Midlife cholesterol levels predict Alzheimer disease with ASCVD

Cardiovascular risk factors and glucose tolerance in midlife and risk of cognitive disorders in old age Up to a 49-year follow-up of the Helsinki Businessmen Study

Literature - Rantanen K, Strandberg AY., Salomaa VV, et al. - Ann Med. 2017 Feb 2:1-30


Primarily neurodegenerative as well as vascular processes contribute to dementia [1-3]. Most common diagnosis for progressing dementia is probable Alzheimer disease (AD). Long-term studies have strongly promoted the idea of AD as vascular state and consequently, sporadic late-onset AD is now considered a potentially preventable condition [4,5].

It is suggested that AD can be predicted by risk factors of atherosclerotic cardiovascular disease (ASCVD). Moreover, late-onset dementia, including AD, have been related to risk factors in midlife, such as high blood pressure (BP), hypercholesterolemia, obesity, physical inactivity, smoking, stroke and diabetes [1,6,7].

However, mixed results have been published regarding potential predictors, probably due to clinical variability of dementia in old age. This heterogeneity was reduced in the Helsinki Businessmen Study (HBS), by using a Finnish, initially healthy, same gender (men, Caucasian) and socioeconomically (highest strata) similar cohort (n=3309 used in the analyses), in which all were born between 1919-1934. The HBS study started in 1964 and investigated the relationship between ASCVD risk and glucose tolerance in midlife and dementia in old age over a period of 49 years in which 1911 deaths occurred.

Dementia types were well distinguished and patients were categorized into the following groups: ‘Pure AD’ (diagnosis of AD without any hint of ASCVD, n=93), AD-ASCVD (diagnosis of AD specified either as a cause of death or in the narrative, with any concomitant ASCVD, n=126), VD (diagnosis of vascular dementia [VD] specified as a cause of death or in the narrative, n=82), dementia or memory disorder mentioned in the death certificate but not as a specific diagnosis (n=27), Lewy body disease (LBD) with or without sign of other types of dementia (n=14), other specific diagnosis for dementia or memory disorder (n=8). Only the 3 largest groups were used for further analyses.

Main results

  • AD-ASCVD patients had significantly higher cholesterol at baseline.
  • APOE Ɛ4 allele was present in 31.5% of a subcohort of men without dementia and 42.9, 51.4 and 45.5% in a subcohort of patients with pure AD, AD-ASCVD and VD, respectively (P=0.06).
  • In this same subcohort, the mini-mental state examination (MMSE) scores were 28.5, 26.2. 27.4 and 25.8 among old-age survivors, pure AD, AD-ASCVD and VD groups, respectively (P<0.001).
  • Pure AD men had the highest use of AD drugs (71%). VD patients had highest use of hypertension and diabetes drugs, which moreover, was lower in pure AD than in men without dementia.
  • Smoking, BMI, systolic BP and cholesterol levels at baseline were not associated with pure AD or VD, but risk of AD-ASCVD was significantly predicted by midlife cholesterol levels in which high cholesterol (≥6.5 mmol/L) increased the risk by 67% as compared to low levels. HR per standard deviation was 1.24 (95% CI 1.04-1.47).
  • One-hour glucose (adjusted for age and smoking) significantly predicted mortality without dementia but not with any type of dementia.


In this study with a long-term follow-up, pure AD (without ASCVD) was not associated with cholesterol levels, blood pressure, glucose tolerance of diabetes, whereas AD with ASCVD was significantly associated with midlife cholesterol levels.


1. Winblad B, Amouyel P, Andrieu S, et al. Defeating Alzheimer’s disease and other dementias: a priority for European science and society. Lancet Neurol. 2016;15:455-532

2. Hachinski V, Shifts in thinking about dementia. JAMA. 2008;300:2172-2173.

3. Dubois B, Feldman HH, Jacova C, et al. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol. 2010;9:1118-27.

4. De la Torre J. Vascular risk factors: A ticking time bomb to Alzheimer’s disease. Am J Alz Dis Other Dem. 2013;28:551-9.

5. Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer disease prevalence. Lancet Neurol. 2011;10:819-828.

6. Kloppenborg RP, van den Berg E, Kappelle LJ, Biessels GJ. Diabetes and other vascular risk factors for dementia: which factor matters most? A systematic review. Eur J Pharmac. 2008;585:97-108.

7. Exalto LG, Quesenberry CP, Barnes D, Kivipelto M, Biessels GJ, Whitmer RA. Midlife risk score for the prediction of dementia four decades later. Alzheimers Dement. 2014:10;562-570.

Find this article online at Ann Med

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