Journal of Alzheimer's Disease - Volume 98, issue 2

Authors: Greenblatt, Charles L. | Lathe, Richard

Article Type: Review Article

Abstract: Vaccines such as Bacille Calmette–Guérin (BCG) can apparently defer dementia onset with an efficacy better than all drugs known to date, as initially reported by Gofrit et al. (PLoS One 14 , e0224433), now confirmed by other studies. Understanding how and why is of immense importance because it could represent a sea-change in how we manage patients with mild cognitive impairment through to dementia. Given that infection and/or inflammation are likely to contribute to the development of dementias such as Alzheimer’s disease (Part II of this work), we provide a historical and molecular background to how vaccines, adjuvants, and …their component molecules can elicit broad-spectrum protective effects against diverse agents. We review early studies in which poxvirus, herpes virus, and tuberculosis (TB) infections afford cross-protection against unrelated pathogens, a concept known as ‘trained immunity’. We then focus on the attenuated TB vaccine, BCG, that was introduced to protect against the causative agent of TB, Mycobacterium tuberculosis . We trace the development of BCG in the 1920 s through to the discovery, by Freund and McDermott in the 1940 s, that extracts of mycobacteria can themselves exert potent immunostimulating (adjuvant) activity; Freund’s complete adjuvant based on mycobacteria remains the most potent immunopotentiator reported to date. We then discuss whether the beneficial effects of BCG require long-term persistence of live bacteria, before focusing on the specific mycobacterial molecules, notably muramyl dipeptides, that mediate immunopotentiation, as well as the receptors involved. Part II addresses evidence that immunopotentiation by BCG and other vaccines can protect against dementia development. Show more

Keywords: Adjuvant, Alzheimer’s disease, Bacille Calmette–Guérin, Freund, immunopotentiation, muramyl dipeptide, mycobacteria, NOD2, trained immunity, vaccine, YB-1

DOI: 10.3233/JAD-231315

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 343-360, 2024

Authors: Greenblatt, Charles L. | Lathe, Richard

Article Type: Review Article

Abstract:  There is growing awareness that infections may contribute to the development of senile dementia including Alzheimer’s disease (AD), and that immunopotentiation is therefore a legitimate target in the management of diseases of the elderly including AD. In Part I of this work, we provided a historical and molecular background to how vaccines, adjuvants, and their component molecules can elicit broad-spectrum protective effects against diverse agents, culminating in the development of the tuberculosis vaccine strain Bacille Calmette–Guérin (BCG) as a treatment for some types of cancer as well as a prophylactic against infections of the elderly such as pneumonia. In Part …II, we critically review studies that BCG and other vaccines may offer a measure of protection against dementia development. Five studies to date have determined that intravesicular BCG administration, the standard of care for bladder cancer, is followed by a mean ∼45% reduction in subsequent AD development in these patients. Although this could potentially be ascribed to confounding factors, the finding that other routine vaccines such as against shingles (herpes zoster virus) and influenza (influenza A virus), among others, also offer a degree of protection against AD (mean 29% over multiple studies) underlines the plausibility that the protective effects are real. We highlight clinical trials that are planned or underway and discuss whether BCG could be replaced by key components of the mycobacterial cell wall such as muramyl dipeptide. We conclude that BCG and similar agents merit far wider consideration as prophylactic agents against dementia. Show more

Keywords: Alzheimer’s disease, Bacille Calmette–Guérin, dementia, herpes zoster, immunopotentiation, influenza, muramyl dipeptide, trained immunity, vaccine

DOI: 10.3233/JAD-231323

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 361-372, 2024

Authors: Zhang, Xiao-Xue | Wang, He-Ran | Meng-Wei, | Hu, Ya-Zhuo | Sun, Hong-Mei | Feng, Yu-Xin | Jia, Jian-Jun

Article Type: Systematic Review

Abstract: Background: Emerging evidence suggests the potential relationship between vitamin D deficiency and risk of cognitive impairment or dementia. To what extent the excess risk of dementia conferred by vitamin D deficiency is less clear. Objective: We summarized the current evidence from several aspects and further quantified these associations. Methods: We collected relevant prospective cohort studies by searching PubMed, Embase and Cochrane up to July 2023. The pooled relative risks (RR) were evaluated by random-effects models. Dose-response analyses were conducted by the method of two-stage generalized least squares regression. Results: Of 9,267 identified literatures, 23 …were eligible for inclusion in the meta-analyses, among which 9 and 4 literatures were included in the dose-response analyses for the risk of dementia and Alzheimer’s disease (AD). Vitamin D deficiency exhibited a 1.42 times risk for dementia (95% confidence interval (CI) = 1.21–1.65) and a 1.57-fold excess risk for AD (95% CI = 1.15–2.14). And vitamin D deficiency was associated with 34% elevated risk with cognitive impairment (95% CI = 1.19–1.52). Additionally, vitamin D was non-linearly related to the risk of dementia (pnonlinearity  = 0.0000) and AD (pnonlinearity  = 0.0042). The approximate 77.5–100 nmol/L 25-hydroxyvitamin D [25(OH)D ] was optimal for reducing dementia risk. And the AD risk seemed to be decreased when the 25(OH)D level >40.1 nmol/L. Conclusions: Vitamin D deficiency was a risk factor for dementia, AD, and cognitive impairment. The nonlinear relationships may further provide the optimum dose of 25(OH)D for dementia prevention. Show more

Keywords: Alzheimer’s disease, cognitive impairment, dementia, dose-response, meta-analysis, vitamin D

DOI: 10.3233/JAD-231381

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 373-385, 2024

Authors: Adams, Jose A. | Uryash, Arkady | Lopez, Jose R.

Article Type: Research Article

Abstract:  Alzheimer’s disease (AD) affects more than 40 million people worldwide and is the leading cause of dementia. This disease is a challenge for both patients and caregivers and puts a significant strain on the global healthcare system. To address this issue, the Lancet Commission recommends focusing on reducing modifiable lifestyle risk factors such as hypertension, diabetes, and physical inactivity. Passive pulsatile shear stress (PPSS) interventions, which use devices like whole-body periodic acceleration, periodic acceleration along the Z-axis (pGz), and the Jogging Device, have shown significant systemic and cellular effects in preclinical and clinical models which address these modifiable risks factors. …Based on this, we propose that PPSS could be a potential non-pharmacological and non-invasive preventive or therapeutic strategy for AD. We perform a comprehensive review of the biological basis based on all publications of PPSS using these devices and demonstrate their effects on the various aspects of AD. We draw from this comprehensive analysis to support our hypothesis. We then delve into the possible application of PPSS as an innovative intervention. We discuss how PPSS holds promise in ameliorating hypertension and diabetes while mitigating physical inactivity, potentially offering a holistic approach to AD prevention and management. Show more

Keywords: Alzheimer’s disease, pulsatile shear stress, exercise, whole body periodic acceleration, Passive Jogging, Gentle Jogger, endothelial nitric oxide

DOI: 10.3233/JAD-231010

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 387-401, 2024

Authors: Norton, Joanna | Gutierrez, Laure-Anne | Gourdeau, Christian | Amieva, Hélène | Bernier, Patrick | Berr, Claudine

Article Type: Short Communication

Abstract: The Cognitive Quotient (QuoCo) classification algorithm monitoring decline on age- and education-adjusted Mini-Mental State Examination (MMSE)-derived cognitive charts has proved superior to the conventionally-used cut-off for identifying incident dementia; however, it remains to be tested in different settings. Data were drawn from the Three-City Cohort to 1) assess the screening accuracy of the QuoCo, and 2) compare its performance to that of serial MMSE tests applying different cut-offs. For the QuoCo, sensitivity was 74.2 (95% CI: 71.4–76.8) and specificity 84.1 (83.6–84.7) and for the MMSE < 24, 64.1 (61.1–67.0) and 94.8 (94.4–95.1), respectively; whereas overall accuracy and sensitivity was highest for MMSE …cut-offs <25 and <26. User-friendly charts for mapping cognitive trajectories over visits with an alert for potentially ‘abnormal’ decline can be of practical use and encourage regular monitoring in primary care where the <24 cut-off is still widely used despite its poor sensitivity. Show more

Keywords: Age, Alzheimer’s disease, cognitive decline, dementia, early detection, education

DOI: 10.3233/JAD-231176

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 403-409, 2024

Authors: Orr, Miranda E.

Article Type: Article Commentary

Abstract: Cellular senescence contributes to Alzheimer’s disease (AD) pathogenesis. Treatments that remove senescent cells, senolytics, improve brain outcomes in AD mice with amyloid-β or tau deposition. 3xTgAD mice develop both AD neuropathologies; however, Ng et al. report low p16INK4a -associated senescence in the brain. Senolytic treatment by genetic removal; dasatinib with quercetin (D+Q), which enter the brain; and ABT-263 with limited brain penetrance all reduced AD neuropathology. Refined measures of senescence and brain exposure would help clarify the benefits of senolytics despite low p16INK4a -associated senescence and potential limited brain penetrance.

Keywords: Alzheimer’s disease, amyloid, blood-brain barrier, brain, cellular senescence, D+Q, geroscience, senolytics, tau, transgenic mice

DOI: 10.3233/JAD-231462

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 411-415, 2024

Authors: Ballenger, Jesse | George, Daniel R. | Whitehouse, Peter J.

Article Type: Article Commentary

Abstract: In response to Finch and Burstein’s provocative argument that the advanced dementias may result from environmental toxins and lifestyle factors associated with post-industrial societies, we call for a more rigorous historical approach, emphasizing the importance of situating ancient texts more fully in their historical and cultural context. Such an approach would also entail consideration of the declining relative rates of dementia in Western countries, which have been linked to population health-level factors and policies that appear to have reduced the risk of dementia by directly and indirectly influencing the social determinants of brain health.

Keywords: Alzheimer’s disease, dementia, environmental factors, history, public health

DOI: 10.3233/JAD-240051

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 417-419, 2024

Authors: O’Caoimh, Rónán

Article Type: Article Commentary

Abstract: The association between hypertension and mild cognitive impairment (MCI) is complex. Both are increasing in prevalence worldwide and will have disproportionate effects on lower income countries across Latin America. Despite this, there is insufficient evidence investigating this relationship in this region or those of Hispanic or Latino ancestry in higher income countries. In this context, the Study of Latinos-Investigation of Neurocognitive Aging represents a unique dataset. Although more research is required, Márquez and colleagues show that hypertension in this population in the United States is associated with decline in cognitive measures and greater odds of MCI over seven years follow-up.

Keywords: Alzheimer’s disease, epidemiology, hypertension, Hispanic, Latino, mild cognitive impairment, prevalence

DOI: 10.3233/JAD-231475

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 421-424, 2024

Authors: Michelutti, Marco | Urso, Daniele | Gnoni, Valentina | Giugno, Alessia | Zecca, Chiara | Vilella, Davide | Accadia, Maria | Barone, Roberta | Dell’Abate, Maria Teresa | De Blasi, Roberto | Manganotti, Paolo | Logroscino, Giancarlo

Article Type: Research Article

Abstract: Background: Behavioral variant frontotemporal dementia (bvFTD) typically involves subtle changes in personality that can delay a timely diagnosis. Objective: Here, we report the case of a patient diagnosed of GRN-positive bvFTD at the age of 52 presenting with a 7-year history of narcissistic personality disorder, accordingly to DSM-5 criteria. Methods: The patient was referred to neurological and neuropsychological examination. She underwent 3 Tesla magnetic resonance imaging (MRI) and genetic studies. Results: The neuropsychological examination revealed profound deficits in all cognitive domains and 3T brain MRI showed marked fronto-temporal atrophy. A mutation in the GRN …gene further confirmed the diagnosis. Conclusions: The present case documents an unusual onset of bvFTD and highlights the problematic nature of the differential diagnosis between prodromal psychiatric features of the disease and primary psychiatric disorders. Early recognition and diagnosis of bvFTD can lead to appropriate management and support for patients and their families. This case highlights the importance of considering neurodegenerative diseases, such as bvFTD, in the differential diagnosis of psychiatric disorders, especially when exacerbations of behavioral traits manifest in adults. Show more

Keywords: Alzheimer’s disease, GRN-related frontotemporal dementia, personality disorders, phenotype, psychiatric disorders

DOI: 10.3233/JAD-230779

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 425-432, 2024

Authors: Angevaare, Milou J. | Pieters, Jack A. | Twisk, Jos W.R. | van Hout, Hein P.J.

Article Type: Research Article

Abstract: Background: Cognitive decline is a major reason for dependence and resource use in long-term care. Objective: We explored whether social activities may prevent cognitive decline of older residents of long-term care facilities. Methods: In a routine care cohort, 3,603 residents of long-term care facilities were assessed on average 4.4 times using the interRAI-Long-Term-Care-Facilities instrument which includes frequency of participation in social activities of long standing interest over the last 30 days and the Cognitive Performance Scale. Linear mixed models repeated measures analyses were performed corrected for age, sex, physical activity, Activities of Daily Living, mood, and …health indicators. Results: Social activity was associated with cognitive preservation over time. This association was stronger in those with no or mild cognitive impairment at baseline, relative to those with moderate to severe impairment. Participation in specific social activities such as conversing and helping others showed a similar positive association. The relation between social activity and cognitive impairment appeared to be bi-directional. Conclusions: The protective effects of social activity offer a window of opportunity to preserve cognitive functioning in long-term care residents. Show more

Keywords: Activity of daily living, Alzheimer’s disease, cognition, cohort analyses, frail older adults, long term care

DOI: 10.3233/JAD-221053

Citation: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 433-443, 2024