30.10.2017, E.U. funded research consortium “LipiDiDiet” finds a way to impact Alzheimer’s Disease before it’s too late: data published in The Lancet Neurology

30 October 2017, Full results from the European LipiDiDiet clinical trial were published online today in The Lancet Neurology1. The trial showed that in people with prodromal Alzheimer’s (the pre-dementia stage of this disease), consumption of a once-daily medical nutrition drink, whilst not improving a specific neuropsychological test battery (NTB)*, did result in a significant stabilisation of everyday cognitive and functional performance, as well as reduced brain shrinkage. The drink contains “Fortasyn Connect”, a specific combination of essential fatty acids, vitamins and other nutrients**.

The pioneering clinical trial is part of a large European Union funded project and involved 311 patients across 11 sites in four countries (Finland, Germany, the Netherlands and Sweden). The trial involved patients with prodromal Alzheimer’s (often referred to as Mild Cognitive Impairment or MCI). Patients were randomised to receive either the nutritional intervention or an iso-caloric control drink for 24 months.

The study’s primary endpoint, impact on NTB, was not met. The decline in the NTB of the control group was less than anticipated rendering this analysis statistically underpowered. However, key secondary endpoints showed significant advantages for nutrient-treated patients with 45% less worsening in the Clinical Dementia Rating-Sum of Box (CDR-SB). This measure is especially important because it tracks the patient’s disease progression based on performance in managing everyday life, such as handling household emergencies, handling financial transactions or forgetting a major event. Furthermore, there was less brain atrophy in the active group, with 26% difference for the hippocampus and 16% for the ventricular volume. Progressive brain degeneration is typical for Alzheimer’s, with hippocampal damage being responsible for many of the associated memory deficits. Over the 24-month period the incidence of any adverse events were similar between the active and control groups.

Professor Hilkka Soininen, Professor in Neurology MD, PhD from the University of Eastern Finland, who headed the clinical trial as part of the LipiDiDiet project, said: "Today's results, published in The Lancet Neurology, are extremely valuable as they bring us closer to understanding the impact of nutritional interventions on prodromal Alzheimer’s, which we are now better at diagnosing but unable to treat due to a lack of approved pharmaceutical options. The LipiDiDiet study illustrates that this nutritional intervention can help to conserve brain tissue and also memory and patients' ability to perform everyday tasks – possibly the most troubling aspects of the disease.”

The LipiDiDiet trial is now the third clinical trial on this nutritional intervention to show favourable effects on memory performance. The two previous clinical trials involved patients with mild Alzheimer’s dementia and reported that daily intake of the nutritional intervention improved memory performance and increased measures of synaptic and functional connectivity in the brain.

Professor Tobias Hartmann, the project’s coordinator, said: “While this nutritional intervention is not a cure for Alzheimer’s, it effectively shows that the earlier in the disease process we intervene, the greater the advantage for the patient. Importantly, reduced atrophy in the patient’s brain shows that the benefit extends beyond symptomatic effects, something never before achieved."

Fortasyn Connect is the combination of active nutrients in a once daily 125ml medical nutrition drink (called Souvenaid). The multi-nutrient combination is supported by almost 20 years of extensive research, based on initial preclinical research by Professor Kiliaan (Radboud University, the Netherlands), by the LipiDiDiet and LipiDiDiet projects, coordinated by Professor Hartmann (Saarland University, Germany) and funded by the European Union FP5 and FP7 research programs, and by Professor Wurtman (formerly at the Massachusetts Institute of Technology, U.S.A) supported principally by the National Institutes of Health.

47 million people have Alzheimer’s or a related dementia for which there is currently no cure.2  Alzheimer’s has a long pre-dementia (or predementia) phase with first signs of cognitive decline appearing several years before the onset of dementia. Many patients with the early symptoms of the disease can now be diagnosed in advance of dementia fully manifesting. The number of people living with Alzheimer’s dementia is expected to double every 20 years, reaching 74.7 million in 2030 and 131.5 million in 2050.

 

* The neuropsychological test battery (NTB) is a composite of different tests. In this case it included learning, recalling and recognising 10 high-frequency, high-imagery nouns, to recollect as many words that belong to the animals category and a letter digit substitution test.

** Fortasyn Connect contains a combination of nutrients including omega-3 fatty acids, choline, uridine monophosphate, phospholipids, antioxidants and B vitamins. It is a Food for Special Medical Purpose (FSMP), clinically proven for the dietary management of early Alzheimer’s disease.

 

For further media information or to be put in touch with Professor Soininen or Professor Hartmann, please contact: Jake Davis, +44 7843 448 252, jake.davis(at)havas.com or Imaan Petra, +44 7515 391 844, imaan.petra(at)havas.com 

 

References

  1. Soininen H, Solomon A, Visser PJ, Hendrix SB, Blennow K, Kivipelto M, and Hartmann T on behalf of the LipiDiDiet clinical study group (2017). 24-month intervention with a specific multinutrient in patients with prodromal Alzheimer’s disease (LipiDiDiet): a randomised, double-blind, controlled trial. The Lancet Neurology. Retrieved from [http://www.thelancet.com/journals/lancet/article/PIIS1474-4422(17)30332-0/fulltext?elsca1=tlxpr]
  2. The World Alzheimer Report 2015: 'The Global Impact of Dementia’. Alzheimer’s Disease International (ADI). Accessed March 2016 via: www.worldalzreport2015.org

30 October 2017, Full results from the European LipiDiDiet clinical trial were published online today in The Lancet Neurology1. The trial showed that in people with prodromal Alzheimer’s (the pre-dementia stage of this disease), consumption of a once-daily medical nutrition drink, whilst not improving a specific neuropsychological test battery (NTB)*, did result in a significant stabilisation of everyday cognitive and functional performance, as well as reduced brain shrinkage. The drink contains “Fortasyn Connect”, a specific combination of essential fatty acids, vitamins and other nutrients**.

The pioneering clinical trial is part of a large European Union funded project and involved 311 patients across 11 sites in four countries (Finland, Germany, the Netherlands and Sweden). The trial involved patients with prodromal Alzheimer’s (often referred to as Mild Cognitive Impairment or MCI). Patients were randomised to receive either the nutritional intervention or an iso-caloric control drink for 24 months.

The study’s primary endpoint, impact on NTB, was not met. The decline in the NTB of the control group was less than anticipated rendering this analysis statistically underpowered. However, key secondary endpoints showed significant advantages for nutrient-treated patients with 45% less worsening in the Clinical Dementia Rating-Sum of Box (CDR-SB). This measure is especially important because it tracks the patient’s disease progression based on performance in managing everyday life, such as handling household emergencies, handling financial transactions or forgetting a major event. Furthermore, there was less brain atrophy in the active group, with 26% difference for the hippocampus and 16% for the ventricular volume. Progressive brain degeneration is typical for Alzheimer’s, with hippocampal damage being responsible for many of the associated memory deficits. Over the 24-month period the incidence of any adverse events were similar between the active and control groups.

Professor Hilkka Soininen, Professor in Neurology MD, PhD from the University of Eastern Finland, who headed the clinical trial as part of the LipiDiDiet project, said: "Today's results, published in The Lancet Neurology, are extremely valuable as they bring us closer to understanding the impact of nutritional interventions on prodromal Alzheimer’s, which we are now better at diagnosing but unable to treat due to a lack of approved pharmaceutical options. The LipiDiDiet study illustrates that this nutritional intervention can help to conserve brain tissue and also memory and patients' ability to perform everyday tasks – possibly the most troubling aspects of the disease.”

The LipiDiDiet trial is now the third clinical trial on this nutritional intervention to show favourable effects on memory performance. The two previous clinical trials involved patients with mild Alzheimer’s dementia and reported that daily intake of the nutritional intervention improved memory performance and increased measures of synaptic and functional connectivity in the brain.

Professor Tobias Hartmann, the project’s coordinator, said: “While this nutritional intervention is not a cure for Alzheimer’s, it effectively shows that the earlier in the disease process we intervene, the greater the advantage for the patient. Importantly, reduced atrophy in the patient’s brain shows that the benefit extends beyond symptomatic effects, something never before achieved."

Fortasyn Connect is the combination of active nutrients in a once daily 125ml medical nutrition drink (called Souvenaid). The multi-nutrient combination is supported by almost 20 years of extensive research, based on initial preclinical research by Professor Kiliaan (Radboud University, the Netherlands), by the LipiDiDiet and LipiDiDiet projects, coordinated by Professor Hartmann (Saarland University, Germany) and funded by the European Union FP5 and FP7 research programs, and by Professor Wurtman (formerly at the Massachusetts Institute of Technology, U.S.A) supported principally by the National Institutes of Health.

47 million people have Alzheimer’s or a related dementia for which there is currently no cure.2  Alzheimer’s has a long pre-dementia (or predementia) phase with first signs of cognitive decline appearing several years before the onset of dementia. Many patients with the early symptoms of the disease can now be diagnosed in advance of dementia fully manifesting. The number of people living with Alzheimer’s dementia is expected to double every 20 years, reaching 74.7 million in 2030 and 131.5 million in 2050.

 

* The neuropsychological test battery (NTB) is a composite of different tests. In this case it included learning, recalling and recognising 10 high-frequency, high-imagery nouns, to recollect as many words that belong to the animals category and a letter digit substitution test.

** Fortasyn Connect contains a combination of nutrients including omega-3 fatty acids, choline, uridine monophosphate, phospholipids, antioxidants and B vitamins. It is a Food for Special Medical Purpose (FSMP), clinically proven for the dietary management of early Alzheimer’s disease.

 

For further media information or to be put in touch with Professor Soininen or Professor Hartmann, please contact: Jake Davis, +44 7843 448 252, jake.davis(at)havas.com or Imaan Petra, +44 7515 391 844, imaan.petra(at)havas.com 

 

References

  1. Soininen H, Solomon A, Visser PJ, Hendrix SB, Blennow K, Kivipelto M, and Hartmann T on behalf of the LipiDiDiet clinical study group (2017). 24-month intervention with a specific multinutrient in patients with prodromal Alzheimer’s disease (LipiDiDiet): a randomised, double-blind, controlled trial. The Lancet Neurology. Retrieved from [http://www.thelancet.com/journals/lancet/article/PIIS1474-4422(17)30332-0/fulltext?elsca1=tlxpr]
  2. The World Alzheimer Report 2015: 'The Global Impact of Dementia’. Alzheimer’s Disease International (ADI). Accessed March 2016 via: www.worldalzreport2015.org
10.03.2016, Lipid-based diets effectively combat Alzheimer's disease in mouse model

A Clinical Trial investigating the effects of Fortasyn Connect (Souvenaid) in Prodromal Alzheimer’s Disease:

Results of the LipiDiDiet study H. Soininen, P.J. Visser, M. Kivipelto, T. Hartmann for the LipiDiDiet study group (2016), presentation held at 14th International Athens/Springfield Symposium on Advances in Alzheimer Therapy, March 10, 2016

>>> Click here for press release
01.05.2015, Vascular effects of oxysterols and oxyphytosterols in apoE -/- mice.

ATHEROSCLEROSIS, 2015 May; 240(1):73-9.

Oliver Weingärtner, Constanze Husche, Hans-Frieder Schött, Timo Speer, Michael Böhm, Charlotte M. Miller, Florence O. McCarthy, Jogchum Plat, Dieter Lütjohann, and Ulrich Laufs

In this study, we investigated the effects of oxidized cholesterol and oxidized sitosterol in mice. The major novel finding in this study is that the i.p. application of plant sterols or their oxidation products result in elevated plasma levels and increases sterol concentrations in the arterial wall. Interestingly, application of non-oxidized cholesterol or sitosterol increases their respective plasma concentrations but does not give rise to increased oxysterol or oxyphytosterol concentrations suggesting that endogenous oxidation does not play a major role in this context. Finally, only the elevation of 7β-OH-sitosterol resulted in increased ROS production in the arterial wall, but this did not affect endothelial cell quantification, endothelial cell migration, endothelial function, and early atherosclerotic lesion development.

>>> Click here for scientific abstract
22.04.2015, Long-term treatment with Ginkgo biloba extract EGb 761 improves symptoms and pathology in a transgenic mouse model of Alzheimer's disease.

Brain Behav Immun. 2015 May;46:121-31.

Liu X, Hao W, Qin Y, Decker Y, Wang X, Burkart M, Schötz K, Menger MD, Fassbender K, Liu Y.

Inflammation in the brain is the main hallmark of Alzheimer’s disease (AD) and contributes to the disease pathogenesis. The extract from leaves of Ginkgo trees has been mixed with docosahexaenoic acid (DHA) an important omega-3 fatty acid and sold as a nutritional product for the prevention of AD. With this publication the LipiDiDiet researchers show how Ginkgo biloba extract reduces the inflammation in the AD brain.

>>> Click here for scientific abstract
01.04.2015, Leisure-time physical activity from mid- to late life, body mass index, and risk of dementia

Alzheimers Dement. 2015 Apr;11(4):434-443

Tolppanen AM, Solomon A, Kulmala J, Kareholt I, Ngandu T, Rusanen M, Laatikainen T, Soininen H, Kivipelto M.

The study investigated the associations between leisure-time physical activity from mid- to late life, the risk of dementia, and the role of body mass index, sex and APOE during 28-year follow-up. Moderate and low levels of midlife physical activity were associated with higher risk of dementia in comparison with the most active category. The benefits were more pronounced among men, overweight individuals, and APOE ε4 non-carriers. Maintaining high levels of physical activity or increasing physical activity after midlife was associated with lower dementia risk.

>>> Click here for scientific abstract
23.03.2015, Increased plant sterol deposition in vascular tissue characterizes patients with severe aortic stenosis and concomitant coronary artery disease.

STEROIDS [Epub ahead of print]

Alexandra Luister, Hans-Frieder Schött, Constanze Husche, Hans-Joachim Schäfers, Michael Böhm, Jogchum Plat, Stefan Gräber, Dieter Lütjohann, Ulrich Laufs, Oliver Weingärtner

This study consists of the data from with 104 patients suffering from severe aortic stenosis, treated with a consecutive aortic valve replacement. In plasma and valve cusp tissue of the patients the concentrations of phytosterols and oxyphytosterols were determined. Patients with concomitant CAD are characterized by increased deposition of plant sterols. Moreover, patients with concomitant CAD were characterized by increased oxyphytosterol concentrations in plasma and aortic valve cusps.

>>> Click here for scientific abstract
17.03.2015, 7β-Hydroxysitosterol crosses the blood-brain barrier more favored than its substrate sitosterol in ApoE-/- mice.

STEROIDS [Epub ahead of print]

Hans-Frieder Schött, Constanze Husche, Charlott M. Miller, Florence O. McCarthy, Ulrich Laufs, Oliver Weingärtner, and Dieter Lütjohann

Highly purified sitosterol, cholesterol, 7β-OH-sitosterol, and 7β-OH-cholesterol were intraperitoneally injected in ApoE knock-out mice in a time period of four weeks. We could obtain new insights on the distribution of the applied compounds in liver, brain, and arterial wall tissue as well as on their impact on surrogate markers of cholesterol biosynthesis and absorption. Additionally, new information about the transport of phytosterols and oxyphytosterols across the blood-brain barrier could be gained.

>>> Click here for scientific abstract
17.02.2015, Validation of an isotope dilution gas chromatography-mass spectrometry method for combined analysis of oxysterols and oxyphytosterols in serum samples.

STEROIDS [Epub ahead of print]

Hans-Frieder Schött and Dieter Lütjohann

An isotope dilution gas-chromatography-mass selective detector method for combined determination of 7-oxygenated cholesterol, campesterol, and sitosterol as well as 4β-, 24(S)-, 25-, 27-OH-cholesterol was developed and validated. This new method allows oxysterol determination in excellent performance and reduced artefact formation. The new validated method will enable for reliable oxysterols results and guarantees a valuable progress in oxysterol research.

>>> Click here for scientific abstract
01.02.2015, 2003-2013: A Decade of Body Mass Index, Alzheimer's Disease, and Dementia

J Alzheimers Dis. 2015, 43(3):739-55.

Emmerzaal TL, Kiliaan AJ, Gustafson DR.

Overweight and obesity have been shown to increase risk for dementia. To understand this better, we evaluated all epidemiologic studies published between 2003 and 2013 that reported on an association between body mass index (BMI) and dementia.  We selected 2003 as a starting point, since this is when the first report came out on this important association. In general, mid-life overweight or obese measures based on BMI were associated with late-life risk of dementia in approximately 50% of published associations.  In contrast, late-life measures of BMI showed overweight to be protective and obesity to not be associated with dementia risk. A snapshot of these mid-life and late-life BMI and dementia associations illustrates the changing relationship between BMI and dementia over the life course.

>>> Click here for scientific abstract
01.01.2015, Impact of fatty acids on brain circulation, structure and function.

Prostaglandins Leukot Essent Fatty Acids. 2015 Jan;92:3-14.

Haast RA, Kiliaan AJ.

The use of dietary intervention has evolved into a promising approach to prevent the onset and progression of brain diseases. Promising results of intake of omega-3 long chain polyunsaturated fatty acids (ω3-LCPUFAs),  are found regarding to the protection of the brain circulation and the brain cells and connections between brain area and cognitive functioning. Contrary, studies investigating diets high in saturated fats provide opposite results, which may eventually lead to diminished brain function and structure. This paper will review in vivo research conducted on the effects of ω3 LCPUFAs and saturated fatty acids on integrity (circulation, structure and function of the brain) of the young, aging and diseased brain.

>>> Click here for scientific abstract
18.12.2014, Impact of DHA on metabolic diseases from womb to tomb.

Mar Drugs. 2014 Dec 18;12(12):6190-212

Arnoldussen IA, Kiliaan AJ

Long chain polyunsaturated fatty acids (LC-PUFAs), are important for human health during life. We especially focus on the omega-3 LC-PUFA docosahexaenoic acid (DHA) which is abundantly present in fish. Adequate DHA levels are essential during neurodevelopment and important for brain functions throughout life but they are also important in cardiovascular diseases, obesity, and diabetes mellitus type 2.  All of these are risk factors for cognitive decline and dementia in later life. Intake of DHA also reduces incidence of both stroke and atherosclerosis, and diabetes prevalence. These findings are discussed in the light of different stages in the human life cycle: childhood, adolescence, adulthood and in later life. From this review, it can be concluded that DHA supplementation is able to inhibit obesity and cardiovascular disease. DHA could therefore be a dietary protector against these diseases during a person’s entire life.

>>> Click here for scientific abstract
01.12.2014, Obesity and dementia: Adipokines interact with the brain.

Eur J Neuropsychopharmacology, 24(12):1982-99.

Arnoldussen IAC, Kiliaan AJ, Gustafson DR

If overweight and obesity are risk factors for dementia, then the next question is how?  Obesity is a pandemic and a serious global health concern. Obesity increases risk for multiple conditions that also increase dementia risk. Adipokines are hormones produced and released by adipose tissue that may influence brain health more than previously thought. In this review article, six adipose tissue hormones and their actions were discussed. It remains unclear as to the specific function of these hormones.

>>> Click here for scientific abstract
15.10.2014, Resting-state functional connectivity changes in aging apoE4 and apoE-KO mice

J Neurosci. 2014 Oct 15;34(42):13963-75.

Zerbi V, Wiesmann M, Emmerzaal TL, Jansen D, Van Beek M, Mutsaers MP, Beckmann CF, Heerschap A, Kiliaan AJ.

In this study we provide new evidence for a relation between the cholesterol transporter apoE and the integrity of connections between brain area, possibly due to impairment in the vasculature such as atherosclerosis and hypercholesterolemia. Our results show that neuroimaging techniques provide an excellent tool to assess brain function and to investigate early neuropathology and aging effects in translational research.

>>> Click here for scientific abstract
01.09.2014, Adipokines: a link between obesity and dementia?

Lancet Neurol. 2014 Sep;13(9):913-923.


Kiliaan AJ, Arnoldussen IA, Gustafson DR.

Being overweight or obese, as measured using body mass index (BMI) or central adiposity (waist circumference), and changes in BMI over the life course have been associated with brain structure and function, as well as late-onset dementia and Alzheimer's disease (AD). This observation led us to question what it is about BMI that is associated with health of the brain and dementia risk. Hormones produced by adipose tissue may be an answer.

>>> Click here for further explanation

>>> Click here for scientific abstract
01.09.2014, Vitamin D in relation to cognitive impairment, cerebrospinal fluid biomarkers, and brain volumes

The Journals of Gerontology, Series A, Biological sciences and medical sciences. 2014 Sept 01; 69(9):1132-1138


Hooshmand B, Lökk J, Solomon A, Mangialasche F, Miralbell J, Spulber G, Annerbo S, Andreasen N, Winblad B, Cedazo-Minguez A, Wahlund LO, Kivipelto M.

The study investigated associations between plasma vitamin D and cognitive impairment, cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD), and brain tissue volumes in 79 memory clinic patients (29 with subjective cognitive impairment, 28 with mild cognitive impairment, 18 with AD). Results suggest that vitamin D may be associated with cognitive status, CSF Aβ42 levels, and brain tissue volumes (e.g. white matter, structures belonging to medial temporal lobe).

>>> Click here for scientific abstract
01.09.2014, Cholesterol in mild cognitive impairment and Alzheimer’s disease in a birth cohort over 14 years.

Eur Arch Psychiatry Clin Neurosci, 2014, 264:485-492.

Toro P, Degen Ch, Pierer M, Gustafson D, Schröder, Schönknecht P.

Higher levels of mid-life blood cholesterol level and blood cholesterol decline have been shown to increase risk for Alzheimer’s disease (AD). Our results confirm this finding.  Those who developed mild cognitive impairment and AD, had higher levels of blood cholesterol in mid-life and blood cholesterol decline prior to diagnosis.  A major risk gene for AD was not associated with these results.

>>> Click here for scientific abstract
01.09.2014, Impact of a multi-nutrient diet on cognition, brain metabolism, hemodynamics, and plasticity in apoE4 carrier and apoE knockout mice.

Brain Struct Funct. 2014 Sep;219(5):1841-68.

Jansen D, Zerbi V, Janssen CI, van Rooij D, Zinnhardt B, Dederen PJ, Wright AJ, Broersen LM, Lütjohann D, Heerschap A, Kiliaan AJ.

In the present study, we tested the effects of long-term consumption of a specific multi-nutrient diet in mice models for atherosclerosis and hypercholesterolemia. This specific multi-nutrient diet was developed to protect the membranes of neurons and stimulate formation of contacts (synapses) between neurons. The specific multi-nutrient diet decreased anxiety-related behavior and increased the concentration of omega-3 fatty acids in the brain. Furthermore, we found that mice fed with this multi-nutrient diet showed locally increased cerebral circulation. Together, these data suggest that a specific dietary intervention has beneficial effects on early cerebral pathological consequences of an impaired vascular system. 

>>> Click here for scientific abstract
21.08.2014, 2003-2013: A Decade of Body Mass Index, Alzheimer's Disease, and Dementia

J Alzheimers Dis. 2014 Aug 21.


Emmerzaal TL, Kiliaan AJ, Gustafson DR.

Overweight and obesity may increase risk for Alzheimer’s Disease (AD) and other dementias occurring in later life or after age 65 years Body Mass Index (BMI) is a common measure of overweight and obesity. BMI influences risk for dementia. Since BMI changes with age over the life course (increasing with increasing age during adult years, and decreasing with increasing age as one gets older) different dementia risk associations are observed in adulthood versus later life.  In midlife (to age 60 years), higher BMI increases risk for dementia. In late-life, higher BMI is protective for dementia.

>>> Click here for further explanation

>>> Click here for scientific abstract
19.07.2014, Involvement of the Apoer2 and Lrp1 receptors in mediating the pathological effects of ApoE4 in vivo

Curr Alzheimer Res. 2014; 11(6):549-57.


Moran Gilat-Frenkel, Anat Boehm-Cagan, Ori Liraz, Xunde Xian, Joachim Herz, and Daniel M. Michaelson

In this study we investigated the effect of apoE4, the main genetic risk factor for Alzheimer's disease, on the levels of two ApoE-receptors, Apoer2 and Lrp1 in different experimental paradigms. We showed that naïve apoE4 mice have decreased levels of the ApoE receptor, Apoer2, while activation of the amyloid cascade results in up-regulation of the ApoE receptor Lrp1. This study show that the levels of hippocampal ApoE receptors Lrp1 and Apoer2 in vivo are affected isoform specifically by ApoE4 and that the type of receptor affected is context dependent.

>>> Click here for scientific abstract
23.06.2014, Simultaneous changes of spatial memory and spine density after intrahippocampal administration of fibrillar Aβ1-42 to the rat brain.

Biomed Res Int. 2014 June; 2014:345305.


Anne Rijpma, Diane Jansen, Ilse Arnoldussen, Tsong Fang, Maximilian Wiesmann, Maartje Mutsaers, Jos Dederen, Carola Janssen and Amanda Kiliaan

Alzheimer’s disease has been the most frequent neurodegenerative disease with loss of memory. There are different animal models simulating the pathophysiological processes of Alzheimer’s disease. We used a rat model and found that injecting the toxic β-amyloid into the hippocampus caused simultaneous decrease of spatial memory and the number of synapses.

>>> Click here for scientific abstract
16.06.2014, PS dependent APP cleavage regulates glucosylceramide synthase and is affected in Alzheimer's disease.

Cell Physiol Biochem. 2014 June 16; 34(1):92-110.


Grimm MO, Hundsdörfer B, Grösgen S, Mett J, Zimmer VC, Stahlmann CP, Haupenthal VJ, Rothhaar TL, Lehmann J, Pätzold A, Zinser EG, Tanila H, Shen J, Müller U, Grimm HS, Hartmann T.

Gangliosides are major lipids in human brain. It is well known that gangliosides influence the processes leading to Alzheimer´s disease. In this publication we elucidate that the link between ganglioside synthesis and the proteins involved in Alzheimer´s disease are bidirectional. Our results reveal complex regulatory cycles which are affected in Alzheimer´s disease and which are potential therapeutical targets.

>>> Click here for scientific abstract
21.05.2014, Reversal of apoE4-Driven Brain Pathology and Behavioral Deficits by Bexarotene

The Journal of Neuroscience. 2014 May 21; 34(21):7293-7301.


Anat Boehm-Cagan and Daniel M. Michaelson

In the present study, we investigated the extent to which a pharmacological approach can correct the lipidation deficiency of apoE4, the main genetic risk factor for Alzheimer's disease, and correct the apoE4-driven pathologies. We found that the RXR agonist bexarotene can reverse the lipidation deficiency of apoE4 and the cognitive impairments and the associated neuronal deficits of apoE4 mice.

>>> Click here for scientific abstract
17.05.2014, ApoE4 induces Aβ42, tau, and neuronal pathology in the hippocampus of young targeted replacement apoE4 mice.

Molecular Neurodegeneration. 2013 May 17; 8:16.


Liraz O, Boehm-Cagan A, Michaelson DM.

ApoE4 is the major genetic risk factor for Alzheimer's disease. Studies have shown that the pathological effects of apoE4 start decades before the onset of the disease. We developed a model to study the early onset pathological effects of apoE4. This model revealed that apoE4 induces cognitive deficits associated with neuronal and synaptic pathology.

>>> Click here for scientific abstract
13.05.2014, Changes in Membrane Cholesterol Differentially Influence Preferential and Non-preferential Signaling of the M1 and M3 Muscarinic Acetylcholine Receptors.

Neurochem Res. 2014 May 13. [Epub ahead of print]

Pavel Michal, Esam E. El-Fakahany, Vladimir Dolezal

The M1 muscarinic receptor is a major cerebral muscarinic receptor subtype that is essential for cognitive functions. In addition, activation of the M1, and also the M3, subtype of muscarinic receptor increases non-amyloidogenic processing of amyloid precursor protein.  Any malfunction of the M1 receptor-mediated signaling may thus adversely impact not only mental performance but also amyloid precursor protein processing and increase amyloid-β generation. Here we demonstrate that particularly the decrease in membrane cholesterol impairs the M1 receptor-mediated signal transduction across plasma membrane and may thus contribute to the progression of beta-amyloid accumulation and cognitive decline in Alzheimer´s disease.

>>> Click here for scientific abstract
11.04.2014, The relationships of phytosterols and oxyphytosterols in plasma and aortic valve cusps in patients with severe aortic stenosis

Biochem Biophys Res Commun. 2014 Apr 11; 446(3):805-10.


Hans-Frieder Schött, Alexandra Luister, Constanze Husche, Hans-Joachim Schäfers, Michael Böhm, Jogchum Plat, Dieter Lütjohann, Ulrich Laufs, Oliver Weingärtner

Plant sterols (PS) and oxyphytosterols (OPS) were determined in plasma and aortic valve cusp that were pre-analytically differenciated in valve tissue and atherosclerotic plaque. PS correlate strongly in and between plasma and valve cusps tissue. OPS correlate strongly in valve cusps tissue. PS and POP correlate strongly in valve cusps tissue.

>>> Click here for scientific abstract
01.03.2014, Multinutrient diets improve cerebral perfusion and neuroprotection in a murine model of Alzheimer's disease.

Neurobiology of Aging 2014 Mar;35(3):600-13.


Valerio Zerbi, Diane Jansen, Maximilian Wiesmann, Tsong Fang, Laus Broersen, Andor Veltien, Arend Heerschap, Amanda Kiliaan

Nutritional intervention may retard the development of Alzheimer's disease (AD).
In this study we tested the effects of 2 multi-nutrient diets in an AD mouse model. The diets were developed to enhance contacts/connections  between nerve cells and improve the vascular health. We measured the cerebral blood flow (CBF) and the connections within the brain with imaging methods. Alzheimer mice have a decreased CBF and loss of brain connections like in patients with AD. Both multinutrient diets were able to increase CBF and connections in the mice brains. We suggest that a specific diet intervention has the potential to slow AD progression, by simultaneously improving cerebrovascular health and enhancing neuroprotective mechanisms.

>>> Click here for scientific abstract
01.03.2014, Sex Differences in Presynaptic Density and Neurogenesis in Middle-Aged ApoE4 and ApoE Knockout Mice

Journal of Neurodegenerative Diseases, Volume2013, Article ID 531326, 9 pages


Anne Rijpma, Diane Jansen, Ilse Arnoldussen, Tsong Fang, Maximilian Wiesmann, Maartje Mutsaers, Jos Dederen, Carola Janssen and Amanda Kiliaan

Atherosclerosis and apolipoprotein E ε4 (APOE4) genotype are risk factors for Alzheimer’s disease (AD) and cardiovascular disease (CVD). Sex differences exist in prevalence and manifestation of both diseases. We investigated sex differences respective to aging, focusing on cognitive parameters in apoE4 and apoE knockout (ko) mouse models of AD and CVD. To our knowledge, no other studies investigating presynaptic density in aging female apoE4 or apoE ko mice are available. Sex-specific differences between APOE genotypes could account for some sex differences in AD and CVD.s

>>> Click here for scientific abstract
01.03.2014, Body mass index, cognition, disability, APOE genotype and mortality: the "TREVISO LONGEVA (TRELONG)" Study.

Am J Geriatr Psychiatry. 2012 Jul;20(7):594-602


Gustafson D, Ongaro F, Meggiolaro S, Antuono P, Forloni GL, Albani D, Gajo GB, De Angeli S, Zanardo A Siculi M, Siculi G, Muffato G, Gava N, Regini C, Gallucci M.

Dynamic, interrelated late-life parameters, such as body mass index (BMI), cognition, and physical functioning on mortality in the elderly are unclear, as is the influence of APOE genotype. We explored these measures in relation to 7-year mortality in long-lived Italian elderly, comprising a representative, age-stratified, population sample from Treviso, Italy, the Treviso Longeva (TRELONG) Study. Three hundred eleven men and 357 women, aged 70 years and older (mean age 84 ± 8 years) were followed for seven-year mortality, which was evaluated in association with BMI, Mini-Mental State Examination (MMSE) score, Activities of Daily Living (ADL), APOE genotype, and a variety of clinical and survey data.
In separate age- and sex-adjusted analyses, BMI <18.5 kg/m(2), MMSE ≤24, and ADL <6, were associated with greater 7-year mortality among adults aged 70 years and older. In a multivariate model including all factors, MMSE ≤24, and ADL <6 were associated with greater mortality; BMI ≥30 kg/m(2) was protective. There were no interactions between BMI, MMSE, or ADL. When excluding those dying within 3 years of baseline, only an MMSE ≤24 was related to mortality. Higher MMSE score, higher ADL score, and higher BMI, independent of age, sex, and other factors, are markers for longer life among northern Italian adults aged 70 years or older. Global cognition, BMI, and physical functioning, assessed by short, simple tests are profound indicators of death within less than a decade.

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01.02.2014, Special lipid-based diets alleviate cognitive deficits in the APPswe/PS1dE9 transgenic mouse model of Alzheimer's disease independent of brain amyloid deposition

Journal of Nutritional Biochemistry. 2014 Feb; 25:157–169

Hennariikka Koivisto, Marcus O. Grimm, Tatjana L. Rothhaar, Róbert Berkecz, Dieter Lütjohann, Rajsa Giniatullina, Mari Takalo, Pasi O. Miettinen, Hanna-Maija Lahtinen, Rashid Giniatullin, Botond Penke, Tamás Janáky, Laus M. Broersen, Tobias Hartmann, Heikki Tanila

The omega-3 fatty acid docosahexaenoic acid (DHA) has been associated with decreased risk in Alzheimer disease in several epidemiological studies. This large preclinical study in Alzheimer model mice assessed the possibility to boost the DHA effect with additional nutrients. One combination of nutrients was particular effective in reversing the memory impairment, while another combination significantly lowered the brain levels of amyloid-beta peptide that is thought to be the main culprit of the disease. The study demontrates the treatment potential of lipid-based diets in an early stage of the disease.

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01.02.2014, Unfolded protein response signaling by transcription factor XBP-1 regulates ADAM10 and is affected in Alzheimer's disease.

FASEB J., 2014 Feb;28(2):978-97.


Reinhardt S, Schuck F, Grösgen S, Riemenschneider M, Hartmann T, Postina R, Grimm M, Endres K.

In Alzheimer´s disease the APP processing is shifted from the protective non-amyloidogenic pathway to the amyloidogenic pathway leading to Ab production, one of the major components of senile plaques. Therefore one aim is to identify pathways leading to an increased protective non-amyloidogenic pathway. In this study we have identified the protein XBP1 in regulating the non-amyloidogenic pathways and identified the underlying mechanisms. XBP1 is a protein being involved in the stress response of cells, especially in the unfolded protein response. Further experiments revealed these regulating mechanisms and the link to the non-amyloidogenic pathway are disturbed in case of Alzheimer´s disease.

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01.02.2014, Outline of therapeutic interventions with muscarinic receptor-mediated transmission.

Physiologica Research. 2014 Feb; 63(Suppl. 1):S177-189.


Jan Jakubik, Eva Santruckova, Alena Randakova, Helena Janickova, Pavel Zimcik, Vladimir Rudajev, Pavel Michal, Esam E. El-Fakahany, and Vladimir Dolezal.

Alzheimer´s disease is invariably accompanied with the impairment of cholinergic neurotransmission. In addition to playing important role in cognitive function, muscarinic receptors are also involved in non-amyloidogenic processing of amyloid precursor protein. This review article summarizes current possibiliteies and shortcomings of selective pharmacotherapeutic interventions with muscarinic receptor-mediated neurotransmission.

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01.01.2014, Impact of Vitamin D on Amyloid Precursor Protein Processing and Amyloid-β Peptide Degradation in Alzheimer's Disease

Neurodegener Dis. 2014;13(2-3):75-81.


Grimm MO, Lehmann J, Mett J, Zimmer VC, Grösgen S, Stahlmann CP, Hundsdörfer B, Haupenthal VJ, Rothhaar TL, Herr C, Bals R, Grimm HS, Hartmann T

Several studies indicate a link between Vitamin D and Alzheimer’s disease. However, the underlying mechanism is not understood. Vitamin D hypovitaminosis affects up to 90% of the elderly population and has been reported to be associated with decreased cognitive function. Here we have examined the underlying mechanism, showing that both, Ab production and degradation, is affected already by a mild to moderate Vitamin D hypovitaminosis in mice and cell culture, leading to a changed Ab level. The enzymes involved in this processes are identified to be b-secretase and neprilysin.

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01.01.2014, Hippocampus-related cognitive impairments in young apoE4 targeted replacement mice.

Neurodegener Dis. 2014; 13(2-3):86-92.


Salomon-Zimri S, Boehm-Cagan A, Liraz O, Michaelson DM.

ApoE4 is the major genetic risk factor for Alzheimer's disease. We have previously shown that the pathological effects of apoE4 can be detected in young, naïve apoE4 targeted replacement mice. This study shows that the apoE4 mice show distinct cognitive deficits in a variety of hippocampus related behavioral paradigms. These behavioral paradigms can be utilized to assess the effectiveness of novel treatments.

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01.01.2014, Targeting synaptic dysfunction in Alzheimer’s disease by administering a specific nutrient combination

J Alzheimers Dis. 2014; 38(3):459-79.


Nick van Wijk, Laus M. Broersen, Martijn C. de Wilde, Robert J.J. Hageman, Martine Groenendijk, John W.C. Sijben, and Patrick J.G.H. Kamphuis

A loss of synaptic connections in the brain is believed to occur already in the early stages of Alzheimer’s disease. A specific combination of nutrients necessary for the formation of new synaptic connections has been designed that may fulfill the specific nutritional needs of Alzheimer patients. In this publication the LipiDiDiet researchers review the available scientific evidence on how these nutrients act together to induce beneficial effect in various experimental models.

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01.01.2014, Midlife and late-life body mass index and late-life dementia: results from a prospective population-based cohort

Journal of Alzheimer’s Disease, 2014; 38(1):201-209


Tolppanen AM, Ngandu T, Kåreholt I, Laatikainen T, Rusanen M, Soininen H, Kivipelto M.

The aim of this study was to investigate the association of midlife and late-life body mass index (BMI) with late-life dementia/Alzheimer's disease (AD) and whether the association was independent of other obesity-related co-morbidities. Higher midlife BMI was related to higher risk of dementia and AD, independently of obesity-related risk factors and co-morbidities. Steeper decrease of BMI and low late-life BMI were associated with higher risk of dementia and AD. These findings highlight the importance of life-course perspective when assessing the association between BMI and cognition.

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23.12.2013, Neprilysin and Aβ Clearance: Impact of the APP Intracellular Domain in NEP Regulation and Implications in Alzheimer's Disease.

Front Aging Neurosci. 2013 Dec 23;5:98.


Grimm MO, Mett J, Stahlmann CP, Haupenthal VJ, Zimmer VC, Hartmann T.

One of the charateristic pathological hallmarks of Alzheimer´s diesease is the accumulation of Amyloid b (Ab). The level of Amyloid b is not only affected by the rate of the de novo synthesis but also by its degradation. One of the major enzymes of the Ab degradation is Neprilysin. In this overview article we summarize the most important facts about the regulation of NEP and its implication in Alzheimer´s disease.

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17.12.2013, Upregulation of PGC-1α expression by Alzheimer's disease-associated pathway: presenilin 1/amyloid precursor protein (APP)/intracellular domain of APP.

Aging Cell. 2014 Apr; 13(2):263-72.


Robinson A, Grösgen S, Mett J, Zimmer VC, Haupenthal VJ, Hundsdörfer B, Stahlmann CP, Slobodskoy Y, Müller UC, Hartmann T, Stein R, Grimm MO.

Recent studies revealed a close link between Alzheimer´s disease and a misregulation in energy metabolism. Here we show that the proteins involved in Alzheimer´s disease are involved in the regulation of the energy metabolism under physiological conditions. Moreover the mechanism how this regulation takes place is investigated. In case of Alzheimer´s disease this regulation is altered leading to a changed energy metabolism.

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01.12.2013, Serum levels of vitamin E forms and risk of cognitive impairment in a Finnish cohort of older adults

Experimental Gerontology. 2013 Dec 1; 48(12):1428-1435.


Mangialasche F, Solomon A, Kareholt I, Hooshmand B, Cecchetti R, Fratiglioni L, Soininen H, Laatikainen T, Mecocci P, Kivipelto M.

Vitamin E includes 8 natural antioxidant compounds (four tocopherols and four tocotrienols), but α-tocopherol has been the main focus of investigation in studies of cognitive impairment and Alzheimer's disease. This study investigated all 8 vitamin E forms in 140 older individuals without cognitive impairment followed-up for 8 years. Elevated levels of tocopherol and tocotrienol forms were associated with reduced risk of cognitive impairment. The association was modulated by cholesterol levels. Various vitamin E forms might play a role in cognitive impairment, and their evaluation can provide a more accurate measure of vitamin E status in humans.

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01.11.2013, Vascular aspects of cognitive impairment and dementia.

Journal of Cerebral Blood Flow & Metabolism. 2013 Nov;33(11):1696-706.


Maximilian Wiesmann, Amanda Kiliaan, Jurgen Claassen

Hypertension and stroke are highly prevalent risk factors for cognitive impairment and dementia. Alzheimer's disease (AD) and vascular dementia (VaD) are the most common forms of dementia, and both conditions are preceded by a stage of cognitive impairment. Stroke is a major risk factor for the development of vascular cognitive impairment (VCI) and VaD; however, stroke may also predispose to AD. Hypertension is a major risk factor for stroke, thus linking hypertension to VCI and VaD, but hypertension is also an important risk factor for AD. Reducing these two major, but modifiable, risk factors-hypertension and stroke-could be a successful strategy for reducing the public health burden of cognitive impairment and dementia. Intake of long-chain omega-3 polyunsaturated fatty acids (LC-n3-FA) and the manipulation of factors involved in the renin-angiotensin system (e.g. angiotensin II or angiotensin-converting enzyme) have been shown to reduce the risk of developing hypertension and stroke, thereby reducing dementia risk. This paper will review the research conducted on the relationship between hypertension, stroke, and dementia and also on the impact of LC-n3-FA or antihypertensive treatments on risk factors for VCI, VaD, and AD.

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09.10.2013, Plant sterols the better cholesterol in Alzheimer's disease? A mechanistical study.

J Neurosci., 2013 Oct 9;33(41):16072-87.

Burg VK, Grimm HS, Rothhaar TL, Grösgen S, Hundsdörfer B, Haupenthal VJ, Zimmer VC, Mett J, Weingärtner O, Laufs U, Broersen LM, Tanila H, Vanmierlo T,Lütjohann D, Hartmann T, Grimm MO.

Accumulation of amyloid peptides is believed to be a main cause for Alzheimer’s disease. It had been observed that cholesterol found in typical western diet, can increase amyloid peptide production. With this publication we elucidate the effect of phytosterols, the equivalent of cholesterol in plants, on amyloid production and the underlying mechanisms.

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01.09.2013, Plasma homocysteine, Alzheimer and cerebrovascular pathology: a population-based autopsy study

BRAIN. 2013 Sept 01; 136(9):2707-2716


Hooshmand B, Polvikoski T, Kivipelto M, Tanskanen M, Myllykangas L, Erkinjuntti T, Mäkelä M, Oinas M, Paetau A, Scheltens P, van Straaten EC, Sulkava R, Solomon A.

This study investigated the links between homocysteine and brain changes at autopsy up to 10 years later in individuals aged ≥85 years. Results suggest that elevated homocysteine may contribute to increased Alzheimer-type pathology, particularly neurofibrillary tangles burden. This effect seems to be more pronounced in the presence of cerebrovascular pathology.

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01.08.2013, Measurements of medial temporal lobe atrophy for prediction of Alzheimer’s disease in subjects with mild cognitive impairment

Neurobiol Aging. 2013 Aug; 34(8):2003-13.

 

Clerx L, van Rossum IA, Burns L, Knol DL, Scheltens P, Verhey F, Aalten P, Lapuerta P, van de Pol L, van Schijndel R, de Jong R, Barkhof F, Wolz R, Rueckert D, Bocchetta M, Tsolaki M, Nobili F, Wahlund LO, Minthon L, Frölich L, Hampel H, Soininen H, Visser PJ.

Atrophy in the medial temporal part of the brain is an early sign of Alzheimer’s disease. We compared 3 different ways to assess atrophy and concluded that an automated measurement is as good as a manual measurement and better than a qualitative rating.

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06.07.2013, Impact of a multi-nutrient diet on cognition, brain metabolism, hemodynamics, and plasticity in apoE4 carrier and apoE knockout mice.

Neurobiology of Aging 2014 Mar;35(3):600-13.


Diane Jansen, Valerio Zerbi, Carola Janssen, Daan van Rooij, Bastian Zinnhardt, Jos Dederen, Alan Wright, Laus Broersen, Dieter Lütjohann, Arend Heerschap, Amanda Kiliaan

In the present study, the effects of long-term consumption of a specific multi-nutrient diet in two mouse models for atherosclerosis and high cholesterol were tested. These vascular conditions are risk factors for AD.  This specific multi-nutrient diet was developed to support neuronal membrane synthesis and was expected to contribute to the maintenance of vascular health. The data suggest that the specific dietary intervention has beneficial effects on early pathological consequences of hypercholesterolemia and vascular risk factors for AD.

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09.06.2013, Effects of Specific Multi-Nutrient Enriched Diets on Cerebral Metabolism, Cognition and Neuropathology in AbPPswe-PS1dE9 Mice

PlosOne 8(9): e75393. doi:10.1371/journal.pone.0075393


Diane Jansen, Valerio Zerbi, Ilse Arnoldussen, Maximilian Wiesmann, Anne Rijpma, Xiaotian T. Fang, Jos Dederen, Maartje Mutsaers, Laus Broersen, Dieter Lutjohann, Malgorzata Miller, Leo Joosten, Arend Heerschap, Amanda Kiliaan

In this study the effect of two specific multi-nutrient diets on cognition en Alzheimer pathology in Alzheimer mouse model was investigated. The current data indicate that specific multi-nutrient diets can influence AD-related processes. Intervention with the specific diet (Fortasyn) might be of interest for several other neurodegenerative and neurological disorders.

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03.05.2013, Docosahexaenoic acid reduces amyloid-ß induced toxicity in cells of the neurovascular unit.

J Alzheimers Dis. 2013 Jan 1;36(3):487-501


Veszelka Sz., Tóth A. E., Walter F.R. Datki Zs., Mózes E., Fülöp L., Bozsó Zs., Hellinge E., Vastag M., Orsolits B., Környei, Zs., Penke B, and Deli M. A.

It has been observed that hypoxia and hypoglycemia play very important role in starting Alzheimer’s disease. Amyloid peptides show toxic effect onto the neurons and brain capillary cells. It was found that docosahexaenoic acid (DHA), an important v 3-fatty acid protects all kinds of cells of the neurovascular unit from affecting by amyloid peptides. With this paper the LipiDIDiet researchers demonstrated that DHA protects brain capillaries against amyloid peptides improving oxygen and glucose supply to neurons.

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01.05.2013, Gray and white matter degeneration revealed by diffusion in an Alzheimer mouse model.

Neurobiology of Aging. 2013 May;34(5):1440-50.


Valerio Zerbi, Michiel Kleinnijenhuis, Tsong Fang, Diane Jansen, Andor Veltien, Sjaak van Asten, Nienke Timmer, Jos Dederen, Arend Heerschap, Amanda Kiliaan

In patients with Alzheimer's disease (AD) the severity of the loss of connections in the brain correlates with the severity  of the disease. In this study we used the new techniue :diffusion-tensor magnetic resonance imaging to study the connections in the Alzheimer mouse brain which were decreased ike in AD patients. This model can therefor be used to investigate future AD prevention strategies.

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01.04.2013, Uncoupling of M1 muscarinic receptor/G-protein interaction by amyloid beta(1-42).

Neuropharmacology. 2013 April; 67:272-283.


Helena Janickova, Vladimir Rudajev, Pavel Zimcik, Jan Jakubik, Heikki Tanila, Esam E. El-Fakahany, and Vladimir Dolezal.

Accumulation of amyloid peptides and formation of amyloid plaques is characteristic feature of Alzheimer’s disease. Here we show that low concentrations of soluble forms of amyloidogenic fragment Abeta(1-42) that do not demonstrate yet overt toxicity already impair muscarinic receptor-mediated signal transduction, specifically through muscarinic M1 receptor. It demonstrates that disturbance of the muscarinic neurotransmission develop rather early, during prodromal (silent) stage in pathogenesis of Alzheimer´s disease.

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19.03.2013, Prediction of Alzheimer disease in subjects with amnestic and nonamnestic MCI.

Neurology. 2013 Mar 19;80(12):1124-32.

 

Vos SJ, van Rossum IA, Verhey F, Knol DL, Soininen H, Wahlund LO, Hampel H, Tsolaki M, Minthon L, Frisoni GB, Froelich L, Nobili F, van der Flier W, Blennow K, Wolz R, Scheltens P, Visser PJ.

Mild cognitive impairment (MCI) refers to cognitive impairment in the absence of dementia. MCI can be a prodromal stage of Alzheimer’s disease. There are 2 main MCI types: MCI with memory impairments (amnestic MCI) and MCI with impairments in other cognitive domains (non-amnestic MCI). We showed that Alzheimer biomarkers could predict the presence of Alzheimer’s disease in both subjects with amnestic and non-amestic MCI.

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13.03.2013, Effect of Different Phospholipids on α-Secretase Activity in the Non-Amyloidogenic Pathway of Alzheimer's Disease.

Int J Mol Sci., 2013 Mar 13;14(3):5879-98.


Grimm MO, Haupenthal VJ, Rothhaar TL, Zimmer VC, Grösgen S, Hundsdörfer B, Lehmann J, Grimm HS, Hartmann T.

Phospholipids as an important part of neuronal membranes vary in different attributes, e.g. fatty acid (FA) acyl chain length, saturation grade, double-bond position and in the polar lipid headgroup, greatly influencing the physicochemical properties of a specific phospholipid. In this paper we have systematically analysed these attributes of phospholipids on their impact on the non-amyloidogenic pathway preventing the production of the toxic Ab. We found that phospholipids with short chain length and polyunsaturated FAs increase the protective non-amyloidogenic pathway by increasing the activity of the ADAM enzymes.  Especially these lipids might therefore be beneficial in preventing or dealing with Alzheimer´s disease..

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22.01.2013, A longitudinal study of cognition, proton MR spectroscopy and synaptic and neuronal pathology in aging wild-type and AβPPswe-PS1dE9 mice

PLoS One. 2013 May 22;8(5):e63643.


Diane Jansen, Valerio Zerbi, Carola Janssen, Jos Dederen, Maartje Mutsaers, Anne Hafkemeijer, Anna Lena Janssen, Cindy Nobelen, Andor Veltien, Sjaak van Asten, Arend Heerschap, Amanda Kiliaan.

Proton magnetic resonance spectroscopy ((1)H MRS) is a valuable tool in Alzheimer's disease research, to investigate the metabolism in the brain. In this study we investigated the metabolism of the brain tisue in adult and old Alzheimer mice and crelated it to their cognition and Alzheimer pathology  We showed that only at older age a lower metabolism was related to impared cognition and also increased Alzheimer pathology

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01.01.2013, Changes in vascular factors 28 years from midlife and late-life cortical thickness

Neurobiology of Aging. 2013 Jan 1; 34(1):100-109


Vuorinen M, Kåreholt I, Julkunen V, Spulber G, Niskanen E, Paajanen T, Soininen H, Kivipelto M, Solomon A.

This study investigated midlife blood pressure, body mass index, total cholesterol, and their changes over time in relation to brain cortical thickness on magnetic resonance imaging 28 years later in 63 elderly at risk of dementia. Midlife hypertension was related to thinner cortex in several brain areas. In elderly with thinner cortex in areas involved in blood pressure regulation (insula), there was a continuous decline in systolic blood pressure after midlife. No associations were found between body mass index or cholesterol and cortical thickness in this group of individuals.

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01.01.2013, Improved spatial learning strategy and memory in aged Alzheimer AβPPswe/PS1dE9 mice on a multi-nutrient diet.

Journal of Alzheimer’s disease. 2013 Jan 1;37(1):233-45

Max Wiesmann, Diane Jansen, Valerio Zerbi , Laus Broersen, Alexander Garthe Amanda Kiliaan.

Lifestyle factors like diet may influence the onset and progression of Alzheimer's disease (AD). In the present study we analyzed learning strategies and memory of 11-month-Alzheimer mice. The specific nutrient combination showed a tendency to improve searching behavior in AD mice by increasing the use of a more efficient search strategy and improving their swim efficiency by decreasing the latency to reach the former platform position.

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01.01.2013, A specific multi-nutrient diet reduces Alzheimer-like pathology in young adult AβPPswe/PS1dE9 mice.

J Alzheimers Dis. 2013;33(1):177-90.


Broersen LM, Kuipers AA, Balvers M, van Wijk N, Savelkoul PJ, de Wilde MC, van der Beek EM, Sijben JW, Hageman RJ, Kamphuis PJ, Kiliaan AJ.

Some diets, like the Mediterranean diet, are well known for their health-promoting effects. Many scientists have tried to pinpoint such effects of diets to single ingredients, but such attempts have not been very successful. We now tested some combinations of ingredients in an animal model of Alzheimer’s disease and showed that beneficial effects of diets may very much depend upon the specific combination of ingredients.

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01.11.2012, Comparison of International Working Group criteria and National Institute on Aging-Alzheimer's Association criteria for Alzheimer's disease.

Alzheimers Dement. 2012 Nov;8(6):560-3

Visser PJ, Vos S, van Rossum I, Scheltens P.

There are two sets of research criteria for Alzheimer’s disease available, those published by an International Working Group in 2007, and the recommendations published by the National Institute on Aging and the Alzheimer's Association (NIA-AA) in 2011. A comparison of the criteria revealed differences in approach, terminology, and use of cognitive markers and biomarkers. Most persons who meet the International Working Group criteria will also meet the NIA-AA criteria and vice versa. However, the NIA-AA criteria allow for a subclassification of persons based on biomarker results within each diagnostic category.

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23.10.2012, Injury markers predict time to dementia in subjects with MCI and amyloid pathology.

Neurology. 2012 Oct 23;79(17):1809-16

van Rossum IA, Vos SJ, Burns L, Knol DL, Scheltens P, Soininen H, Wahlund LO, Hampel H, Tsolaki M, Minthon L, L'italien G, van der Flier WM, Teunissen CE, Blennow K, Barkhof F, Rueckert D, Wolz R, Verhey F, Visser PJ.

Amyloid pathology is one of the hallmarks of Alzheimer’s disease (AD) and levels of beta-amyloid 1-42 can be measured in cerebrospinal fluid (CSF). Abnormal levels of beta-amyloid 1-42 in CSF can already be found in subjects with mild cognitive impairment (MCI), however clinical progression in those subjects is variable. In this study we found that in subjects with MCI and abnormal CSF beta-amyloid 1-42, increased levels of t-tau in CSF and hippocampal atrophy on MRI predicted further cognitive decline and progression to AD-type dementia.

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01.10.2012, Test sequence of CSF and MRI biomarkers for prediction of AD in subjects with MCI.

Neurobiol Aging. 2012 Oct;33(10):2272-81

Vos S, van Rossum I, Burns L, Knol D, Scheltens P, Soininen H, Wahlund LO, Hampel H, Tsolaki M, Minthon L, Handels R, L'Italien G, van der Flier W, Aalten P, Teunissen C, Barkhof F, Blennow K, Wolz R, Rueckert D, Verhey F, Visser PJ.

Biomarkers in cerebrospinal fluid (CSF) and MRI-scan are known to predict Alzheimer’s disease (AD) in subjects with mild cognitive impairment (MCI). With this study we showed that CSF biomarkers increased predictive accuracy for AD, regardless of the findings on MRI. When CSF was tested first, MRI further increased predictive accuracy only in subjects with normal CSF.

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01.10.2012, Trans fatty acids enhance amyloidogenic processing of the Alzheimer amyloid precursor protein (APP)

J Nutr Biochem. 2012 Oct;23(10):1214-23

Grimm MO, Rothhaar TL, Grösgen S, Burg VK, Hundsdörfer B, Haupenthal VJ, Friess P, Kins S, Grimm HS, Hartmann T.

Throughout human history trans fatty acids had been a very rare component of human diet. However recently, hydrogenation of oils and diary products of ruminant animals lead to strongly increasing amounts of trans fatty acids in the human diet. Trans fatty acids are incorporated in several lipids and accumulate in the membrane of cells. Trans fatty acids are a known risk factor for cardiovascular diseases (CVD). Since many CVD risk factors are also risk factors for Alzheimer’s disease (AD), we investigated whether trans fatty acids might afect critical process involved in AD pathogenesis. Indeed we found that trans fatty acids cause an unexpectedly strong increase in amyloidogenic and processing of APP, resulting in increased production of amyloid beta (Aβ) peptides, main components of senile plaques, which are a characteristic neuropathological hallmark for Alzheimer's disease (AD). Moreover, our results show that oligomerization and aggregation of Aβ are increased by trans fatty acids as well. Therefore trans fatty acids increase several molecular risk factors for AD in vitro.

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01.09.2012, Cholesterol and synaptic compensatory mechanisms in Alzheimer's disease mice brain during aging.

J Alzheimers Dis. 2012; 31(4):813-26.

Jansen D, Janssen CI, Vanmierlo T, Dederen PJ, van Rooij D, Zinnhardt B, Nobelen CL, Janssen AL, Hafkemeijer A, Mutsaers MP, Doedée AM, Kuipers AA, Broersen LM, Mulder M, Kiliaan AJ.

Research into the development of Alzheimer's disease (AD) provides increasing evidence that vascular risk factors, including high serum cholesterol, might influence the progression of cognitive impairment and neural degeneration. In this study, we investigated the effects of high dietary cholesterol intake on capillary density, amyloid-β deposition, and presynaptic boutons in the hippocampus of adult (8 months) and aged (15 months) AβPPswe-PS1dE9 and wild-type mice to elucidate how cholesterol may affect neurodegenerative processes in aging and AD. The findings suggest a synaptic compensatory response to maintain connectivity during aging.

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01.09.2012, Microvascular cerebral blood volume changes in aging APP(swe)/PS1 (dE9) AD mouse model: a voxel-wise approach.

Brain Struct Funct. 2012

Zerbi V, Jansen D, Dederen PJ, Veltien A, Hamans B, Liu Y, Heerschap A, Kiliaan AJ.

Vascular disorders can either be cause or consequence in the development of Alzheimer's disease (AD). We developed a new method to obtain microvascular relative cerebral blood volume (rCBV(micro to characterize the occurrence of vascular impairment in a double transgenic mouse model for AD (APP(swe)/PS1(dE9)) during aging. With this methodology the development of cerebral microvascular impairments in in vivo mouse brain can be described. At 8 months, impaired rCBV(micro) appeared in some cortical regions and in the thalamus, which spreads over several sub-cortical areas and the hippocampus at 13 months. We further showed that hippocampal rCBV(micro) in 13-month-old wild-type and APP(swe)/PS1(dE9) mice correlates well with capillary density measured with immunohistochemical staining. Theresults further suggest that rCBV(micro) reduction is caused by an impaired vasoactivity of capillaries and arterioles, which is not directly correlated with the amount of Aβ deposition in parenchyma nor blood vessel walls.

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15.07.2012, Nutritional intervention with Fortasyn™ Connect: Beneficial effects in experimental models of Alzheimer's pathology and functional decline.

Alzheimer's & Dementia 2012 July 15, 8(4):419


Nick van Wijk, Martijn de Wilde, Almar Kuipers, Martin Balvers, Martine Groenendijk, Patrick Kamphuis, Hennariikka Koivisto, Heikki Tanila, Diane Jansen, Valerio Zerbi, Amanda Kiliaan, Laus Broersen

Nutrition provides components that are required for neuronal membrane synthesis. LipiDiDiet researchers in different laboratories now show that the supplementation of a specific combination of such nutrients beneficially affects membrane-bound processes involved in amyloid toxicity and its consequences for behavior and cognition.

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01.07.2012, Leptin and dementia over 32 years – the Prospective Population Study of Women.

Alzheimers Dement. 2012 Jul;8(4):272-7.


Gustafson DR, Bäckman K, Waern M, Östling S, Guo X, Lissner L, Carlson L, Bengtsson C, Skoog I.

Leptin is an adipose tissue hormone that interacts with the brain and may be a mechanistic link between adiposity, cognition and dementia.  These analyses show that leptin levels measured 32 years before dementia onset are not associated with dementia risk.

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02.04.2012, Dietary intake of plant sterols stably increases plant sterol levels in the murine brain.

J Lipid Res. 2012 Apr;53(4):726-35.

Vanmierlo T, Weingärtner O, van der Pol S, Husche C, Kerksiek A, Friedrichs S, Sijbrands E, Steinbusch H, Grimm M, Hartmann T, Laufs U, Böhm M, de Vries HE, Mulder M, Lütjohann D.

Long-term consumption of large amounts of plant sterols results in virtually irreversible accumulation of plant sterols in murine brains. Passage of sterols across the endothelial monolayer depends on the molecular complexity of their side chain and preferentially accumulate within DRM´s of brain cells.

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01.04.2012, Adiposity and cognitive decline: underlying mechanisms.

J Alzheimers Dis. 2012;30 Suppl 2:S97-112


Gustafson DR

Level of adiposity is linked to dementia and Alzheimer's disease in epidemiological studies. Overweight and obesity in mid- and late-life may increase risk for dementia, whereas decline in body weight or body mass index and underweight in years preceding and at the time of a dementia diagnosis may also relate to dementia. This is a review that focuses on potential mechanisms whereby adipose tissue may influence or interact with the brain and/or dementia risk during the dynamic period of life characterized by both body weight and cognitive decline.

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01.04.2012, Blood pressure trajectories from midlife to late life in relation to dementia in women followed for 37 years.

Hypertension. 2012 Apr;59(4):796-801.


Joas E, Bäckman K, Gustafson DR, Östling S, Waern M, Guo X, Skoog I.

Hypertension a marker of cardiovascular risk and correlate of overweight and obesity. Hypertension is a consistently observed risk factor for dementia. In this study, higher systolic blood pressure at baseline was associated with dementia and Alzheimer disease among those not treated with antihypertensives. Those with history of antihypertensive treatment had higher baseline systolic blood pressure than those who were never treated; and in this group, those who developed dementia and Alzheimer disease had lower baseline systolic blood pressure and a steeper increase in systolic blood pressure from 1968 to 1992 than those who did not. A steeper decline in systolic blood pressure during the later part of the study was observed in those who developed dementia regardless of antihypertensive treatment.

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01.04.2012, Plasmalogens inhibit APP processing by directly affecting g-secretase activity in Alzheimer’s disease

ScientificWorldJournal. 2012;2012:141240


Tatjana L. Rothhaar, Sven Grösgen, Viola J. Haupenthal, Verena K. Burg, Benjamin Hundsdörfer, Janine Mett, Matthias Riemenschneider, Heike S. Grimm, Tobias Hartmann, Marcus O.W. Grimm

Previously we have shown that total phosphatidyllethanolamin plasmalogen levels and some phosphatidylcholin plasmalogen species are reduced in Alzheimer´s disease. Here we could further substantiate these results by identifying the plasmalogen species being most prominently altered in human AD post mortem brain and the mechanism how plasmalogens in return influence molecular pathways being important for Alzheimer´s disease. 

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28.03.2012, Amyloid Precursor Protein (APP) Mediated Regulation of Ganglioside Homeostasis Linking Alzheimer’s Disease Pathology with Ganglioside Metabolism

PLoS One. 2012;7(3):e34095.

Grimm MO, Zinser EG, Grösgen S, Hundsdörfer B, Rothhaar TL, Burg VK, Kaestner L, Bayer TA, Lipp P, Müller U, Grimm HS, Hartmann T.

Gangliosides are important lipids of the nervous and other cellular systems. There are many different gangliosides. Here we found that the ß-Amyloid peptides and the Amyloid Precursor Protein intracellular domain regulate the brain amounts of all major brain gangliosides. This is a relevant finding, because it helps to better understand the physiological biological function of ß-Amyloid peptides and how it is possible that a normal peptide turns into a pathological entity causing Alzheimer’s disease. E.g. one critical aspect is that, ß-Amyloid peptides binds to certain gangliosides, in the next step the bound ganglioside binds to a ganglioside converting enzyme and then the Aß inactivates this enzyme. Because the ganglioside converting enzyme is now inactivated, the ganglioside composition changes. Under normal conditions, this is a desired regulatory event, but there are conditions, e.g. if there is too much Aß peptide, that this process does more harm than good and may even increase neurodegeneration and Aß production further.

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15.03.2012, The isoform-specific pathological effects of apoE4 in vivo are prevented by a fish oil (DHA) diet and are modified by cholesterol.

J Alzheimers Dis. 2012;28(3):667-83.

Kariv-Inbal Z, Yacobson S, Berkecz R, Peter M, Janaky T, Lütjohann D, Broersen LM, Hartmann T, Michaelson DM.

Apolipoprotein E, the major brain lipoprotein, exists as several isoforms of which the isoform called apolipoprotein E4 (apoE4) is the most prevalent genetic risk factor of Alzheimer's disease. In view of the close interactions between apoE4 and brain lipids we examined the extend to which the pathological effects of apoE4 in transgenic mice which express this molecule can be modulated by diet and whether apoE4 can affect the brain lipid composition. The results obtained revealed that the neuronal and cognitive impairments which are induced by apoE4 are affected dramatically by diet and that they can be completely presented by feeding the mice with a fish oil diet which is enriched in w3 fatty acids. The diets were found to have an effect on brain lipid composition, but this effect, however, was not modulated by apoE4. These animal model findings show that the pathological effects of apoE4 can be prevented by fish oil diet and suggest that such a diet will also have preventive and /or therapeutic effects in Alzheimer's disease.

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15.03.2012, The genetic architecture of Alzheimer's disease: beyond APP, PSENs and APOE.

Neurobiol Aging. 2012 Mar;33(3):437-56.

Guerreiro RJ, Gustafson DR, Hardy J.

Alzheimer’s disease (AD) is complex and there is a genetic component. Three genes have been found in relation to familial forms of AD, which tend to be early onset. The commonest form of the disease occurs in late life, and is considered sporadic, or without a clear genetic component. Trying to find genes that are related to late onset AD has been attempted in a large number of studies. To date, only one gene, APOE, has been identified as a risk factor for AD. New technologies have allowed a renewed look at genes related to AD, which are discussed in this review.

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15.03.2012, Immunomodulation of microglia by docosahexaenoic acid and eicosapentaenoic acid.

Curr Opin Clin Nutr Metab Care. 2012 Mar;15(2):134-43.

Hjorth E, Freund-Levi Y.

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01.02.2012, Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a longitudinal study.

J Intern Med. 2012 Feb;271(2):204-12. doi: 10.1111/j.1365-2796.2011.02484.x. Epub 2011 Dec 30.

Hooshmand B, Solomon A, Kåreholt I, Rusanen M, Hänninen T, Leiviskä J, Winblad B, Laatikainen T, Soininen H, Kivipelto M.

Vitamin B12 and folate deficiencies are common conditions in elderly populations and may lead to increased risk of Alzheimer’s disease and worse cognitive functioning in the elderly through increase in the levels of the amino acid homocysteine, although the evidence is mixed. In this study, the LipiDiDiet researchers show that holotranscobalamin (the active fraction of vitamin B12), folate, and homocysteine are associated with cognitive performance 7-years later even in non-demented elderly subjects.

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01.02.2012, The Effects of Apolipoproteins E3 and E4 on the Transforming Growth Factor-β System in Targeted Replacement Mice.

Neurodegener Dis. 2012 Feb 1; 10:41-45

Haas A, Liraz O, Michaelson DM.

The passage of information between nerve cells is mediated via distinct receptors and ligands whose interaction triggers distinct signaling cascades. This study focused on lipoprotein E4 (apoE4), which is the most prevalent genetic risk factor of Alzheimer's disease and on an examination of the hypothesis that the pathological effects of apoE4 are mediated via specific impairments in neuronal signaling. This revealed that apoE4 has specific effects on the Transforming Growth Factor-β system. This suggests that the effects of apoE4 may be mediated via this signaling system and suggest that it may be a useful Alzheimer's disease related therapeutic target.

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01.02.2012, A specific multi-nutrient formulation enhances M1 muscarinic acetylcholine receptor responses in vitro.

J Neurochem. 2012 Feb;120(4):631-40.

Savelkoul PJ, Janickova H, Kuipers AA, Hageman RJ, Kamphuis PJ, Dolezal V, Broersen LM.

Nutrition provides components that are required for neuronal membrane synthesis. LipiDiDiet researchers now show that the supplementation of a specific combination of such nutrients beneficially affects membrane-bound processes involved in neurotransmission.

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28.01.2012, 37 years of body mass index and dementia: observations from the prospective population study of women in Gothenburg, Sweden.

J Alzheimers Dis. 2012 Jan;28(1):163-71.

Gustafson DR, Bäckman K, Joas E, Waern M, Östling S, Guo X, Skoog I.

Body mass index (BMI) a measure of overweight and obesity is linked to dementia in epidemiological studies. Overweight and obesity during middle-age and among elderly may increase risk for dementia. However, decreases in body weight or BMI and underweight in years preceding and at the time of a dementia diagnosis may also relate to dementia. Studies conducted over long periods of time are necessary to understand of the relationship between BMI and dementia over the life course. We took a look at the natural history of BMI in relation to dementia over 37 years in the Prospective Population Study of Women (PPSW) in Sweden. We observed that women who developed dementia increased less in BMI from age 38 to 70 years. After age 70, BMI decreased. A lower BMI before and during dementia onset was observed.

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01.01.2012, Injury Markers but not Amyloid Markers are Associated with Rapid Progression from Mild Cognitive Impairment to Dementia in Alzheimer's Disease.

J Alzheimers Dis. 2012 Jan 1;29(2):319-27.

van Rossum IA, Visser PJ, Knol DL, van der Flier WM, Teunissen CE, Barkhof F, Blankenstein MA, Scheltens P.

Alzheimer’s disease starts with mild cognitive impairment. The time between mild cognitive impairment and progression to dementia is however highly variable, ranging from a few months up to 10 years. This publication shows that subjects with mild cognitive impairment who had brain atrophy on MRI scan or a high level of tau protein in the cerebrospinal fluid showed more rapid cognitive decline than subjects without these abnormalities.

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21.10.2011, From brain to food: analysis of phosphatidylcholins, lyso-phosphatidylcholins and phosphatidylcholin-plasmalogens derivates in Alzheimer's disease human post mortem brains and mice model via mass spectrometry.

J Chromatogr A. 2011 Oct 21;1218(42):7713-22.

Grimm MO, Grösgen S, Riemenschneider M, Tanila H, Grimm HS, Hartmann T.

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15.09.2011, The plant sterol brassicasterol as additional CSF biomarker in Alzheimer's disease.

Acta Psychiatr Scand. 2011 Sep;124(3):184-92.

Vanmierlo T, Popp J, Kölsch H, Friedrichs S, Jessen F, Stoffel-Wagner B, Bertsch T, Hartmann T, Maier W, von Bergmann K, Steinbusch H, Mulder M, Lütjohann D.

Comparison of lipid parameters per diagnosis based on relevant predictors revealed significantly lower concentrations of brassicasterol (P < 0.001) in cerebrospinal fluid of patients with Alzheimer disease. Our data suggest that the secretion of plant sterols from plasma via the choroid plexus into cerebrospinal fluid is disturbed in association with AD pathogenesis.

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15.09.2011, Validation of an isotope dilution gas chromatography-mass spectrometry method for analysis of 7-oxygenated campesterol and sitosterol in human serum.

Chem Phys Lipids. 2011 Sep;164(6):425-31.

Husche C, Weingärtner O, Pettersson H, Vanmierlo T, Böhm M, Laufs U, Lütjohann D.

A highly sensitive, reproducible and accurate method based on isotope-dilution gas chromatography-mass spectrometry for simultaneous quantification of Oxyphytosterols from human serum samples and tissues opens new possibilities to investigate the role of Oxyphytosterols in the induction of atherosclerotique processes and intracellular lipid accumulation.

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15.09.2011, Neuroprotective effects of a specific multi-nutrient intervention against Aβ42-induced toxicity in rats.

J Alzheimers Dis. 2011;27(2):327-39.

de Wilde MC, Penke B, van der Beek EM, Kuipers AA, Kamphuis PJ, Broersen LM.

Toxic amyloid peptides are thought to cause neurodegeneration in Alzheimer’s disease. With this publication the LipiDiDiet researchers show that a specific dietary intervention can reduce the impact of amyloid toxicity in the brain. The dietary intervention is called “Fortasyn Connect“ and contains a combination of nutrients that is directly or indirectly involved in neuronal membrane synthesis.

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15.08.2011, IAGG workshop: health promotion program on prevention of late onset dementia.

J Nutr Health Aging. 2011 Aug;15(7):562-75.

Andrieu S, Aboderin I, Baeyens JP, Beard J, Benetos A, Berrut G, Brainin M, Cha HB, Chen LK, Du P, Forette B, Forette F, Franco A, Fratiglioni L, Gillette-Guyonnet S, Gold G, Gomez F, Guimaraes R, Gustafson D, Khachaturian A, Luchsinger J, Mangialasche F, Mathiex-Fortunet H, Michel JP, Richard E, Schneider LS, Solomon A, Vellas B.

The World Health Organization (WHO) reports a 223% expected increase from 1970 to 2025 in adults age 60 years and above. By 2025, there will be 1.2 billion people in this age group worldwide. At this age, and perhaps before, declines in cognition occur, often leading to AD and aging-related dementias. Due to these projections of increasing numbers elderly around the world, and potential numbers with dementia, the World Health Organization convened an expert panel to discuss the prevention of late-onset dementia. Experts from Europe presented on evidence on lifestyle and pharmaceutical studies from the epidemiology and clinical trials. In addition, ideas were shared related to strategies for the future in terms intervention ideas and data base development.

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15.07.2011, Changes in vascular risk factors from midlife to late life and white matter lesions: a 20-year follow-up study.

Dement Geriatr Cogn Disord. 2011;31(2):119-25.

Vuorinen M, Solomon A, Rovio S, Nieminen L, Kåreholt I, Tuomilehto J, Soininen H, Kivipelto M.

White matter lesions (WML) are often seen in MRI and CT scans of elderly and these changes have been associated with decreased cognitive functioning. There is no medication for already existing WML, but it might be possible to delay or prevent their development with early primary prevention. In many cross-sectional studies vascular risk factors, such as hypertension, have been linked with WML, but the long-term effect of these risk factors has not been studied enough. In the following publication we suggest that midlife hypertension and overweight increase the risk of WML in late-life.

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22.04.2011, Docosahexaenoic Acid Reduces Amyloid β Production via Multiple Pleiotropic Mechanisms

THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 286, NO. 16, pp. 14028-14039, April 22, 2011

Marcus O. W. Grimm, Johanna Kuchenbecker, Sven Groesgen, Verena K.Burg, Benjamin Hundsdoerfer, Tatjana L. Rothhaar, Petra Friess, Martijn C. de Wilde, Laus M. Broersen, Botond Penke, Maria Peter, Laszlo Vígh, Heike S. Grimm, and Tobias Hartmann

Accumulation of amyloid peptides is believed to be a main cause for Alzheimer’s disease. Already for quite some time it had been observed that docosahexaenoic acid (DHA) an important omega-3 fatty acid typically found in fish-oil, can reduce amyloid peptide production. With this publication the LipiDiDiet researcher show how DHA reduces amyloid production.

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15.03.2011, Plasmalogen synthesis is regulated via alkyl-dihydroxyacetonephosphate-synthase by amyloid precursor protein processing and is affected in Alzheimer's disease.

J Neurochem. 2011 Mar;116(5):916-25.

Grimm MO, Kuchenbecker J, Rothhaar TL, Grösgen S, Hundsdörfer B, Burg VK, Friess P, Müller U, Grimm HS, Riemenschneider M, Hartmann T.

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03.03.2011, Midlife homocysteine and late-life dementia in women. A prospective population study.

Neurobiol Aging. 2011 Mar;32(3):380-6.

Zylberstein DE, Lissner L, Björkelund C, Mehlig K, Thelle DS, Gustafson D, Ostling S, Waern M, Guo X, Skoog I.

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15.02.2011, ApoE4-Driven Accumulation of Intraneuronal Oligomerized Aβ42 following Activation of the Amyloid Cascade In Vivo Is Mediated by a Gain of Function.

Int J Alzheimers Dis. 2011 Feb 15;2011:792070.

Zepa L, Frenkel M, Belinson H, Kariv-Inbal Z, Kayed R, Masliah E, Michaelson DM.

Recent studies suggest that the neurotoxic peptide amyloid-beta can aggregate to form soluble extremely toxic complexes and that these complexes play an important role in the initiation and progression of Alzheimer's disease. The preset study examined the hypothesis that apoE4, the most prevalent genetic risk factor of Alzheimer's disease, can cross interact with the Amyloid –beta peptide. The results obtained show that apoE4 stimulates the aggregation of the peptide in transgenic mice and increases its toxicity. These findings show that apoE4 and amyloid-beta cross interact and suggest that such interactions also synergize the effects of apoe4 and amyloid- beta in Alzheimer's disease.

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15.01.2011, Intracellular APP Domain Regulates Serine-Palmitoyl-CoA Transferase Expression and Is Affected in Alzheimer's Disease.

Int J Alzheimers Dis. 2011 Jan;2011:695413.

Grimm MO, Grösgen S, Rothhaar TL, Burg VK, Hundsdörfer B, Haupenthal VJ, Friess P, Müller U, Fassbender K, Riemenschneider M, Grimm HS, Hartmann T.

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01.01.2011, Midlife healthy-diet index and late-life dementia and Alzheimer's disease.

Dement Geriatr Cogn Dis Extra. 2011 Jan;1(1):103-12.

Eskelinen MH, Ngandu T, Tuomilehto J, Soininen H, Kivipelto M.

This study investigated long-term effects of dietary patterns on dementia and Alzheimer's disease (AD). For this purpose 525 subjects were randomly selected from population-based cohorts surveyed at midlife, a total of 385 (73%) subjects were re-examined 14 years later in the CAIDE study. A healthy-diet index (range 0–17) was constructed including both healthy and unhealthy dietary components. The study showed that persons with a healthy diet (healthy-diet index >8 points) had a decreased risk of dementia (OR 0.12) and AD (OR 0.08) compared with those with an unhealthy diet (0–8 points), even if several confounding factors were taken into account.

We can conclude that healthy diet at midlife is associated with a decreased risk of dementia/AD in late life. These findings highlight the importance of dietary patterns when prevention and delaying onset of dementia and AD are considered.

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15.12.2010, Adiposity hormones and dementia.

J Neurol Sci. 2010 Dec 15;299(1-2):30-4.

Gustafson DR.

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01.12.2010, Temporal lobe atrophy and white matter lesions are related to major depression over 5 years in the elderly.

Neuropsychopharmacology. 2010 Dec;35(13):2638-45.

Olesen PJ, Gustafson DR, Simoni M, Pantoni L, Ostling S, Guo X, Skoog I.

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23.11.2010, The 32-year relationship between cholesterol and dementia from midlife to late life.

Dement Geriatr Cogn Disord. 2011;31(2):119-25.

Mielke MM, Zandi PP, Shao H, Waern M, Östling S, Guo X, Björkelund C, Lissner L, Skoog I, Gustafson DR.

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19.10.2010, Homocysteine and holotranscobalamin and the risk of Alzheimer disease: a longitudinal study.

Neurology. 2010 Oct 19;75(16):1408-14.

Hooshmand B, Solomon A, Kåreholt I, Leiviskä J, Rusanen M, Ahtiluoto S, Winblad B, Laatikainen T, Soininen H, Kivipelto M.

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15.07.2010, Lipid-lowering treatment is related to decreased risk of dementia: a population-based study (FINRISK).

Neurodegener Dis. 2010;7(1-3):180-2.

Solomon A, Sippola R, Soininen H, Wolozin B, Tuomilehto J, Laatikainen T, Kivipelto M.

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01.07.2010, Biomarkers as predictors for conversion from mild cognitive impairment to Alzheimer-type dementia: implications for trial design.

J Alzheimers Dis. 2010;20(3):881-91

van Rossum IA, Vos S, Handels R, Visser PJ.

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01.07.2010, Possible role of tau in mediating pathological effects of apoE4 in vivo prior to and following activation of the amyloid cascade.

Neurodegener Dis. 2010;7(1-3):16-23.

Inbar D, Belinson H, Rosenman H, Michaelson DM.

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01.05.2010, High plasma levels of vitamin E forms and reduced Alzheimer's disease risk in advanced age.

J Alzheimers Dis. 2010;20(4):1029-37.

Mangialasche F, Kivipelto M, Mecocci P, Rizzuto D, Palmer K, Winblad B, Fratiglioni L.

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21.04.2010, Docosahexaenoic acid reduces amyloid-β₁₋₄₂ secretion in human AβPP-transfected CHO-cells by mechanisms other than inflammation related to PGE₂.

J Alzheimers Dis. 2010;21(4):1271-81.

de Wilde MC, van der Beek EM, Kiliaan AJ, Leenders I, Kuipers AA, Kamphuis PJ, Broersen LM.

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15.04.2010, Functional cholinergic damage develops with amyloid accumulation in young adult APPswe/PS1dE9 transgenic mice.

Neurobiol Dis. 2010 Apr;38(1):27-35.

Machová E, Rudajev V, Smycková H, Koivisto H, Tanila H, Dolezal V.

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01.03.2010, Thyroid hormones are associated with poorer cognition in mild cognitive impairment.

Dement Geriatr Cogn Disord. 2010;30(3):205-11.

Quinlan P, Nordlund A, Lind K, Gustafson D, Edman A, Wallin A.

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01.03.2010, Following activation of the amyloid cascade, apolipoprotein E4 drives the in vivo oligomerization of amyloid-β resulting in neurodegeneration.

J Alzheimers Dis. 2010;22(3):959-70.

Belinson H, Kariv-Inbal Z, Kayed R, Masliah E, Michaelson DM.

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10.11.2009, Adiposity indicators and dementia over 32 years in Sweden.

Neurology. 2009 Nov 10;73(19):1559-66.

Gustafson DR, Bäckman K, Waern M, Ostling S, Guo X, Zandi P, Mielke MM, Bengtsson C, Skoog I.

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01.11.2009, ApoE4-dependent Abeta-mediated neurodegeneration is associated with inflammatory activation in the hippocampus but not the septum.

J Neural Transm. 2009 Nov;116(11):1427-34.

Belinson H, Michaelson DM.

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26.08.2009, New Alzheimer amyloid beta responsive genes identified in human neuroblastoma cells by hierarchical clustering.

PLoS One. 2009 Aug 26;4(8):e6779.

Uhrig M, Ittrich C, Wiedmann V, Knyazev Y, Weninger A, Riemenschneider M, Hartmann T.

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01.08.2009, Pathological synergism between amyloid-beta and apolipoprotein E4--the most prevalent yet understudied genetic risk factor for Alzheimer's disease.

J Alzheimers Dis. 2009;17(3):469-81.

Belinson H, Michaelson DM.

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15.07.2009, Homocysteine and holo-transcobalamin and the risk of dementia and Alzheimers disease: a prospective study.

Eur J Neurol. 2009 Jul;16(7):808-13.

Kivipelto M, Annerbo S, Hultdin J, Bäckman L, Viitanen M, Fratiglioni L, Lökk J.

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15.05.2009, Cholesterol-modifying strategies for Alzheimer's disease.

Expert Rev Neurother. 2009 May;9(5):695-709.

Solomon A, Kivipelto M.

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15.03.2009, Membrane cholesterol content influences binding properties of muscarinic M2 receptors and differentially impacts activation of second messenger pathways.

Eur J Pharmacol. 2009 Mar 15;606(1-3):50-60.

Michal P, Rudajev V, El-Fakahany EE, Dolezal V.

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12.01.2009, Adiposity and Alzheimer's disease.

Curr Opin Clin Nutr Metab Care. 2009 Jan;12(1):15-21.

Luchsinger JA, Gustafson DR.

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05.01.2009, Omega-3 fatty acid supplementation effects on weight and appetite in patients with Alzheimer's disease: the omega-3 Alzheimer's disease study.

J Am Geriatr Soc. 2009 Jan;57(1):11-7.

Irving GF, Freund-Levi Y, Eriksdotter-Jönhagen M, Basun H, Brismar K, Hjorth E, Palmblad J, Vessby B, Vedin I, Wahlund LO, Cederholm T.

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01.12.2008, Upregulation of CRABP1 in human neuroblastoma cells overproducing the Alzheimer-typical Abeta42 reduces their differentiation potential.

BMC Med. 2008 Dec 16;6:38.

Uhrig M, Brechlin P, Jahn O, Knyazev Y, Weninger A, Busia L, Honarnejad K, Otto M, Hartmann T.

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01.12.2008, Apolipoprotein E epsilon4 magnifies lifestyle risks for dementia: a population-based study.

J Cell Mol Med. 2008 Dec;12(6B):2762-71.

Kivipelto M, Rovio S, Ngandu T, Kåreholt I, Eskelinen M, Winblad B, Hachinski V, Cedazo-Minguez A, Soininen H, Tuomilehto J, Nissinen A.

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