Platelet phospholipase A<Subscript>2</Subscript> activity in Alzheimer’s disease and mild cognitive impairment

Summary. Phospholipase A₂ (PLA₂) controls the metabolism of phospholipids in cell membranes. In the brain, PLA₂ influences the processing of the amyloid precursor protein (APP) and thus the production of the amyloid-beta peptides (A), which are the major components of the senile plaques in Alzheimers disease (AD). Reduced PLA₂ activity has been reported in brain and in platelets of AD patients. In the present study we investigated PLA₂ activity in platelets from 21 AD patients as compared to 17 healthy elderly controls and 11 individuals with mild cognitive impairment (MCI). Subjects were cognitively assessed by the Mini-Mental State Examination (MMSE) and the CAMDEX schedule. Platelet PLA₂ activity was determined by radio-enzymatic assay, which mainly detected a calcium-independent form of the enzyme present also in the brain (iPLA₂). PLA₂ activity was significantly lower in AD than in controls (p<0.001). Mean PLA₂ activity in MCI individuals was between the values of AD patients and controls, with a subgroup showing PLA as low as the lowest AD patients, but the differences from MCI were not significant from AD and control groups. Lower PLA₂ activity was significantly correlated with a worse cognitive performance both at the MMSE (p=0.001) and the cognitive sub-scale of the CAMDEX inventory (p=0.002). Our data replicate previous findings of reduced platelet PLA₂ activity in AD. Both reduced PLA₂ activity and the correlation with impaired cognition were also reported in brain tissue of AD patients, suggesting thus that the present determinations in platelets may be related to a reduction in the brain. In the brain the inhibition of PLA₂ inhibits the physiological secretion of the APP, a mechanism that increases A formation. Further longitudinal studies should investigate whether those MCI individuals with the lowest PLA₂ values in platelets would be at a higher risk to develop AD during a longitudinal follow up.     

The genetics and neuropathology of Alzheimer’s disease

Here we review the genetic causes and risks for Alzheimer’s disease (AD). Early work identified mutations in three genes that cause AD: APP, PSEN1 and PSEN2. Although mutations in these genes are rare causes of AD, their discovery had a major impact on our understanding of molecular mechanisms of AD. Early work also revealed the ε4 allele of the APOE as a strong risk factor for AD. Subsequently, SORL1 also was identified as an AD risk gene. More recently, advances in our knowledge of the human genome, made possible by technological advances and methods to analyze genomic data, permit systematic identification of genes that contribute to AD risk. This work, so far accomplished through single nucleotide polymorphism arrays, has revealed nine new genes implicated in AD risk (ABCA7, BIN1, CD33, CD2AP, CLU, CR1, EPHA1, MS4A4E/MS4A6A, and PICALM). We review the relationship between these mutations and genetic variants and the neuropathologic features of AD and related disorders. Together, these discoveries point toward a new era in neurodegenerative disease research that impacts not only AD but also related illnesses that produce cognitive and behavioral deficits.     

Platelet phospholipase A<Subscript>2</Subscript> activity in patients with Alzheimer’s disease,vascular dementia and ischemic stroke

Summary Phospholipase A₂ (E.C. 3.1.1.4, PLA₂) plays an essential role in metabolism of membrane phospholipids, it is related to inflammatory reactions, secretion of amyloid precursor protein and activation of NMDA receptor after ischemia. In the present study we investigated PLA₂ activity in platelets from 37 Alzheimer’s disease (AD) patients, 32 vascular dementia (VaD) patients and 32 individuals with ischemic stroke as compared to 27 healthy elderly controls. PLA₂ activity was determined using radiometric assay. Mean platelet PLA₂ activity was increased in individuals with Alzheimer’s disease (p < 0.001). In VaD group the enzyme activity was between the values in AD and controls, these differences being significant from both groups. In the group of patients with ischemic stroke mean PLA₂ activity was higher either 48 h after the stroke or 7 days later (in both cases p < 0.001). The results may be particularly interesting in light of the fact, that inhibitors of PLA₂ activity are known.     

Variations in the neuropathology of familial Alzheimer’s disease

Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes cause autosomal dominant familial Alzheimer’s disease (AD). PSEN1 and PSEN2 are essential components of the γ-secretase complex, which cleaves APP to affect Aβ processing. Disruptions in Aβ processing have been hypothesised to be the major cause of AD (the amyloid cascade hypothesis). These genetic cases exhibit all the classic hallmark pathologies of AD including neuritic plaques, neurofibrillary tangles (NFT), tissue atrophy, neuronal loss and inflammation, often in significantly enhanced quantities. In particular, these cases have average greater hippocampal atrophy and NFT, more significant cortical Aβ42 plaque deposition and more substantial inflammation. Enhanced cerebral Aβ40 angiopathy is a feature of many cases, but particularly those with APP mutations where it can be the dominant pathology. Additional frontotemporal neuronal loss in association with increased tau pathology appears unique to PSEN mutations, with mutations in exons 8 and 9 having enlarged cotton wool plaques throughout their cortex. The mechanisms driving these pathological differences in AD are discussed.     

GAB2 is not associated with late-onset Alzheimer’s disease in Chinese Han

It has recently been shown that GAB2 alleles modify the risk for late-onset Alzheimer disease (LOAD) in apolipoprotein E (ApoE)ε4 allele carriers in a genome-wide association study. Some studies subsequently in Caucasians population, though not all, have demonstrated that GAB2 polymorphisms might be associated with LOAD susceptibility. The aim of this study is to evaluate the reported polymorphisms (rs2373115 and rs1385600) and GAB2 haplotypes (rs2373115–rs1385600) for an interaction with the ApoEε4 allele in a cohort of Chinese LOAD. We conducted a case–control study in 292 LOAD and 227 non-demented controls from the Chinese Han population. Our study does not find any association between the two tested SNPs and GAB2 haplotypes and LOAD or any synergetic interaction between the SNPs and ApoE either. However, since the sample size required to show this point is large, our finding needs to be confirmed by a large independent sample of Chinese population.     

Increased skin temperature in Alzheimer’s disease is associated with sleepiness

The 24-h rhythms in sleep and temperature both change in Alzheimer's disease (AD). Characteristic changes consist of a more fragmented diurnal sleep profile with frequent nocturnal awakenings and daytime sleepiness, as well as a reduction in the amplitude of the 24-h rhythm in core body temperature (CBT). Although the 24-h rhythm in CBT is to a large extent the result of a 24-h rhythm in heat loss from the skin caused by pronounced changes in skin blood flow and consequently skin temperature (Ts), changes in the diurnal skin temperature profile in AD as compared to normal aging have remained unexplored. Because recent work indicates a causal contribution of fluctuations in skin temperature to daytime sleepiness and nocturnal sleep depth, the present study aimed to investigate the skin temperature rhythm in AD and its association with daytime sleepiness and nocturnal sleep. Ambulatory recorders were used to estimate sleep and 24-h rhythms in skin temperature in 55 AD patients and 26 matched non-demented elderly controls. Subjective sleep and daytime sleepiness were obtained using questionnaires. The results indicate that AD patients had a significantly higher daytime proximal skin temperature (PST) than elderly controls. In both AD patients and elderly controls, an elevated daytime PST was associated with more daytime sleepiness. The findings suggest a deficient downregulation of daytime proximal skin blood flow that might contribute to daytime sleepiness. Because daytime sleepiness contributes to cognitive dysfunction in AD, further research into the underlying mechanisms and possible reversibility is warranted.     

Serum α<Subscript>1</Subscript>-antitrypsin level and phenotype associated with familial moyamoya disease

Background Obstructive vascular lesions at the terminal portion of the internal carotid arteries are thought to be the primary and essential lesions in moyamoya disease. The etiology remains unknown. To detect possible mediators of the thickened intima of moyamoya disease, we measured serum alpha-1-antitrypsin (1-AT) levels and characterized the phenotype of patients with familial moyamoya disease.Patients and methods Fifty-six individuals were examined, including 29 patients with moyamoya disease from 14 families. Serum 1-AT levels were analyzed by electroimmunoassay and genomic phenotype by isoelectric focusing.Results All individuals had a normal 1-AT phenotype. The average serum 1-AT level in moyamoya disease patients was significantly higher than that of normal individuals, although both were within the normal range.Conclusions These findings suggest that serum 1-AT level may be a marker, rather than an etiologic factor, indicating the progression of moyamoya disease.     

T1rho (T<Subscript>1ρ</Subscript>) MR imaging in Alzheimer’ disease and Parkinson’s disease with and without dementia

In the current study, we aim to measure T1rho (T _1ρ) in the hippocampus in the brain of control, Alzheimer’s disease (AD), Parkinson’s disease (PD), and PD patients with dementia (PDD), and to determine efficacy of T _1ρ in differentiating these cohorts. With informed consent, 53 AD patients, 62 PD patients, 11 PDD patients, and 46 age-matched controls underwent a standardized clinical assessment including mini-mental state examination (MMSE) and brain T _1ρ MRI on a 1.5-T clinical-scanner. T_1ρ maps were generated by fitting each pixel’s intensity as a function of the spin-lock pulse duration. In control, AD, PD and PDD, mean ± SE T _1ρ values in the right hippocampus (RH) were 92.15 ± 2.00, 99.65 ± 1.98, 85.68 ± 1.87, 102.47 ± 4.66 ms while in the left hippocampus (LH) these values were 90.16 ± 1.82, 99.53 ± 1.91, 84.33 ± 2.03, 95.33 ± 4.64 ms. Significant difference for both RH and LH T _1ρ across the groups (p < 0.001) was observed. Both RH and LH T _1ρ were significantly increased in AD compared to control (p = 0.034, p = 0.001) and PD (p < 0.001, p < 0.001). In control, both RH and LH T _1ρ values were significantly increased compared to PD (p = 0.031, p = 0.027) while compared to PDD only the RH T _1ρ value was significantly decreased (p = 0.043). Both RH and LH T _1ρ values in PD were significantly lower than PDD (p = 0.004, p = 0.032). No significant correlation between the T _1ρ and age as well as between T _1ρ and MMSE scores was observed. The serial measurement of T_1ρ in both AD and PD may provide the nature of disease progression and may contribute to their early diagnosis.     

Absence of brain-derived neurotrophic factor and trkB receptor immunoreactivity in glia of Alzheimer’s disease

Alterations in the neuronal expression of some neurotrophins have been shown in various neurodegenerative processes, particularly Alzheimer’s disease (AD). Glia may up-regulate neurotrophins and their high-affinity tyrosine kinase (trk) receptors in response to neural injury. In human immunodeficiency virus type 1 (HIV-1) encephalitis, activated microglia were shown to express brain-derived neurotrophic factor (BDNF), while reactive astrocytes expressed trkB receptor. This observation has suggested the existence of local neurotrophic regulation between different glial populations. To characterize the glial cellular distribution of BDNF and trkB receptor proteins in AD, we studied selected regions of postmortem brains from four AD and three age-matched control patients by double-immunofluorescence confocal microscopy. In both groups, BDNF immunoreactivity was distributed in neuronal perikarya and neuritic processes in the neocortex and hippocampus. No BDNF immunoreactivity was observed in microglia or astrocytes within and between senile plaques of AD. Catalytic trkB receptor immunoreactivity was present in neuronal perikarya in the neocortex and hippocampus. Reactive astrocytes and microglia were not immunoreactive for catalytic trkB. The absence of BDNF and trkB proteins in glia in AD patients is in contrast to the finding in patients with HIV-1 encephalitis. This difference suggests that glial expression of BDNF and trkB proteins may be characteristic of particular disease processes, rather than merely representing a stereotyped response to any type of neural injury. Received: 13 July 1998 / Revised, accepted: 25 February 1999     

Parkinson’s disease is not associated with gastrointestinal myenteric ganglion neuron loss

Gastrointestinal dysfunction is a prominent non-motor feature of Parkinson’s disease (PD) that contributes directly to the morbidity of patients, complicates management of motor symptoms, and may herald incipient PD in patients without motor disability. Although PD has traditionally been considered a disease of dopaminergic neurons in the substantia nigra, analyses of gastrointestinal samples from PD patients have consistently revealed pathology in the enteric nervous system. The relationship of PD pathology to GI dysmotility is poorly understood, and this lack of understanding has led to limited success in developing treatments for PD-related GI symptoms. We have quantitatively compared myenteric neuron density and relative abundance of NO, VIP, and catecholamine neurons between patients with PD and control individuals along the length of the GI tract. In addition, we have examined the frequency of GI α-synuclein neuritic pathology and its co-localization with the same neuronal markers. We have included a comparison with a small population of patients with incidental Lewy bodies found at autopsy. These data indicate that there is no neuronal loss in the myenteric plexus in PD. Lewy body pathology parallels parasympathetic autonomic input from the dorsal motor nucleus of the vagus, not the distribution of extrinsic sympathetic input or intrinsic enteric neurons, and is only rarely co-localized with tyrosine hydroxylase. These data provide a critical background to which further analyses of the effect of PD on the GI tract may be compared and suggest that neuropathology in myenteric neurons is unlikely to be a causative factor in PD-related GI dysmotility.     

The role of phospholipase A<Subscript>2</Subscript> in neuronal homeostasis and memory formation: implications for the pathogenesis of Alzheimer’s disease

Summary. Phospholipase A₂ (PLA₂) is a key enzyme in cerebral phospholipid metabolism. Preliminary post-mortem studies have shown that PLA₂ activity is decreased in frontal and parietal areas of the AD brain, which is in accordance with recent ³¹P-Magnetic Resonance Spectroscopy evidence of reduced phospholipid turnover in the pre-frontal cortex of moderately demented AD patients. Such abnormality may also be observed in peripheral cells, and reduced PLA₂ activity in platelet membranes of AD patients, and correlates with the severity of dementia. In rat hippocampal slices, PLA₂ has been implicated in mechanisms of synaptic plasticity. In adult rats, the stereotaxic injection of PLA₂ inhibitors in the CA1 area of hippocampus impaired, in a dose-dependent manner, the formation of short- and long-term memory. Additionally, such inhibition resulted in a reduction of the fluidity of hippocampal membranes. In primary cultures of cortical and hippocampal neurons, the inhibition of PLA₂ precluded neurite outgrowth, and the sustained inhibition of the enzyme in mature cultures lead to loss of viability. Taken together, these findings reinforce the involvement of PLA₂ enzymes in neurodevelopment and neurodegeneration processes, and further suggest that reduced PLA₂ activity, probably reducing membrane phospholipids breakdown, may contribute to the memory impairment in AD.     

A novel ARC gene polymorphism is associated with reduced risk of Alzheimer’s disease

Alzheimer's disease (AD) is the most common neurodegenerative disease, and is clinically characterized by cognitive disturbances and the accumulation of the amyloid β (Aβ) peptides in plaques in the brain. Recent studies have shown the links between AD and the immediate-early gene Arc (activity-regulated cytoskeleton-associated protein), involved in synaptic plasticity and memory consolidation. For example, AD mouse models show a decreased expression of Arc mRNA in the brain. In additional, acute Aβ application to brain slices leads to a widespread ARC protein diffusion, unlike the normal defined localization to synapses. In this study, we investigated genetic variation in human ARC and the risk of developing AD. To this end, we genotyped 713 subjects diagnosed with AD and 841 controls without dementia. ARC was sequenced in a group of healthy individuals, and seven previously known SNPs and three novel SNPs were identified. Two of the newly found SNPs were intronic and one, +2852(G/A), was located in the 3'UTR. Three tag SNPs were selected, including the novel SNP +2852(G/A), to relate to risk of AD, Mini Mental State Examination (MMSE) scores and cerebrospinal fluid (CSF) biomarker levels of total tau (T-tau), hyperphosphorylated tau181 (P-tau(181)) and Aβ(1-42). The AA genotype of the newly found 3'-UTR SNP +2852(A/G), was associated with a decreased risk of AD (p (c)?=?0.005; OR?=?0.74; 95?% CI: 0.61-0.89). No associations of single SNPs or haplotypes with MMSE score or CSF biomarkers were found. Here we report a novel ARC SNP associated with a reduced risk of developing AD. To our knowledge, this is the first study associating a gene variant of ARC with any disease. The location of the SNP within the 3'UTR indicates that dendritic targeting of ARC mRNA could be involved in the molecular mechanisms underlying this protective function. However, further investigation of the importance of this SNP for ARC function, ARC processing and the pathology of AD is needed.     

CR1 is potentially associated with rate of decline in sporadic Alzheimer’s disease

The objective of this study was to investigate potential associations of Alzheimer’s disease risk single nucleotide polymorphisms (SNP) with disease progression. SNP in ACE, ApoE, BIN1, CLU, CR1, CST3, EXOC3L2, GWA14q32.13, IL8, LDLR, PICALM, and TNK1 were determined in 40 Alzheimer’s disease patients who were observed for 2 to 3 years. Annual Mini Mental State Examination (MMSE) loss was used as the outcome parameter in multiple regression analyses. Regarding a CR1 SNP (rs3818361) G-allele carriers featured faster declines (approximately 3 MMSE points per year). To summarize, in addition to being a risk factor for Alzheimer’s disease development, a CR1 SNP appears to be associated with higher rates of medium-term disease progression. Therefore, it may serve as a prognostic marker (among others) and may aid in differentiating slow from fast progressors early in the disease course.     

Pyroglutamylated amyloid-β is associated with hyperphosphorylated tau and severity of Alzheimer’s disease

Pyroglutamylated amyloid-β (pE(3)-Aβ) has been suggested to play a major role in Alzheimer’s disease (AD) pathogenesis as amyloid-β (Aβ) oligomers containing pE(3)-Aβ might initiate tau-dependent cytotoxicity. We aimed to further elucidate the associations among pE(3)-Aβ, full-length Aβ and hyperphosphorylated tau (HP-τ) in human brain tissue. We examined 41 post mortem brains of both AD (n = 18) and controls. Sections from frontal and entorhinal cortices were stained with pE(3)-Aβ, HP-τ and full-length Aβ antibodies. The respective loads were assessed using image analysis and western blot analysis was performed in a subset of cases. All loads were significantly higher in AD, but when using Aβ loads as independent variables only frontal pE(3)-Aβ load predicted AD. In frontal and entorhinal cortices pE(3)-Aβ load independently predicted HP-τ load while non-pE(3)-Aβ failed to do so. All loads correlated with the severity of AD neuropathology. However, partial correlation analysis revealed respective correlations in the frontal cortex only for pE(3)-Aβ load only while in the entorhinal cortex respective correlations were seen for both HP-τ and non-pE(3)-Aβ loads. Mini Mental State Examination scores were independently predicted by entorhinal HP-τ load and by frontal pE(3)-Aβ load. Here, we report an association between pE(3)-Aβ and HP-τ in human brain tissue and an influence of frontal pE(3)-Aβ on both the severity of AD neuropathology and clinical dementia. Our findings further support the notion that pE(3)-Aβ may represent an important link between Aβ and HP-τ, and investigations into its role as diagnostic and therapeutic target in AD are warranted.     

Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer’s disease and tauopathies

Neuronal insulin signaling abnormalities have been associated with Alzheimer’s disease (AD). However, the specificity of this association and its underlying mechanisms have been unclear. This study investigated the expression of abnormal serine phosphorylation of insulin receptor substrate 1 (IRS1) in 157 human brain autopsy cases that included AD, tauopathies, α-synucleinopathies, TDP-43 proteinopathies, and normal aging. IRS1-pS⁶¹⁶, IRS1-pS³¹² and downstream target Akt-pS⁴⁷³ measures were most elevated in AD but were also significantly increased in the tauopathies: Pick’s disease, corticobasal degeneration and progressive supranuclear palsy. Double immunofluorescence labeling showed frequent co-expression of IRS1-pS⁶¹⁶ with pathologic tau in neurons and dystrophic neurites. To further investigate an association between tau and abnormal serine phosphorylation of IRS1, we examined the presence of abnormal IRS1-pS⁶¹⁶ expression in pathological tau-expressing transgenic mice and demonstrated that abnormal IRS1-pS⁶¹⁶ frequently co-localizes in tangle-bearing neurons. Conversely, we observed increased levels of hyperphosphorylated tau in the high-fat diet-fed mouse, a model of insulin resistance. These results provide confirmation and specificity that abnormal phosphorylation of IRS1 is a pathological feature of AD and other tauopathies, and provide support for an association between insulin resistance and abnormal tau as well as amyloid-β.     

Increased Cerebrospinal Fluid F<Subscript>2</Subscript>-Isoprostanes are Associated with Aging and Latent Alzheimer’s Disease as Identified by Biomarkers

Alzheimer’s disease (AD) is a common age-related chronic illness with latent, prodrome, and fully symptomatic dementia stages. Increased free radical injury to regions of brain is one feature of prodrome and dementia stages of AD; however, it also is associated with advancing age. This raises the possibility that age-related free radical injury to brain might be caused in part or in full by latent AD. We quantified free radical injury in the central nervous system with cerebrospinal fluid (CSF) F₂-isoprostanes (IsoPs) in 421 clinically normal individuals and observed a significant increase over the adult human lifespan (P < 0.001). Using CSF amyloid (A) β₄₂ and tau, we defined normality using results from 28 clinically normal individuals <50 years old, and then stratified 74 clinically normal subjects ≥60 years into those with CSF that had normal CSF Aβ₄₂ and tau (n = 37); abnormal CSF Aβ₄₂ and tau, the biomarker signature of AD (n = 24); decreased Aβ₄₂ only (n = 4); or increased tau only (n = 9). Increased CSF F₂-IsoPs were present in clinically normal subjects with the biomarker signature of AD (P < 0.05) and those subjects with increased CSF tau (P < 0.001). Finally, we analyzed the relationship between age and CSF F₂-IsoPs for those clinically normal adults with normal CSF (n = 37) and those with abnormal CSF Aβ₄₂ and/or tau (n = 37); only those with normal CSF demonstrated a significant increase with age (P < 0.01). These results show that CSF F₂-IsoPs increased across the human lifespan and that this age-related increase in free radical injury to brain persisted after culling those with laboratory evidence of latent AD.     

IRF-8 is Involved in Amyloid-β<Subscript>1–40</Subscript> (Aβ<Subscript>1–40</Subscript>)-induced Microglial Activation: a New Implication in Alzheimer’s Disease

Using microarray analysis, we detected microRNA-124 (miR-124) to be abundantly expressed in the olfactory bulb (OB). miR-124 regulates adult neurogenesis in the subventricular zone (SVZ). However, much less is known about its role in newborn OB neurons. Here, using both gain-of-function and loss-of-function approaches, we demonstrate that brain-specific miR-124 affects dendritic morphogenesis and spine density in newborn OB neurons. Functional Annotation Clustering of miR-124 targets was enriched in “cell morphogenesis involved in neuron differentiation.”     

Periodic Variation of AAK1 in an Aβ<Subscript>1–42</Subscript>-Induced Mouse Model of Alzheimer’s Disease

Inhibition of endocytosis in an Alzheimer’s disease (AD) model has been shown to be able to prevent amyloid β (Aβ)-induced damage and to exert a beneficial effect in treating AD. Adaptor-associated kinase 1 (AAK1), which binds to the adaptor protein complex 2 (AP-2), regulates the process of clathrin-mediated endocytosis. However, how AAK1 expression varies over the course of AD is unknown. In this study, we investigated AAK1 levels in AD model mice over time. Aβ_1–42 was used to establish a mouse AD model, and the Morris water maze test was used to characterize the time course of Aβ_1–42-induced cognition changes. ELISA was used to determine AAK1 levels in plasma and Aβ_1–42 levels in brain tissues. Subsequently, the protein or gene levels of AAK1, AP-2, and Rab5 (an early endosome marker) were tested in each group. The cognitive function of Aβ_1–42-induced mice was significantly declined compared to control group, and the deficits reached a peak on day 14, but partly recovered on day 30. Moreover, the level of Aβ_1–42 detected with ELISA was highest on day 14, but reduced on day 30, paralleling the cognitive changes in the mice in our study. AAK1, AP-2, and Rab5 expression showed the same periodic variation as the changes in cognition. Thus, periodic variation in AAK1 expression is closely correlated to the decline in cognition, and AAK1 might be a suitable indicator for Alzheimer’s disease.     

TDP-43 in Alzheimer’s disease is not associated with clinical FTLD or Parkinsonism

Widespread deposition of TAR DNA-binding protein of 43 kDa (TDP-43), a major protein inclusion commonly found in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) can also be seen in a subset of cases with Alzheimer’s disease (AD). Some of these AD cases have TDP-43 immunoreactivity in basal ganglia (BG) and substantia nigra (SN), regions that when affected can be associated with parkinsonian signs or symptoms, or even features suggestive of frontotemporal dementia. Here, we examined the presence of clinical features of FTLD, parkinsonian signs and symptoms, and BG atrophy on MRI, in 51 pathologically confirmed AD cases (Braak neurofibrillary tangle stage IV–VI) with widespread TDP-43 deposition, with and without BG and SN involvement. All 51 cases had presented with progressive cognitive impairment with prominent memory deficits. None of the patients demonstrated early behavioral disinhibition, apathy, loss of empathy, stereotyped behavior, hyperorality, and/or executive deficits. Furthermore, TDP-43 deposition in BG or SN had no significant association with tremor (p = 0.80), rigidity (p = 0.19), bradykinesia (p = 0.19), and gait/postural instability (p = 0.39). Volumes of the BG structures were not associated with TDP-43 deposition in the BG. The present study demonstrates that TDP-43 deposition in pathologically confirmed AD cases is not associated with a clinical manifestation suggestive of FTLD, or parkinsonian features.