Alzheimer disease (AD) is one of, if not the most, feared diseases associated with aging. The prevalence of AD increases exponentially with age after 60 years. Increasing life expectancy coupled with the absence of any approved disease-modifying therapies at present position AD as a dominant public health problem. Major advances have occurred in the development of disease biomarkers for AD in the past 2 decades. At present, the most well-developed AD biomarkers are the cerebrospinal fluid analytes amyloid-β 42 and tau and the brain imaging measures amyloid positron emission tomography (PET), fluorodeoxyglucose PET, and magnetic resonance imaging. CSF and imaging biomarkers are incorporated into revised diagnostic guidelines for AD, which have recently been updated for the first time since their original formulation in 1984. Results of recent studies suggest the possibility of an ordered evolution of AD biomarker abnormalities that can be used to stage the typical 20-30-year course of the disease. When compared with biomarkers in other areas of medicine, however, the absence of standardized quantitative metrics for AD imaging biomarkers constitutes a major deficiency. Failure to move toward a standardized system of quantitative metrics has substantially limited potential diagnostic usefulness of imaging in AD. This presents an important opportunity that, if widely embraced, could greatly expand the application of imaging to improve clinical diagnosis and the quality and efficiency of clinical trials.

The current pathogenic scenarios of different types of dementia are based on a number of common mechanisms of neurodegeneration, such as accumulation of abnormal proteins (within or outside cells), mitochondrial dysfunction and oxidative stress, calcium homeostasis dysregulation, early synaptic disconnection and late apoptotic cell death. Ageing itself is associated with mild cognitive deterioration, probably due to subtle multifactorial changes resulting in a global decrease of a functional brain reserve. Increased age is a risk factor for neurodegeneration and key pathological features of dementia can also be found in aged brains. One of the underexplored brain structures in ageing and dementia is the blood-brain barrier (BBB), a complex cellular gate which regulates tightly the transport of molecules into and from the central nervous system. Disruption of this barrier is now increasingly documented not only in brain vascular disease but also in ageing and neurodegenerative disorders. To date, such evidence points mainly at an association between various dementia forms and disruption of the BBB. But, in reviewing such results, and taking into account the exquisite sensitivity of neuronal function to the composition of the interstitial brain fluid (IBF), which is regulated by the BBB, we would like to propose the existence of a possible causal link between alterations of BBB and conditions associated with cognitive decline.

<h4>Background</h4>Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique for Alzheimer's disease (AD). rTMS, with high- or low-frequency, is thought to enhance or inhibit the cortical activities, respectively. This meta-analysis of randomized controlled trials (RCTs) was to summarize the efficacy of the rTMS on the cognition of AD patients and to identify its potential influential factors.<h4>Methods</h4>Literature from the Pubmed, Embase, Cochrane Library and Web of Science were searched and screened to identify eligible studies. Standardized mean difference (SMD) and 95% confidence interval were used to evaluate the therapeutic effects of rTMS. Subgroup analyses were performed to investigate the influential factors.<h4>Results</h4>Ten studies with 15 trials involving 240 patients were included. Compared with sham stimulation, rTMS could significantly improve cognition in AD (SMD, 0.42; 95% CI 0.18-0.67; P = 0.0006). Subgroup analysis suggested significant cognitive enhancement in participants receiving rTMS on multiple sites rather than on single site, and in patients receiving rTMS of more than 10 sessions, but not ≤ 10 sessions. Compared with rTMS as the single therapeutic method, rTMS with concurrent cognitive training seemed to produce greater improvement. Moreover, 20 Hz rTMS, seemed to be more effective than 10 Hz or 1 Hz rTMS. Furthermore, patients with higher education, or with mild-to-moderate AD were more likely to benefit from rTMS than patients with lower education, or with severe dementia, respectively.<h4>Conclusions</h4>Based on the current evidence, rTMS was an effective therapy for cognitive impairment in AD. Large RCTs are warranted to further validate the results of our subgroup analyses.

Introduction: Observational studies have found that physical activity is associated with a reduced risk of cognitive decline and dementia. Whether physical activity may also reduce the level of AD pathology, remains undetermined. Objective: To examine the relationship between physical activity and AD biomarkers (beta-amyloid1- 42, total tau and phosphorylated tau in CSF, amyloid PET, hippocampal atrophy on MRI and parietotemporal hypometabolism on brain 18F-FDG-PET). Methods: We carried out a systematic review of the observational studies of physical activity and AD biomarkers in healthy subjects, subjective cognitive complaints, mild cognitive impairment (MCI) and AD dementia. Results: We identified a total of 40 papers, which were eligible for inclusion. Thirty-four studies were conducted on healthy subjects, 3 on MCI and healthy subjects, 1 on MCI, and 2 on AD and healthy controls. Six studies reported on CSF biomarkers, 9 on amyloid PET, 29 on MRI and 4 on brain 18FFDG- PET. The majority of studies did not find a significant association between physical activity and AD biomarkers Conclusion: The quality of included studies with only a few longitudinal studies, limits the conclusions which may be drawn from the present findings especially regarding the biomarkers other than hippocampal volume. However, the majority of the identified studies did not find a significant association. Whether physical activity may also reduce the level of AD pathology, remains undetermined. Objective: To examine the relationship between physical activity and AD biomarkers (beta-amyloid1- 42, total tau and phosphorylated tau in CSF, amyloid PET, hippocampal atrophy on MRI and parietotemporal hypometabolism on brain 18F-FDG-PET). Methods: We carried out a systematic review of the observational studies of physical activity and AD biomarkers in healthy subjects, subjective cognitive complaints, mild cognitive impairment (MCI) and AD dementia. Results: We identified a total of 40 papers, which were eligible for inclusion. A combined cognitive stimulation and physical exercise programme (mindvital) in early dementia: differential effects on single- and dual-task gait performance. Gerontology 62(6): 604-10. (2016). [10] Baker LD, Frank LL, Foster-Schubert K, Green PS, Wilkinson CW, McTiernan A, et al. Effects of aerobic exercise on mild cognitive impairment. Arch Neurol 67(1): 71-9. (2010). [11] Nguyen J, Suarez A, Le Saout E, Meignier M, Nizard J, Lefaucheur J. Brain Stimulation Combining cognitive training and multi-site rTMS to improve cognitive functions in Alzheimer ’ s disease. Brain Stimul 12. (2018). [12] Bayer-Carter JL, Green PS, Montine TJ, VanFossen B, Baker LD, Watson GS, et al. [29] Cabral D, Beach TG, Vedders L, Sue LI, Jacobson S, Myers K, et al. Frequency of Alzheimer’s disease pathology at autopsy in patients with clinical normal pressure hydrocephalus. Alzheimers Dement 7(5): 509-13. (2011). [30] Frederiksen KS, Gjerum L, Waldemar G, Hasselbalch SG. Effects of physical exercise on Alzheimer’s disease biomarkers: a systematic review of intervention studies. J Alzheimers Dis 61(1): 359-72. (2017). [31] Groot C, Hooghiemstra AM, Raijmakers PGHM, van Berckel BNM, Scheltens P, Scherder EJA, et al. The effect of physical activity on cognitive function in patients with dementia: a meta-analysis of randomized control trials (2016). Masters athletes exhibit larger regional brain volume and better cognitive performance than sedentary older adults. J Magn Reson Imaging 38(5): 1169-76. (2013). [45] Erickson KI, Raji CA, Lopez OL, Becker JT, Rosano C, Newman AB, et al. Physical activity predicts gray matter volume in late adulthood: The cardiovascular health study. Neurology 75(16): 141522. (2010). [46] Vidoni ED, Honea R, Billinger S, Swerdlow RH, Burns JM. Cardiorespiratory fitness is associated with atrophy in Alzheimer’s and aging over 2 years. Neurobiol Aging 33(8): 1624-32. (2012). [47] Smith JC, Nielson KA, Woodard JL, Seidenberg M, Durgerian S, [63] Szabo AN, McAuley E, Erickson KI, Voss M, Prakash RS, Mailey EL, et al. Cardiorespiratory fitness, hippocampal volume, and frequency of forgetting in older adults. Neuropsychology 25(5): 545-53. (2011). [64] Boots EA, Schultz SA, Oh JM, Larson J, Edwards D, Cook D, et al. Cardiorespiratory fitness is associated with brain structure, cognition, and mood in a middle-aged cohort at risk for Alzheimer’s disease. Brain Imaging Behav 9(3): 639-49. (2015). [65] Doi T, Makizako H, Shimada H, Tsutsumimoto K, Hotta R, Nakakubo S, et al. Objectively measured physical activity, brain atrophy, and white matter lesions in older adults with mild cognitive impairment. Exp Gerontol 62: 1-6. (2015). [66] Honea RA, Thomas GP, Harsha A, Anderson HS, Donnelly JE, Brooks WM, et al. Cardiorespiratory fitness and preserved medial temporal lobe volume in Alzheimer disease. Alzheimer Dis Assoc Disord 23(3): 188-97. (2009). [67] Makizako H, Liu-Ambrose T, Shimada H, Doi T, Park H, Tsutsumimoto K, et al. Moderate-intensity physical activity, hippocampal volume, and memory in older adults with mild cognitive impairment. Journals Gerontol Ser A Biol Sci. Med Sci 70(4): 480-6. (2015). [68] Tan ZS, Spartano NL, Beiser AS, DeCarli C, Auerbach SH, Vasan RS, et al. Physical Activity, brain volume, and dementia risk: the framingham study. J Gerontol Ser A Biol Sci Med Sci 17(3): glw130. (2016). Mark Item Purchase PDF Rights & Permissions Print Cite Cite as --> Current Alzheimer Research Title: Physical Activity as a Moderator of Alzheimer Pathology: A Systematic Review of Observational Studies Volume: 16 Issue: 4 Author(s): Kristian Steen Frederiksen*, Le Gjerum, Gunhild Waldemar and Steen Gregers Hasselbalch Affiliation: Danish Dementia Research Centre, Section 6911, Department of Neurology, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, DK-2100 Copenhagen,Denmark Keywords: Dementia , Alzheimer’s disease , physical activity , exercise , amyloid , hippocampus , tau , MRI.

There have been increasing efforts to investigate the effects of neuromodulation techniques, such as transcranial direct current stimulation (tDCS), on cognitive impairment in dementia and related conditions. In this systematic review and meta-analysis, we assessed the efficacy of multisession anodal tDCS compared with sham stimulation for improving global cognition and specific cognitive domains in both Alzheimer's disease and mild cognitive impairment. Eight articles meeting the criteria for inclusion in the meta-analysis were selected. Five studies used the Mini-Mental State Examination to examine mild cognitive impairment and dementia. In a fixed-effect model, there was a mean difference in the change score of -0.13 points. Three trials for dementia using the Alzheimer's Disease Assessment Scale-Cognition showed a mean difference of -0.53 points. At present, there is a lack of clear evidence concerning the efficacy of multisession anodal tDCS due to the small number of studies and different measures used. This underscores the need for further investigations using larger samples and common outcome measures.

<h4>Background</h4>To prevent and control dementia, many scholars have focused on the transition stage between normal ageing and dementia, mild cognitive impairment (MCI) which is a key interventional target for dementia. Studies have shown that non-invasive brain stimulation (NIBS) is beneficial to improve cognitive function of MCI patients. However, whether NIBS is conducive to the protection of cognitive ability in MCI patients remains unknown due to limited evidence. The aim of the study was to systematically evaluate the modulation effect of NIBS on cognitive function (global cognitive ability and specific domains of cognition) in patients with MCI.<h4>Results</h4>A total of 11 RCTs comprising a total of 367 MCI participants. Meta-analysis showed that NIBS can significantly improve global cognition (n = 271, SMD = 0.94, 95% CI 0.47-1.41, p < 0.0001) and verbal fluency (n = 72, MD = 2.03, 95% CI 0.17-3.88, p = 0.03). However, there was no significant improvement in other domains of cognition.<h4>Conclusions</h4>NIBS has a positive effect on improving global cognitive function and verbal fluency. At the same time, it has a small positive effect on improving executive function. However, these findings should be interpreted carefully due to the limitations of the study.

Introduction: Responsiveness to treatment with cholinesterase inhibitors (ChEIs) is difficult to predict in Alzheimer’s disease (AD). In the current review, vascular burden is considered as a potential moderator of treatment responsiveness. Cerebrovascular burden co-occurs in at least 30% of AD brains, although it is debated if vascular pathology plays a causal or synergistic role in AD pathogenesis. Vascular burden, therefore, could potentially limit response to treatment due to limited brain reserve or foster treatment efficacy as those with vascular pathology may represent a subgroup with comparable clinical expression but less progressed AD neurodegeneration. Methods: A systematic search of Web of Science, Pubmed, Scopus and EthoS identified 32 papers which met the criteria for inclusion. Association of treatment response and vascular burden across five broad markers are discussed: cerebral hypoperfusion, intima-media thickness, white matter changes, cerebral microbleeds and co-existing diagnosis of cerebrovascular disease. Results: Analysis of frontal regional cerebral blood flow and intima-media thickness may have predictive ability to distinguish those with AD who may respond optimally to short-term treatment with ChEIs. The impact of white matter changes is less consistent; the majority of studies demonstrates no association with treatment response and those that do implicate changes in executive functioning. There is preliminary evidence that deep cerebral microbleeds limit treatment response in subcortical cognitive domains, but this finding requires replication. The use of diagnosis of co-occurring cerebrovascular disease yields no robust variability in response to ChEIs in AD. Conclusion: There is limited evidence that markers of cerebral hypoperfusion, intima-media thickness and cerebral microbleeds moderate response to ChEIs. Findings for other markers of vascular burden are less consistent and do not support any moderating effect.

To test the hypothesis that distinct subtypes of Alzheimer disease (AD) exist and underlie the heterogeneity within AD, we conducted a systematic review and meta-analysis on AD subtype studies based on postmortem and neuroimaging data. EMBASE, PubMed, and Web of Science databases were consulted until July 2019. Neuropathology and neuroimaging studies have consistently identified 3 subtypes of AD based on the distribution of tau-related pathology and regional brain atrophy: typical, limbic-predominant, and hippocampal-sparing AD. A fourth subtype, minimal atrophy AD, has been identified in several neuroimaging studies. Typical AD displays tau-related pathology and atrophy both in hippocampus and association cortex and has a pooled frequency of 55%. Limbic-predominant, hippocampal-sparing, and minimal atrophy AD had a pooled frequency of 21%, 17%, and 15%, respectively. Between-subtype differences were found in age at onset, age at assessment, sex distribution, years of education, global cognitive status, disease duration, APOE ε4 genotype, and CSF biomarker levels. We identified 2 core dimensions of heterogeneity: typicality and severity. We propose that these 2 dimensions determine individuals' belonging to one of the AD subtypes based on the combination of protective factors, risk factors, and concomitant non-AD brain pathologies. This model is envisioned to aid with framing hypotheses, study design, interpretation of results, and understanding mechanisms in future subtype studies. Our model can be used along the A/T/N classification scheme for AD biomarkers. Unraveling the heterogeneity within AD is critical for implementing precision medicine approaches and for ultimately developing successful disease-modifying drugs for AD. Abstract Objective To test the hypothesis that distinct subtypes of Alzheimer disease (AD) exist and underlie the heterogeneity within AD, we conducted a systematic review and meta-analysis on AD subtype studies based on postmortem and neuroimaging data. Methods EMBASE, PubMed, and Web of Science databases were consulted until July 2019. Results Neuropathology and neuroimaging studies have consistently identified 3 subtypes of AD based on the distribution of tau-related pathology and regional brain atrophy: typical, limbic-predominant, and hippocampal-sparing AD. A fourth subtype, minimal atrophy AD, has been identified in several neuroimaging studies. Typical AD displays tau-related pathology and atrophy both in hippocampus and association cortex and has a pooled frequency of 55%. Limbic-predominant, hippocampal-sparing, and minimal atrophy AD had a pooled frequency of 21%, 17%, and 15%, respectively. Between-subtype differences were found in age at onset, age at assessment, sex distribution, years of education, global cognitive status, disease duration, APOE ε4 genotype, and CSF biomarker levels. Conclusion We identified 2 core dimensions of heterogeneity: typicality and severity. status released display-pdf yes is-olf no is-manuscript no is-preprint no is-journal-matter no is-scanned no is-retracted no Received 2019 Aug 16; Accepted 2019 Dec 17. Alzheimer disease (AD) is a heterogeneous disease. Variability in age at onset and clinical presentation is known since the very first reports. Extensive research showed marked differences between early-onset and late-onset AD, mostly with early-onset AD showing more pronounced pathologic findings such as more tau-related pathology and brain atrophy. We identified 3 dimensions that are major drivers of the heterogeneity within AD: (1) risk factors, including sex, APOE, and age; (2) protective factors, including aspects such as cognitive reserve, brain resilience, and brain resistance; and (3) concomitant non-AD pathologies that together with amyloid (A) and tau-related pathology (T) may contribute to the neurodegeneration (N) seen in AD, which are formulated under the A/T/N framework for AD. 35 The current meta-analysis revealed that hippocampal-sparing AD had the earliest disease onset, and typical and limbic-predominant AD had the latest disease onset. We suggest that high education could be one of the factors protecting the hippocampus so that pathologies affecting the posterior cortex and thus contributing to hippocampal-sparing AD may be unmasked and have a greater contribution to the clinical expression of the disease. The concepts of cognitive reserve, brain resilience/resistance connect directly with brain pathology, in this case, amyloid, tau-related pathology, and neurodegeneration. The theory of cognitive reserve postulates that people with higher reserve can cope with brain pathology better. 39 At similar levels of clinical severity, the cognitive reserve theory would foresee more pathology in individuals with higher reserve and less pathology in individuals with less reserve. The finding of more intense neurodegeneration and more aggressive disease progression in hippocampal-sparing, 9 , 10 , 18 , 23 , 29 the subtype with the highest level of reserve, supports this hypothesis. The absence of overt brain atrophy in minimal atrophy AD, the subtype with the lowest level of reserve, also supports this hypothesis. The big question is which pathology or pathologies are patients with minimal atrophy AD so vulnerable to? All these factors increase heterogeneity within AD and lead to subtypes according to the spread and location of pathology (neuropathologically and neuroimaging-defined subtypes) often aligning with clinically defined subtypes according to the age at onset and the cognitive presentation (in green in the figure). AD = Alzheimer disease. Our proposal for explaining what determines individuals' location along the typicality dimension is as follows. The medial temporal lobes are a frequent site for deposition of various pathologies (i.e., tau aggregates, TDP-43, and hippocampal sclerosis) and are also more vulnerable to cerebrovascular pathology.

Alzheimer’s disease (AD) is a complex and chronic neurodegenerative disorder that involves a progressive and severe decline in cognition and memory. During the last few decades a considerable amount of research has been done in order to better understand tau-pathology, inflammatory activity and neuronal synapse loss in AD, all of them contributing to cognitive decline. Early hippocampal network dysfunction is one of the main factors associated with cognitive decline in AD. Much has been published about amyloid-beta 1-42 (Aβ 1-42 )-mediated excitotoxicity in AD. However, increasing evidence demonstrates that the remodeling of the inhibitory gamma-aminobutyric acid (GABAergic) system contributes to the excitatory/inhibitory (E/I) disruption in the AD hippocampus, but the underlying mechanisms are not well understood. In the present study, we show that hippocampal injection of Aβ 1-42 is sufficient to induce cognitive deficits 7 days post-injection. We demonstrate using in vitro whole-cell patch-clamping an increased inhibitory GABAergic tonic conductance mediated by extrasynaptic type A GABA receptors (GABA A Rs), recorded in the CA1 region of the mouse hippocampus following Aβ 1-42 micro injection. Such alterations in GABA neurotransmission and/or inhibitory GABA A Rs could have a significant impact on both hippocampal structure and function, causing E/I balance disruption and potentially contributing to cognitive deficits in AD.

Multiple factors are involved in the development of cognitive impairment in Parkinson's disease (PD) and related disorders. Notably, several underlying factors, such as monoaminergic dysfunction, Lewy body pathology, Alzheimer disease-like pathology and cerebrovascular disease are implied in the PD pathophysiology of cognitive impairment. The mesocortical dopaminergic system is associated with executive functions which are frequently affected in PD and are influenced by local levodopa concentration, dopamine metabolism and baseline performance status. The ventral striatum and frontal cortex are associated with impulse control disorders reported in PD patients treated with dopamine replacement therapy. Cholinergic impairment in PD plays a cardinal role in the development of dementia. Acetylcholinesterase positron emission tomography demonstrates that posterior brain areas are related to cognitive decline in PD patients. Amyloid radiotracer illustrates that patients with PD with severe cognitive impairment were prone to accompanied cortical amyloid deposition. Metabolism/perfusion change associated with cognitive impairment in PD, so-called PD related cognitive pattern, is characterised by reduced frontoparietal activity and is an effective way to differentiate and monitor cognitive function of individual PD patients. Cognitive impairment in PD cannot be explained by a single mechanism and is entangled by multiple factors. Imaging studies can unravel each pathological domain, f

Aberrant microglial activation has been proposed to contribute to the cognitive decline in Alzheimer disease (AD), but the underlying molecular mechanisms remain enigmatic. Fractalkine signaling, a pathway mediating the communication between microglia and neurons, is deficient in AD brains and down-regulated by amyloid-β. Although fractalkine receptor (CX3CR1) on microglia was found to regulate plaque load, no functional effects have been reported. Our study demonstrates that CX3CR1 deficiency worsens the AD-related neuronal and behavioral deficits. The effects were associated with cytokine production but not with plaque deposition. Ablation of CX3CR1 in mice overexpressing human amyloid precursor protein enhanced Tau pathology and exacerbated the depletion of calbindin in the dentate gyrus. The levels of calbindin in the dentate gyrus correlated negatively with those of tumor necrosis factor α and interleukin 6, suggesting neurotoxic effects of inflammatory factors. Functionally, removing CX3CR1 in human amyloid precursor protein mice worsened the memory retention in passive avoidance and novel object recognition tests, and their memory loss in the novel object recognition test is associated with high levels of interleukin 6. Our findings identify CX3CR1 as a key microglial pathway in protecting against AD-related cognitive deficits that are associated with aberrant microglial activation and elevated inflammatory cytokines.

Alzheimer’s disease (AD) is characterized by progressive cognitive decline associated with a featured neuropathology (neuritic plaques and neurofibrillary tangles). Several studies have implicated oxidative damage to DNA, DNA repair, and altered cell-cycle regulation in addition to cell death in AD post-mitotic neurons. However, there is a lack of studies that systematically assess those biological processes in patients with AD neuropathology but with no evidence of cognitive impairment. We evaluated markers of oxidative DNA damage (8-OHdG, H2AX), DNA repair (p53, BRCA1, PTEN), and cell-cycle