAD and LOAD patients. There was no association between any of the detected Aβ oligomer assemblies and fibrillar Aβ levels measured by N-methyl[(3)H] 2-(40-methylaminophenyl)-6-hydroxy-benzothiazole ([(3)H]PIB) binding. Levels of pentamers in the soluble fraction significantly correlated with a reduction in choline acetyltransferase activity in AD patients. The number of nicotinic acetylcholine receptors negatively correlated with the total amount of Aβ oligomers in the insoluble fraction in EOAD patients, and with decamers in the soluble fraction in LOAD patients. These novel findings suggest that distinct Aβ oligomers induce impairment of cholinergic neurotransmission in AD pathogenesis.