Miia Kivipelto

Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria

During the past decade, a conceptual shift occurred in the field of Alzheimers disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this “silent” stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations.

Are the CSF levels of 24S-hydroxycholesterol a sensitive biomarker for mild cognitive impairment?

There is a need for effective biomarkers showing whether or not a patient with mild cognitive impairment (MCI) will progress to Alzheimers disease (AD) with dementia. At the present three cerebrospinal fluid (CSF) biomarkers are in general use: total tau, phospho-tau and beta-Amyloid. These markers are regarded to have high capacity to differentiate early AD from normal ageing. We have analysed CSF levels of a new marker for neuronal degeneration, 24S-hydroxycholesterol (24OHC) in patients with MCI. For reasons of comparison, we also analysed these levels in patients with AD. There was a significant correlation between CSF levels of 24OHC and total tau (as well as phospho-tau) in both groups of patients. Fifty percent of the patients contemplated for MCI were found to have elevated levels of 24OHC (using a 95th upper percentile set cut-off). All the MCI patients with normal levels of 24OHC had normal levels of the other markers. In patients with AD, the percentages of those with increased levels of 24OHC, tau and phospho tau were similar (55-67%). In this pilot study, we discuss the possibility that 24OHC may be a sensitive test for MCI.

Why has therapy development for dementia failed in the last two decades

The success rate of the pharmaceutical research and development (R&D) for dementia drugs has been abysmally low, in the last two decades. Also low has been the number of pipeline drugs in development, compared to other therapy areas. However, the rationale of early terminations has not been reported in the majority of trials. These are key findings of the recently published pharmaceutical pipeline analysis by the UK‐based Office of Health Economics (OHE). Our understanding of main challenges include (1) the significant gaps of knowledge in the nosology and complexity of the underpinning biological mechanisms of the commonest, not familial, forms of late onset dementias; (2) low signal‐to‐noise ratio, notwithstanding the lack of validated biomarkers as entry and/or end‐point criteria; (3) recruitment and retention, particularly in the asymptomatic and early disease stages. A number of current and future strategies aimed at ameliorating drug development are outlined and discussed.

Risk of Alzheimer’s disease among users of postmenopausal hormone therapy: A nationwide case-control study

OBJECTIVE To examine the association between postmenopausal hormone therapy (HT) and Alzheimers disease (AD). METHODS Medicine and Alzheimers disease (MEDALZ) is a nested case-control study of the entire Finnish population with clinically verified AD from 2005 to 2011 and up to 4 matched controls per case. This study comprises 230,580 women (46,117 cases and 184,463 controls). Data on HT use from 1995 to 2011 was extracted from the national prescription register using following ATC codes: G03C (estrogen), G03D (progestogen) and G03F (estrogen and progestogen in combination). Only systemic HT (oral or transdermal) was considered. RESULTS Use of systemic estrogen and progestogen was associated with an increased risk of AD, with ORs (95% CI) of 1.10 (1.06-1.12) and 1.13 (1.10-1.17) respectively, but use of systemic estrogen HT for >10years (OR, 95% CI: 0.91, 0.84-0.99) was protective against AD. Long-term (>10years) use of progestogen and combination HT was not related to AD risk (OR, 95% CI: 1.0, 0.90-1.2). CONCLUSION Our findings do not suggest HT is an important determinant of AD risk.

The Epidemiology and Prevention of Alzheimer’s Disease and Projected Burden of Disease

Today there are more than 36 million demented persons worldwide. With the aging of populations, the prevalence of dementia and Alzheimer’s disease (AD) is expected to more than triple in the coming 40 years. Besides high age and genetic factors, evidence from observational studies shows that many modifiable vascular and lifestyle-related risk factors at midlife affect the risk of the disease. Control of vascular and metabolic risk factors, healthy diet, and maintenance of AN active lifestyle (physical, mental, and social components) may thus be the key issues on the road to prevent or delay the onset of AD. As the pathologic processes leading to AD may take decades to develop, it is crucial to identify optimal time windows for preventive efforts. Targeting several risk factors simultaneously and long duration of the intervention may be needed for the optimal preventive effect. As many persons are affected, relatively small effects of an integrative intervention on common risk factors may have a huge public health impact. Usage of biomarkers may help in identifying different risk phenotypes and in monitoring effects of the interventions. International collaboration is necessary to initiate future large-scale dementia prevention studies that are needed to formulate evidence-based preventive measures in cognitive decline and dementia.

Midlife Work-Related Stress is Associated with Late-Life Gray Matter Volume Atrophy

Background: Work-related stress has been associated with an increased dementia risk. However, less is known about the mechanisms that underlie these associations. Objective: The goal is to examine associations between midlife work-related stress and late-life structural brain alterations. Methods: The Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study participants were randomly selected from independent population-based surveys (mean age 50) in Finland. MRI measurements included gray matter (GM) volume, white matter lesions (WML) and medial temporal atrophy (MTA) (1st re-examination, n = 102); and GM volume, hippocampal volume, WML volume, cortical thickness, and MTA (2nd re-examination, n = 64). Work-related stress comprised a score from two questions administered in midlife. Results: Higher levels of midlife work-related stress were associated with lower GM volume (β= –0.077, p = 0.033) at the first re-examination, even after adjusting for several confounders. No significant associations were found with MTA, WML, or MRI measurements at the second re-examination. Conclusion: Previously shown associations of midlife work-related stress with dementia risk may be at least partly explained by associations with lower GM volume in late-life. The lack of associations at the second re-examination may indicate a critical time window for the effects of midlife work-related stress, and/or selective survival/participation.

Prevention of Alzheimer's Disease: Backward through the Lifespan

This is a brief summary of experiences from Finland related to Alzheimers disease (AD) prevention research. The first signals that AD may have vascular modifiable risk factors came from studies on cardiovascular conditions and diabetes. Cardiovascular prevention projects such as North Karelia Project and WHO-MONICA in the 1970-1980 s were focused on younger populations, which led to the idea of looking for risk factors as far back as middle age. Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) is one of the few studies in the world focusing on late-life cognition with a large and representative population-based cohort, baseline examination at midlife, and follow-up time up to three decades. Since 1998, it has identified several modifiable risk factors for cognitive impairment/dementia, and produced the first risk score for estimating dementia risk based on midlife profiles. The CAIDE Dementia Risk Score has been used to select participants in the Finnish Geriatric Intervention Study to prevent cognitive impairment and disability (FINGER). FINGER is an ongoing multicenter RCT involving 1,200 participants aged 60-77 years, and testing the effects of a two-year multi-domain intervention targeting several risk factors simultaneously. It started in September 2009 and will be completed at the end of 2013. The FINGER study is at the forefront of international collaborative efforts to solve the clinical and public health problems of early identification of individuals at increased risk of late-life cognitive impairment, and of developing intervention strategies to prevent or delay the onset of cognitive impairment and dementia.