Mild cognitive impairment/Secondary dementia prevention

Cognitive impairment in non-demented elderly persons, often labeled mild cognitive impairment (MCI), is one of the strongest predictors of dementia. It has been estimated that on a yearly basis, 6.8% of people with MCI progress to dementia. A total of 4.9% of people with MCI develop Alzheimer’s disease (AD) within three years. If prevention of cognitive deterioration and dementia is to be effectively pursued, we must understand the extent of MCI in the population, its underlying mechanisms, and the likelihood that it will progress toward more severe stages of cognitive decline. Three research lines have been developed:

a. Mild cognitive impairment: occurrence and risk factors. Using information from the nationwide Swedish Twin Registry on 11,926 dementia-free and cognitive impairment no dementia (CIND)-free individuals, it has been estimated that one out of four Swedes (25%) aged 65 years or older have some degree of cognitive impairment¹. In twin pairs with discordant CIND status, formal education was the only environmental factor that could explain the differences in outcomes¹. This finding confirms the protective value of education on cognitive decline, independent of genetic background and early life environment. In another study based on the same cohort of Swedish twins, mental, musculoskeletal, respiratory, urological, and endocrine diseases were all significantly associated with increased odds of CIND². Co-twin analyses showed that genetic and early-life environmental factors partially explained the association between CIND and chronic diseases. In a study based on the Kungsholmen cohort, we also found that being in a low mood almost tripled the risk of developing MCI within three years³. Further, low mood seems to have a more prominent role in the early, rather than in more advanced, stages of cognitive decline. Finally, people carrying one APOE ɛ4 allele are at increased risk of both amnestic MCI and global MCI⁴. Low mood interacts with APOE ɛ4 allele so that cognitively healthy elderly people with both risk factors have a 12-fold increased risk of developing MCI within three years³.

b. Preclinical dementia and natural evolution of mild cognitive impairment. In the Kungsholmen Project, it was observed that people in the preclinical stage of AD deviated from the normal aging curve earlier than people in the preclinical stage of vascular dementia. Those in the preclinical stage of AD deviated up to nine years before diagnosis, and those with vascular dementia deviated up to six years before diagnosis. However, once people with preclinical vascular dementia started to decline, they deteriorated at a faster rate than people with preclinical AD⁵. Data regarding two different cohorts of 70-year-olds from the Kungsholmen and the H70 projects indicated that decline in cognitive test results occurred 5 to 10 years before dementia diagnosis. The onset occurs earlier for fluid cognitive abilities (such as memory and speed) than crystallized abilities (such as verbal abilities), but acceleration after onset is faster for the latter. Finally, among the 160 persons age 75+ from the Kungsholmen Project with incident MCI, low mood three years before the detection of MCI was an effective predictor of progression to dementia three years after the diagnosis of MCI. This finding suggests that low mood may be an early sign of initial cognitive deterioration rather than a “true” risk factor for or consequence of MCI³ . We also found that people with MCI who carried two APOE ɛ4 alleles (ɛ4 homozygotes) progressed substantially faster to dementia than people with MCI who were not APOE ɛ4carriers; those with two ɛ4 alleles developed dementia more than three years earlier⁴. On the other hand, accelerated progression from MCI to AD and dementia occurs when white matter lesions at MRI examination co-occur with vascular diseases or vascular risk factors⁶.

c. Pre-MCI. The research focus here shifted from MCI to earlier syndromes of cognitive impairment, namely, pre-MCI. The most-studied sign of this early phase is subjective cognitive complaints, the subjective feeling of deterioration in one’s own cognitive capabilities, also known as SCI. Longitudinal studies support the idea that a proportion of people who will later develop dementia pass through a stage when cognitive decline is not yet evident, but there is a subjective perception of it. The prevalence of SCI was unknown until recently, when we used information from the Swedish Twin Registry on nearly 12,000 dementia- and MCI-free individuals to estimate that 39% of Swedish people aged 65 years and older present with SCI¹. The same study showed that SCI and MCI have distinct sociodemographic profiles. One important question about both SCI and MCI is to what extent they are determined by genetic background and early life environment (genes and family environment). Caracciolo et al.¹ found that at the SCI and MCI stage, adult life environment is more important than genetic and familial background factors in discriminating people who perform well and perceive themselves as functioning optimally from those with signs or symptoms of initial cognitive deterioration. Similarly to people with CIND, those with subjective cognitive complaints are more likely to be affected by chronic diseases. Indeed, SCI was found to be associated with most chronic diseases, suggesting that general rather than specific mechanisms underlie the association. Also, in this case, adult life environment rather than genetic background and early life environment appears to be prominent in explaining the association between SCI and chronic disease.

1. Caracciolo B, Gatz M, Xu W, Pedersen NL, Fratiglioni L. Differential distribution of subjective and objective cognitive impairment in the population: a nation-wide twin-study. J Alzheimers Dis 2012; 29(2):393-403.
2. Caracciolo B, Gatz M, Xu W, Marengoni A, Pedersen NL, Fratiglioni L. Relationship of subjective cognitive impairment and cognitive impairment no dementia to chronic disease and multimorbidity in a nation-wide twin study. J Alzheimers Dis [In press: online] 2013. Available from: doi 10.3233/JAD-122050
3. Caracciolo B, Bäckman L, Monastero R, Winblad B, Fratiglioni L. The symptom of low mood in the prodromal stage of mild cognitive impairment and dementia: a cohort study of community-dwelling elderly. J Neurol Neurosurg Psychiatry 2011; 82(7):788-793.
4. Xu WL, Caracciolo B, Wang HX, Santoni G, Winblad B, Fratiglioni L. Accelerated progression from mild cognitive impairment to dementia among APOE ɛ4ɛ4 carriers. J Alzheimers Dis 2013; 33(2):507-15.
5. Laukka EJ, MacDonald S, Fratiglioni L, Bäckman L. Preclinical cognitive trajectories differ for Alzheimer’s disease and vascular dementia. J Int Neuropsychol Soc 2012; 18(2):191-199.
6. Clerici F, Caracciolo B, Cova I, Fusari Imperatori S, Maggiore L, Galimberti D, etal. Does vascular burden contribute to the progression of mild cognitive impairment to dementia? Dement Geriatr Cogn Disord 2012; 34:235-243.