Association Between Later Life Lifestyle Factors and Alzheimer’s Disease Biomarkers in Non-Demented Individuals: A Longitudinal Descriptive Cohort Study

Individuals

We selected in total 464 individuals. 111 SCD and 254 MCI individuals were from the DESCRIPA study [14] and 99 individuals with MCI were from the Kuopio longitudinal-MCI (Kuopio L-MCI) study [15 –18]. The DESCRIPA study (n = 881) recruited individuals from eleven memory clinics across Europe between 2003 and 2005. The KUOPIOL-MCI study (n = 145) pooled individuals from two population-based studies in Eastern Finland between 1996 and 2001 [15 , 17–19].

Inclusion criteria for SCD were age above 55 years, referral to the memory clinic for an evaluation of complaints, no cognitive impairment on neuropsychological tests, and absence of dementia.

Inclusion criteria for MCI in DESCRIPA were similar to the criteria for SCD except that a cognitive impairment was required on a neuropsychological test. Impairment was defined as age, gender, and education corrected z-score below –1.5 in any cognitive domain [20]. In Kuopio L-MCI, MCI was defined as: 1) memory complaint by patient, family, or physician; 2) normal activities of daily living; 3) normal global cognitive function; 4) objective impairment below –1.5 SD in any cognitive domain; 5) CDR score of 0.5; and 6) absence of dementia [20, 21].

For both studies, the diagnosis of AD-type dementia was based on the NINCDS-ADRDA criteria [22]. From both studies, we selected individuals based on the availability of CSF data or hippocampal volumes and at least one lifestyle factor.

Baseline and follow-up assessment

At baseline we performed an assessment of clinical history, Mini-Mental State Examination (MMSE [23]), lifestyle factors, and APOE ɛ4 genotyping, and performed medical, neuropsychological, neuroimaging, and CSF assessments. At follow-up, the clinical and neuropsychological assessments were repeated. The average follow-up time was 2.4 years(SD = 1.3).

Lifestyle factors

Data on physical activity, alcohol consumption, and current smoking were available in both the DESCRIPA study and the Kuopio L-MCI study. Data on social activity, cognitive activity, and sleep problems were only collected in DESCRIPA. All measures were self-reported and collected in a clinical interview unless reported otherwise.

Being socially active was defined as having at least one social activity reported several times a week or having at least two activities several times a month. Social activities included visiting family and friends, babysitting, going to church/church choir, club membership (e.g., pensioners, garden, social or golf club) and volunteer’s work.

Being physically active was defined in DESCRIPA as either: 1) every day or about every day walking or cycling, or 2) at least several times a week one of the following self-reported activities: dancing, badminton, tennis, swimming, water exercise, squash, skating, or going to the gym. In KUOPIO L-MCI, being physically active was defined as either 1) a physical activity at least several times a week causing breathlessness or sweating, or 2) a physical activity of at least 2–4 h or 15–30 km per week. This definition was more or less equivalent to the amount of exercise recommended by the Centers for Disease Control (CDC), the American College of Sports Medicine (ACSM) and the American Heart Association (ASA) (i.e., at least five days per week of 30 min moderate intensity activity or 3 days of 20 min vigorous intensity activity) [24, 25].

Cognitive activity was measured with the 7-item Cognitive Activity Scale (CAS) [26]. Cognitive activities measured in this CAS are viewing television; reading newspapers; reading magazines; reading books; playing games such as cards, checkers, crosswords, or other; and going to museums. For every activity, the individual had to rate the frequency on the following 5-point Likert scale: once a year or less (1), several times a year (2), several times a month (3), several times a week (4), every day or about every day (5). Individuals with an average frequency rating >3.9 were considered cognitively active. Individuals (n = 4) with more than 2 missing items on the CAS were excluded.

Mild to moderate alcohol consumption was defined in DESCRIPA as consumption of maximum two alcoholic units a day and in Kuopio L-MCI a consumption of maximum 14 alcoholic units per week. We compared individuals with mild to moderate alcohol consumption (n = 249) with individuals with no alcohol consumption (n = 169), and with individuals with severe alcohol consumption (i.e., more than two units a day or more than 14 per week, n = 39).

Current smoking was defined as any present smoking in DESCRIPA and Kuopio-L MCI.

Sleep problems was defined as sleep problems reported by the patient and/or caregiver in clinical interview or a total score (i.e., frequency x severity) of more than two on the sleep item on the Neuropsychiatry Inventory (NPI [27]).

CSF collection, storage, and analysis

In DESCRIPA, CSF samples were collected in 10 mL polypropylene tubes and stored at –80°C. CSF analyses were centrally performed at the Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Sweden. Aβ₄₂ and total tau (t-tau) were measured with single-parameter ELISA kits (Fujirebio, formerly, Innogenetics, Ghent, Belgium). Concentrations below 550 pg/ml for Aβ₄₂ and above 375 pg/ml for t-tau were considered abnormal according to local cut-off values [28].

In Kuopio L-MCI, CSF samples were collected in 10 mL polypropylene tubes and stored at –70°C. CSF analyses were measured with commercial ELISA (Fujirebio, formerly, Innogenetics, Ghent, Belgium). Concentrations below 452 pg/ml for Aβ₄₂ and above 399 pg/ml for t-tau were considered abnormal according to local cut-off values [29]. In both studies, investigators were blinded to the CSFresults.

Hippocampal volume

The scanning was performed at 1.0 or 1.5 Tesla and included for DESCRIPA 3D T1 weighed gradient echo and a fast fluid attenuated inversion recovery (FLAIR) sequence and for Kuopio L-MCI anatomical high-resolution T1-weighed images using a 3D-MPRAGE sequence [21, 30]. The hippocampal volumes were computed from segmentations generated by a multi-atlas segmentation tool [31]. Age and gender corrected continuous hippocampal volumes were used, which were calculated by a linear regression model [32]. In addition, a cutoff was calculated in an independent cohort (Alzheimer’s Disease Neuroimaging Initiative) that could best discriminate controls from individuals with AD-type dementia when corrected to age of 70 years. Abnormal hippocampal volume was defined as a volume <4216 mm³ for males and <3930 mm³ for females (left and right side summed).

APOE genotype

In DESCRIPA, apolipoprotein E (APOE) ɛ4 genotyping was determined with polymerase chain reaction (PCR) of genomic DNA extracted from coagulated blood.

In Kuopio L-MCI, the APOE genotype was determined from blood leukocytes and extracted by standard phenol-chloroform extraction, and analyzed by PCR and HhaI digestion [33].

Statistical analyses

Statistical analyses were conducted with IBM SPSS statistics version 24. Group differences at baseline were examined with independent t-tests for continuous variables and with χ ² tests for categorical variables. All lifestyle factors were dichotomized into present versus absent. The association between lifestyle factors and dichotomous AD markers (i.e., abnormal Aβ₄₂, abnormal tau, and abnormal hippocampal values) were analyzed by logistic regression analyses corrected for age, gender, education, diagnosis and center in all individuals with SCD and MCI. The moderator effect of all lifestyle factors on continuous AD markers (i.e., CSF Aβ₄₂ pg/ml concentrations, CSF t-tau pg/ml concentrations, corrected hippocampal volumes) in converting to AD-type dementia were analyzed by performing survival analyses with Cox Regression corrected for age, gender, education, and center (the 11 single centers)in individuals with MCI. Assumptions of Cox regression were met.

Post-hoc, analyses were repeated with correction for APOE ɛ4 carriership to control for a possible genetic predisposition for AD-type dementia. In addition, for lifestyle factors with data from both the DESCRIPA and Kuopio L-MCI study (i.e., physical activity, alcohol consumption, and current smoking) analyses were repeated with correction for study (DESCRIPA versus Kuopio L-MCI). Furthermore, logistic regression analyses were also performed with age and gender corrected hippocampal volumes [32] as a continuous outcome measure.

Lifestyle factors and AD biomarkers

Social activity, physical activity, cognitive activity, mild to moderate alcohol consumption, current smoking and sleep problems at time of diagnosis were not associated with abnormal Aβ₄₂, abnormal tau or abnormal hippocampal volumes in individuals with SCD and MCI at baseline. Table 2 lists the relations between these lifestyle factors and AD markers.Similar results were found when analyses were repeated with corrected continuous measures of hippocampal volumes or when analyses were corrected for study (DESCRIPA versus Kuopio L-MCI). Furthermore, there was no moderator effect of diagnosis and results were comparable when correcting for APOE ɛ4 carriership (data not shown).

The effect of lifestyle factors on conversion to AD-type dementia

Later life lifestyle factors were not associated with conversion to AD-type dementia in individuals with MCI (Table 3). Lower CSF Aβ₄₂ concentrations (HR = 0.998, p < 0.01), higher CSF t-tau concentrations (HR = 1.002, p < 0.001) and lower hippocampal volumes (HR = 0.999, p < 0.001) were associated with conversion to AD-type dementia, but these associations were not modulated by lifestyle factors except for mild to moderate alcohol consumption (Table 3). The effect of mild to moderate alcohol consumption relative to no alcohol intake on conversion to AD-type dementia was dependent on the CSF tau status. In individuals with normal tau concentrations, mild to moderate alcohol consumption tended to decrease the risk for conversion to AD-type dementia (HR = 0.178, p = 0.081, Fig. 1), but in individuals with abnormal tau mild to moderate alcohol consumption did not decrease the risk for conversion to AD-type dementia (HR = 0.949, p = 0.908, Fig. 1). Findings remained similar after correction for APOE ɛ4 genotype and also after correction for study (DESCRIPA versus Kuopio L-MCI) (data not shown).

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Fig.1

Association between CSF tau and mild to moderate alcohol consumption. Figure displays Cox regression lines of individuals with normal CSF tau (blue lines) and abnormal CSF tau concentrations (red lines) with mild to moderate alcohol consumption (solid lines) and with no alcohol consumption (dashed lines).