The findings in this paper are interesting. The finding that ApoE4 is much more frequent in offspring in which there was a parent with AD versus those without is predicted and is being found in virtually all studies. This is a very strong effect. The unexpected findings are that blood pressure is slightly but significantly elevated in the children with a parent with AD versus those without a parent with AD. This was independent of ApoE4. In addition, stimulated levels of IL1-β were higher. The question is whether the blood pressure and IL1-β changes are primary or secondary. The children whose parents had AD had higher stress levels as measured by an inventory than those whose parents did not have AD. Did this result in higher stress, higher blood pressure, and higher IL1-β? Or are the changes in blood pressure and IL1-β separate issues? It is hard to tell from this study, though it certainly suggests that looking at inflammatory biomarkers in plasma continues to be worth pursuing in the area of antecedent biomarkers.

View all comments by David Holtzman

This new familial study of dementia in patients from the Memory Clinical of the Free University of Amsterdam (VU) brings to light further risk factors beyond the commonly studied ApoE alleles (C/R112). The study shows the expected twofold higher frequency of ApoE4 (R112) with Alzheimer's, but it also shows higher pro-inflammatory cytokine response and hypertension during middle age that are independent of these coding differences. Further SNP analysis of these families might reveal additional ApoE associations with inflammation and Alzheimer disease, as indicated for cardiovascular disease and the ApoE 5'-promoter in the Copenhagen Heart Study (Stengård et al., 2007).

View all comments by Caleb (Tuck) Finch

We have known for a long time that family history is a risk factor for the development of AD. This study is confirming what we and others are finding in our Wisconsin Registry for Alzheimer's Prevention (WRAP) cohort of middle-aged adult offspring of persons with AD. Offspring with a parental history have a high prevalence of the ApoE4 genotype, and risk factors in mid-life such as hypertension and inflammation are potentially modifiable in this population. I think this study also illustrates the value of studying middle-aged persons with a family history in order to better understand the biological and lifestyle risk factors for the disease decades before anyone becomes symptomatic. In other words, persons with a family history of AD may be ideal subjects for interventions designed to prevent or slow the progression of AD.

View all comments by Mark Sager

The results of this study provide further evidence that changes in innate immunity/inflammatory processes are primary events in Alzheimer disease development. Last month, we and others published new susceptibility genes for Alzheimer disease (Harold et al., 2009), some of which code for important elements of the classical complement pathway (CLU and CR1). The van Exel study also sought to identify early markers of disease which relate to genetic susceptibility. The fact that both studies using different methods implicate inflammatory processes is noteworthy. As the authors point out, signs of inflammation have been associated with Alzheimer disease for many years, but the direction of effect was unknown. The van Exel study and other lines of support now provide convincing evidence that these factors are early events in disease. I strongly recommend this paper.

View all comments by Julie Williams

Dr. van Exel's timely paper adds to the Zeitgeist that pro-inflammatory cytokines, and the innate immune system in general, have a key role to play in the development and progression of late-onset AD. Our recent paper in Neurology (1) suggests that peripheral pro-inflammatory signals are associated with increased cognitive decline in late-onset AD. Other recent genetic studies (2,3) have suggested that innate immunity also has an important role to play in the development of AD. This paper supports that view with a focus on genetic differences in the production of pro-inflammatory cytokines as shown by stimulation studies in progeny of AD patients. These findings are consistent but also complementary to our results. Thus, it is our contention that systemic (or indeed central) inflammation, caused by infections, trauma, etc., can exacerbate the central pro-inflammatory cytokine response by activation of primed microglia leading to neuronal cell loss. Priming of microglial cells can be initiated by a number of factors, although the buildup of amyloid plaques is clearly important....  Read more

Dr. van Exel's timely paper adds to the Zeitgeist that pro-inflammatory cytokines, and the innate immune system in general, have a key role to play in the development and progression of late-onset AD. Our recent paper in Neurology (1) suggests that peripheral pro-inflammatory signals are associated with increased cognitive decline in late-onset AD. Other recent genetic studies (2,3) have suggested that innate immunity also has an important role to play in the development of AD. This paper supports that view with a focus on genetic differences in the production of pro-inflammatory cytokines as shown by stimulation studies in progeny of AD patients. These findings are consistent but also complementary to our results. Thus, it is our contention that systemic (or indeed central) inflammation, caused by infections, trauma, etc., can exacerbate the central pro-inflammatory cytokine response by activation of primed microglia leading to neuronal cell loss. Priming of microglial cells can be initiated by a number of factors, although the buildup of amyloid plaques is clearly important. Since the production capacity of the central pro-inflammatory response is also influenced by genetic factors, we would envisage that over time, subjects with primed microglial cells will react to an identical inflammatory insult with higher or lower accumulated cytotoxic damage according to their genetic profile, and that this would influence the age of onset of the disease and thus act as a genetic risk factor in case- control studies. Interesting times, and a boost to those of us who have never given up on the importance of inflammation in this disease.

References:
1. Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, Culliford D, Perry VH. Systemic inflammation and disease progression in Alzheimer disease. Neurology. 2009 Sep 8;73(10):768-74. Abstract

2. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O'Donovan M, Owen MJ, Williams J. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009 Oct;41(10):1088-93. Abstract

3. Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fiévet N, Barberger-Gateau P, Engelborghs S, De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O, European Alzheimer's Disease Initiative Investigators, de Pancorbo MM, Lendon C, Dufouil C, Jaillard C, Leveillard T, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Piccardi P, Annoni G, Seripa D, Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Blanché H, Dartigues JF, Tzourio C, Gut I, Van Broeckhoven C, Alpérovitch A, Lathrop M, Amouyel P. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet. 2009 Oct;41(10):1094-9. Abstract

View all comments by Clive Holmes

This study provides support for one hypothesis about the way in which APOE can influence the development of Alzheimer disease.

View all comments by Richard C. Mohs