Risk for Alzheimer’s disease: A review of long-term episodic memory encoding and retrieval fMRI studies

Many risk factors have been identified that predict future progression to Alzheimer’s disease (AD). However, clear links have yet to be made between these risk factors and how they affect brain functioning in early stages of AD. We conducted a narrative review and a quantitative analysis to better understand the relationship between nine categories of AD risk (i.e., brain pathology, genetics/family history, vascular health, head trauma, cognitive decline, engagement in daily life, late-life depression, sex/gender, and ethnoracial group) and task-evoked fMRI activity during episodic memory in cognitively-normal older adults. Our narrative review revealed widespread regional alterations of both greater and lower brain activity with AD risk. Nevertheless, our quantitative analysis revealed that a subset of studies converged on two patterns: AD risk was associated with (1) greater brain activity in frontal and parietal regions, but (2) reduced brain activity in hippocampal and occipital regions. The brain regions affected depended on the assessed memory stage (encoding or retrieval). Although the results clearly indicate that AD risks impact brain activity, we caution against using fMRI as a diagnostic tool for AD at the current time because the above consistencies were present among much variability, even among the same risk factor.     

APOE mediated neuroinflammation and neurodegeneration in Alzheimer’s disease

Neuroinflammation is a central mechanism involved in neurodegeneration as observed in Alzheimer’s disease (AD), the most prevalent form of neurodegenerative disease. Apolipoprotein E4 (APOE4), the strongest genetic risk factor for AD, directly influences disease onset and progression by interacting with the major pathological hallmarks of AD including amyloid-β plaques, neurofibrillary tau tangles, as well as neuroinflammation. Microglia and astrocytes, the two major immune cells in the brain, exist in an immune-vigilant state providing immunological defense as well as housekeeping functions that promote neuronal well-being. It is becoming increasingly evident that under disease conditions, these immune cells become progressively dysfunctional in regulating metabolic and immunoregulatory pathways, thereby promoting chronic inflammation-induced neurodegeneration. Here, we review and discuss how APOE and specifically APOE4 directly influences amyloid-β and tau pathology, and disrupts microglial as well as astroglial immunomodulating functions leading to chronic inflammation that contributes to neurodegeneration in AD.     

Autobiographical memory decline in Alzheimer’s disease,a theoretical and clinical overview

Autobiographical memory, or memory for personal experiences, allows individuals to define themselves and construct a meaningful life story. Decline of this ability, as observed in Alzheimer’s disease (AD), results in an impaired sense of self and identity. In our model (AMAD: Autobiographical Memory in Alzheimer’s Disease), we present a critical review of theories and findings regarding cognitive and neuroanatomical underpinnings of autobiographical memory and its decline in AD and highlight studies on its clinical rehabilitation. We propose that autobiographical recall in AD is mainly characterized by loss of associated episodic information, which leads to de-contextualization of autobiographical memories and a shift from reliving past events to a general sense of familiarity. This decline refers to retrograde, but also anterograde amnesia that affects newly acquired memories besides remote ones. One consequence of autobiographical memory decline in AD is decreased access to memories that shape self-consciousness, self-knowledge, and self-images, leading to a diminished sense of self and identity. The link between autobiographical decline and compromised sense of self in AD can also manifest itself as low correspondence and coherence between past memories and current goals and beliefs. By linking cognitive, neuroanatomical, and clinical aspects of autobiographical decline in AD, our review provides a theoretical foundation, which may lead to better rehabilitation strategies.     

Apolipoprotein E ε4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease

Objectives

Investigate apolipoprotein E ε4 (APOE4) gene and aging effects on florbetapir F18 positron emission tomography (PET) in normal aging and Alzheimer's disease (AD). Methods: Florbetapir F18 PET images were analyzed from 245 participants, 18–92 years of age, from Avid Radiopharmaceutical's multicenter registered trials, including 86 younger healthy control volunteers (yHC), 61 older healthy control volunteers (oHC), 53 mild cognitive impairment (MCI) patients, and 45 AD dementia patients (DAT). Mean florbetapir standard uptake value ratios (SUVRs) were used to evaluate the effects of APOE4 carrier status, older age, and their interaction in each of these groups. Results: In comparison with non-carriers, the APOE4 carriers in each of the oHC, MCI, and DAT groups had higher mean cortical-to-cerebellar florbetapir SUVRs, patterns of florbetapir PET elevations characteristic of DAT, and a higher proportion meeting florbetapir PET positivity criteria. Only the oHC group had a significant association between mean cortical florbetapir SUVRs and age. In cognitively normal adults, without regards to APOE4 genotype, amyloid began to increase at age 58 (95% confidence interval [CI]: 52.3–63.7), with a predicted typical age of florbetapir positivity occurring around age 71 years. Presence of the APOE4 gene reduced the age of predicted florbetapir positivity in normal aging to around age 56 years, approximately 20 years younger than non-carriers. Interpretation: Cerebral amyloid deposition is associated with APOE4 carrier status in older healthy control subjects and symptomatic AD patients, and increases with age in older cognitively normal individuals. Amyloid imaging positivity appears to begin near age 56 years in cognitively intact APOE4 carriers and age 76 years in APOE4 non-carriers.     

Deep brain stimulation of fornix for memory improvement in Alzheimer’s disease: A critical review

Memory reflects the brain function in encoding, storage and retrieval of the data or information, which is a fundamental ability for any live organism. The development of approaches to improve memory attracts much attention due to the underlying mechanistic insight and therapeutic potential to treat neurodegenerative diseases with memory loss, such as Alzheimer’s disease (AD). Deep brain stimulation (DBS), a reversible, adjustable, and non-ablative therapy, has been shown to be safe and effective in many clinical trials for neurodegenerative and neuropsychiatric disorders. Among all potential regions with access to invasive electrodes, fornix is considered as it is the major afferent and efferent connection of the hippocampus known to be closely associated with learning and memory. Indeed, clinical trials have demonstrated that fornix DBS globally improved cognitive function in a subset of patients with AD, indicating fornix can serve as a potential target for neurosurgical intervention in treating memory impairment in AD. The present review aims to provide a better understanding of recent progresses in the application of fornix DBS for ameliorating memory impairments in AD patients.     

Medial temporal lobe dysfunction during encoding and retrieval of episodic memory in non-demented APOE ε4 carriers

Presence of the apolipoprotein E (APOE) ε4 allele is linked to an increased risk to develop Alzheimer's dementia (AD). However, there are controversial data concerning the impact of the APOE genotype on cognitive functioning and brain activity in healthy subjects. We used event-related functional magnetic resonance imaging (fMRI) to investigate the effects of APOE genotype on spatial contextual memory encoding and retrieval success in healthy older adults. Eighteen subjects (eight APOE4 heterozygotes (ε4+) and 10 non-carriers (ε4−), mean age 60.0±5.0 years) were included in the present analysis. Behaviorally, ε4+ subjects performed significantly worse than ε4− subjects in item memory and spatial context retrieval. fMRI data revealed that ε4+ subjects, compared to ε4-subjects, predominantly showed an increase of neural activity specific to encoding of items and their spatial context in prefrontal, temporal and parietal regions. In contrast, ε4+ subjects showed activity decreases in the right amygdala during successful item recognition and in the prefrontal cortex bilaterally during spatial context retrieval when compared to ε4− subjects. While the activity increases during encoding may reflect compensatory activity in the attempt to maintain normal performance, the decreases during retrieval indicate incipient neural decline in ε4+ subjects. These data highlight that preclinical ApoE-related changes in neural activity are not unidirectional but dissociate depending on the memory phase, i.e., encoding or retrieval.     

Prospective biomarkers of Alzheimer’s disease: A systematic review and meta-analysis

ObjectiveAlzheimer’s disease (AD) involves a series of pathological changes and some biomarkers were reported to assist in monitoring and predicting disease progression before the emergence of clinical symptoms. We aimed to identify prospective biomarkers and quantify their effect on AD progression.MethodsPubMed, EMBASE and Web of Science databases were searched for prospective cohort studies published up to October 2021. Eligible studies were included, and the available data were extracted. Meta-analyses were conducted based on random-effect models. Relative risk (RR) with 95% confidence interval (CI) was adopted as the final effect size.ResultsTotally 48,769 articles were identified, of which 84 studies with 20 prospective biomarkers were included in meta-analyses. In the present study, 15 biomarkers were associated with AD progression, comprising CSF Aβ42 (RR=2.49, 95%CI=1.68–3.69), t-tau (RR=1.88, 95%CI=1.49–2.37), p-tau (RR=1.74, 95%CI=1.37–2.21), tau/Aβ42 ratio (RR=5.11, 95%CI=2.01–13.00); peripheral blood Aβ42/Aβ40 (RR=1.26, 95%CI=1.05–1.51), t-tau (RR=1.33, 95%CI=1.08–1.64), NFL (RR=1.75, 95%CI=1.07–2.87); whole, left and right hippocampal volume (HV) (whole: RR=1.65, 95%CI=1.39–1.95; left: RR=2.60, 95%CI=1.02–6.64; right: RR=1.43, 95%CI=1.23–1.66), entorhinal cortex (EC) volume (RR=1.69, 95%CI=1.24–2.30), medial temporal lobe atrophy (MTA) (RR=1.52, 95%CI=1.33–1.74), 18 F-FDG PET (RR=2.24, 95%CI=1.29–3.89), 11 C-labeled Pittsburgh Compound B PET (11 C-PIB PET) (RR=3.91, 95%CI=1.06–14.41); APOE ε4 (RR=2.16, 1.83–2.55). A total of 70 articles were included in the qualitative review, in which 61 biomarkers were additionally associated with AD progression.ConclusionCSF Aβ42, t-tau, p-tau, tau/Aβ42; peripheral blood t-tau, Aβ42/Aβ40, NFL; whole, left and right HV, EC volume, MTA, 18 F-FDG PET, 11 C-PIB PET; APOE ε4 may be promising prospective biomarkers for AD progression.     

Retinal biomarkers in Alzheimer’s disease and mild cognitive impairment: A systematic review and meta-analysis

BackgroundRetinal changes may reflect the pathophysiological processes in the central nervous system and can be assessed by imaging modalities non-invasively. We aim to localize candidate retinal biomarkers in Alzheimer’s disease (AD), mild cognitive impairment (MCI), and preclinical AD.MethodsWe systematically searched PubMed, EMBASE, Scopus, and Web of Science from inception to January 2021 for observational studies that investigated retinal imaging and electrophysiological markers in AD, MCI, and preclinical AD. Between-groups standardized mean differences (SMDs) with 95 % confidence intervals were computed using random-effects models.ResultsOf 19,727 citations identified, 126 articles were eligible for inclusion. Compared with healthy controls, the thickness of peripapillary retinal nerve fiber layer (pRNFL; SMD = -0.723, p < 0.001), total macular (SMD = -0.612, p < 0.001), and subfoveal choroid (SMD = -0.888, p < 0.001) were significantly reduced in patients with AD. Compared with healthy controls, patients with MCI also had lower thickness of pRNFL (SMD = -0.324, p < 0.001), total macular (SMD = -0.302, p < 0.001), and subfoveal choroid (SMD = -0.462, p = 0.020). Other candidate biomarkers included the optic nerve head morphology, retinal amyloid deposition, microvascular morphology and densities, blood flow, and electrophysiological markers.ConclusionsRetinal structural, vascular, and electrophysiological biomarkers hold great potential for the diagnosis, prognosis and risk assessment of AD and MCI. These biomarkers warrant further development in the future, especially in diagnostic test accuracy and longitudinal studies.     

Cerebral small vessel disease and the risk of Alzheimer’s disease: A systematic review

BackgroundCerebral small vessel disease (CSVD) comprises a variety of disorders affecting small arteries and microvessels of the brain, manifesting as white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), and deep brain infarcts. In addition to its contribution to vascular dementia (VaD), it has also been suggested to contribute to the pathogenesis of Alzheimer’s disease (AD).MethodA systematic review of the literature available on Medline, Embase and Pubmed was undertaken, whereby CSVD was divided into WMHs, CMBs and deep brain infarcts. Biomarkers of AD pathology in the cerebrospinal fluid or plasma, or positron emission tomographic imaging for amyloid and/or tau deposition were used for AD pathology.ResultsA total of 4117 articles were identified and 41 articles met criteria for inclusion. These consisted of 17 articles on vascular risk factors for clinical AD, 21 articles on Aβ pathology and 15 articles on tau pathology, permitting ten meta-analyses. CMBs or lobar CMBs were associated with pooled relative risk (RR) of AD at 1.546, (95%CI 0.842–2.838, z = 1.41 p = 0.160) and 1.526(95%CI 0.760–3.063, z = 1.19, p = 0.235) respectively, both non-significant. Microinfarcts were associated with significantly increased AD risk, with pooled odds ratio OR at 1.203(95%CI 1.014–1.428, 2.12 p = 0.034). Aβ pathology was significantly associated with WMHs in AD patients but not in normal age-matched controls. The pooled β (linear regression) for total WMHs with CSF Aβ42 in AD patients was -0.19(95%CI -0.26–0.11, z = 4.83 p = 0.000) and the pooled r (correlation coefficient) for WMHs and PiB in the normal population was -0.10 (95%CI -0.11–0.30, 0.93 p = 0.351). CMBs were significantly associated with Aβ pathology in AD patients. The pooled standardized mean difference (SMD) was -0.453, 95%CI -0.697– -0.208, z = 3.63 p = 0.000. There was no significant relationship between the incidence of lacunes and levels of CSFAβ, with a pooled β of 0.057 (95%CI -0.050–0.163, z = 1.05 p = 0.295). No significant relationship was found between CMBs and the levels of CSFt-tau/CSFp-tau in AD patients (-0.014, 95%CI -0.556–0.529, z = 0.05 p = 0.960; -0.058, 95%CI -0.630–0.515, z = 0.20 p = 0.844) and cortical CMBs and CSF p-tau in the normal population (0.000, 95%CI -0.706–0.706, z = 0.00 p = 0.999).ConclusionsSome CSVD markers were significantly associated with clinical AD pathology and may be associated with Aβ/tau pathology. WMHs and microinfarcts were associated with increased risk of AD. It remains unclear whether they precede or follow AD pathology.     

Blood fatty acids in Alzheimer’s disease and mild cognitive impairment: A meta-analysis and systematic review

Plasma fatty acids have been reported to be dysregulated in mild cognitive impairment (MCI) and Alzheimer’s disease (AD), though outcomes are not always consistent, and subject numbers often small. Our aim was to use a meta-analysis and systematic review approach to identify if plasma fatty acid dysregulation would be observed in case control studies of AD and MCI. Six databases were searched for studies reporting quantified levels of fatty acids in MCI and/or AD individuals, relative to cognitively normal controls. Docosahexaenoic (DHA) and vaccenic acids were significantly lower and higher respectively in MCI relative to controls. Total fatty acids were 27.2% lower in AD relative to controls, and this was reflected almost uniformly in all specific fatty acids in AD. Changes to plasma/serum fatty acids were identified in both MCI and AD relative to age and gender matched controls. Differences were greatest in AD, in both total number of fatty acids significantly altered, and the degree of change. Docosahexaenoic acid was lower in both MCI and AD, suggesting that it may be a driver of pathology.     

Cerebral blood flow in mild cognitive impairment and Alzheimer’s disease: A systematic review and meta-analysis

BackgroundReduced cerebral blood flow (CBF) contributes to the pathophysiology of Alzheimer’s disease (AD). However, it is unclear whether there is a spatial-temporal-specific pattern of changed CBF in AD progression.MethodsWe systematically screened literature databases for cross-sectional and longitudinal studies reporting resting CBF or CBF velocity (CBFv) among patients with AD, mild cognitive impairment (MCI), and healthy controls (HCs). Standardised mean differences (SMDs) for CBF and mean differences (MDs) for CBFv were calculated. Quality assessments, meta-analysis, subgroup analysis, and meta-regression were subsequently performed (PROSPERO: CRD42020207548).ResultsOverall, 244 studies comprising 13,644 participants and 60 regions were included. Compared with HCs, AD subjects had decreased resting CBF throughout the brain (SMD range: -1.87 to -0.32), especially within the posterior cingulate and temporal-parietal regions. However, MCI subjects presented decreased CBF in ten regions with modest effects (SMD range: -0.86 to -0.25), especially in the precuneus. We identified the decreased CBF in the temporal, parietal, and hippocampal regions was associated with the lower AD Mini-Mental State Examination scores.ConclusionsOur findings suggest that the spatial-temporal pattern of CBF decreased from the precuneus, posterior cingulate and temporal-parietal regions to broader areas with progression from HC to MCI to AD, supporting the incorporation of CBF into the AD research framework.     

Exercise interventions in Alzheimer’s disease: A systematic review and meta-analysis of randomized controlled trials

AimsTo assess the potential multi-domain benefits of exercise interventions on patients with Alzheimer’s disease (AD), as well as to determine the specific effects of different exercise modalities (aerobic, strength, or combined training).MethodsA systematic search was conducted in PubMed and Web of Science until March 2021 for randomized controlled trials assessing the effect of exercise interventions (compared with no exercise) on patients with AD. Outcomes included cognitive function (mini-mental state examination [MMSE] test), physical function (e.g., 6-minute walking test [6MWT]), functional independence (Barthel index), and neuropsychiatric symptoms (Neuropsychiatric Inventory [NPI]). A random-effects meta-analysis was conducted.Results28 studies (total n = 1337 participants, average age 79–90 years) were included in the systematic review, of which 21 could be meta-analyzed. Although considerable heterogeneity was found, exercise interventions induced several significant benefits, including in Barthel index (n = 147 patients, mean difference [MD]=8.36 points, 95% confidence interval [CI]=0.63–16.09), 6MWT (n = 369, MD=84 m, 95% CI=44–133)), and NPI (n = 263, MD=−4.4 points, 95% CI=−8.42 to −0.38). Benefits were also found in the MMSE test, albeit significance was only reached for aerobic exercise (n = 187, MD=2.31 points, 95% CI 0.45–4.27).ConclusionsExercise interventions appear to exert multi-domain benefits in patients with AD.     

Neuropsychological profile of Alzheimer’s disease in women: moderate and moderately severe cognitive decline

Summary Introduction: Alzheimers disease (AD) is characterised by progressive cognitive and functional decline. There is evidence that AD is more prevalent in women. This study aims at identifying the clinical and sociodemographic variables associated with the cognitive functions and the pattern of decline in women with moderate to moderately severe AD.Methods: Cross-sectional observational study of 165 women with dementia of the AD type according to NINCDS-ADRDA criteria. The cognitive functions were assessed using the Cambridge Cognitive Examination (CAMCOG). The sociodemographic and clinical data were collected from the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX) interview, and the Neuropsychiatric Inventory (NPI) was administrated to the caregiver.Results: The number of years of schooling and the score on the CAMDEX depression scale were the variables associated with the CAMCOG score. The effect of these variables was not homogenous for all the CAMCOG subtests.Conclusions: The number of years of schooling and the presence of depressive symptomatology influence the results of the neuropsychological exploration, but the effect is moderate and not homogenous for all the CAMCOG subtests. The differences in cognitive profile between moderate and moderately severe are characterised by a greater effect on temporal orientation, calculation and perception.     

Cortisol hypersecretion and the risk of Alzheimer’s disease: A systematic review and meta-analysis

BackgroundMorning cortisol levels have been reported to be elevated among patients with Alzheimer’s disease (AD); yet no meta-analysis has been conducted to confirm the existence and magnitude of this association. It also remains unclear whether hypercortisolism is a risk factor for AD.MethodsPubMed, EMBASE, and PsycINFO were systematically searched for eligible studies. Cross-sectional data were pooled using random-effects meta-analyses; the differences in morning cortisol levels between patients and cognitively normal controls were quantified. Longitudinal studies were qualitatively synthesised due to methodological heterogeneity.Results17,245 participants from 57 cross-sectional studies and 19 prospective cohort studies were included. Compared with cognitively normal controls, AD patients had moderately increased morning cortisol in blood (g = 0.422, P < 0.001; I² = 48.5 %), saliva (g = 0.540, P < 0.001; I² = 13.6 %), and cerebrospinal fluids (g = 0.565, P = 0.003; I² = 75.3 %). A moderate elevation of morning cortisol was also detected in cerebrospinal fluids from patients with mild cognitive impairment (MCI) versus controls (g = 0.309, P = 0.001; I² = 0.0 %). Cohort studies suggested that higher morning cortisol may accelerate cognitive decline in MCI or mild AD patients, but the results in cognitively healthy adults were inconsistent.ConclusionsMorning cortisol was confirmed to be moderately elevated in AD patients and may have diagnostic and prognostic values for AD.     

Neuroinflammation in mild cognitive impairment and Alzheimer’s disease: A meta-analysis

BackgroundIncreasingly, evidence from brain imaging supports the role of neuroinflammation in dementia progression. Yet, it is not clear if there are patterns of spatial and temporal susceptibility to neuroinflammatory processes in the brain that may correspond to dementia staging or symptom expression.MethodsWe searched literature databases for case-control studies examining levels of translocator protein (TSPO) levels using positron emission tomography, representing neuroinflammation, in regional analyses between healthy controls and mild cognitive impairment (MCI) or Alzheimer’s disease (AD) subjects. Standardised mean differences (SMDs) were calculated and results meta-analysed using random-effects models. Quality assessments, sensitivity analysis, subgroup analysis and meta-regressions were also performed.ResultsTwenty-eight studies comprising 755 (HC = 318, MCI = 168, AD = 269) participants and 37 brain regions were included. Compared to HCs, AD participants had increased TSPO levels throughout the brain (SMD range: 0.43–1.76), especially within fronto-temporal regions. MCI subjects also had increased TSPO levels, mainly within the neocortex, with more modest effects (SMD range: 0.46 - 0.90). Meta-regression analysis identified an inverse association between TSPO levels in the parietal region and Mini-Mental State Examination scores, a proxy for disease severity, in AD subjects (estimate: -0.11, 95% confidence interval: −0.21 to −0.02; P = 0.024).ConclusionsOur findings support the association of increased neuroinflammation during the progression of MCI and AD, relative to HCs.     

Subjective cognitive decline in idiopathic Parkinson´s disease: A systematic review

Cognitive symptoms of Parkinson’s disease (PD) have been long underestimated, but are some of the most disabling non-motor features of the disease. In order to establish signs that allow for earlier detection of cognitive decline in PD, the concept of `subjective cognitive decline´ (SCD) has gained a growing interest. SCD refers to patients who report a decline in subjective cognitive capacities, while their results on neuropsychological tests are within the normal performance range, indicating adequate cognitive functions. The aim of this review was to evaluate the concept of SCD in PD and give an overview of the current research. A systematic literature search in PubMed was performed to identify articles published before December 2020. We included 18 studies with a total of n = 2,654 patients. While there is currently no consensus on research or clinical criteria for SCD in PD, this review presents the accumulated evidence for SCD in PD patients and supports the importance of early identification of cognitive deficits, due to the relatively high prevalence for SCD in PD and the added risk of future cognitive impairment it entails. The publications included in this review indicate that SCD may be part of the PD spectrum but further research is needed. Expanding research on SCD in PD will allow for earlier detection of cognitive impairment and may foster preventive interventions.     

The neurochemistry of agitation in Alzheimer’s disease: a systematic review

ObjectiveTo provide an up-to-date systematic review of the characteristics, methodology and findings of studies that have investigated the neurochemistry of agitation in Alzheimer’s disease (AD).MethodsElectronic databases were searched for published peer-reviewed articles which provided data on any neurotransmitter system in relation to agitation in AD. Screening of titles and abstracts and data extraction from full texts were conducted in duplicate.ResultsForty-five studies were included. Monoamines (serotonin, dopamine and noradrenaline) were most commonly investigated. A variety of methods were used to investigate the neurochemistry underlying agitation in AD and, although there were several conflicting findings, there was evidence of serotonergic deficit, relatively preserved dopaminergic function and compensatory overactivity of postsynaptic noradrenergic neurons in agitation in AD.ConclusionsDisruption of the dynamic balance between multiple neurotransmitter systems could impair functional neural networks involved in affective regulation and executive function. Differences in study design and methodology may have contributed to conflicting findings. Future studies that overcome these limitations (e.g. using standardized criteria to define agitation) and employ neuroimaging methods such as MRI/PET to investigate specific neural networks are needed to clarify the role of neurotransmitter alterations in these patients.     

Anthocyanin as a therapeutic in Alzheimer’s disease: A systematic review of preclinical evidences

BackgroundThe aim of this systematic review is to ponder the possible mechanism of action of anthocyanin in Alzheimer’s disease (AD), to prompt the development of anthocyanin-based dietary supplementation or therapeutic intervention for AD and to explore the natural sources of anthocyanins.MethodsElectronic bibliographic databases such as PubMed, ScienceDirect, Proquest, DOAJ, Scopus, and Google Scholar were searched for preclinical studies probing the efficacy of anthocyanin on AD. The search strategy included no time limit, but was restricted to English. The review protocol is registered on PROSPERO, registration no. CRD42021272972. The systematic review followed the PICO approach for inclusion of reports. All the reports were appraised for risk of bias using the SYRCLE's RoB tool.ResultsBibliographic details of the article, animal strain/weight/age, induction model, anthocyanin source, type of anthocyanin, dose, route of administration, duration, and the outcome measures were extracted from 12 retrieved reports explicitly. The implication of food-based anthocyanin in acute and long-term cognition and Aβ mediated neurodegeneration appears alluring. Majority of the studies comprehended in this review had moderate methodological quality.DiscussionEfficacy of anthocyanin in alleviating oxidative stress, reactive astrogliosis, cholinergic dysfunction, apoptosis, synaptotoxicity, neuroinflammation, tau hyperphosphorylation, dysregulated membrane potential, neuronal extracellular calcium, dysfunctional amyloidogenic pathway, and cognitive deficits in various rodent models of AD is manifested compositely in 12 studies.