The frequency of NPS is high in MCI and AD and increases with the severity of cognitive decline. The subgroups of NPS were relatively consistent from MCI to moderate-severe AD. The subgroup elation appeared only in moderate-severe AD.

Abstract. While APOE ε4 is the major genetic risk factor for Alzheimer's disease (AD), amyloid dysmetabolism is an initial or early event predicting clinical disease and is an important focus for secondary intervention trials. To improve identification of cases with increased AD risk, we evaluated recruitment procedures using pathological CSF concentrations of A␤ 42 (pA␤) and APOE ε4 as risk markers in a multi-center study in Norway. In total, 490 subjects aged 40-80 y were included after response to advertisements and media coverage or memory clinics referrals. Controls (n = 164) were classified as normal controls without first-degree relatives with dementia (NC), normal controls with first-degree relatives with dementia (NCFD), or controls scoring below norms on cognitive screening. Patients (n = 301) were classified as subjective cognitive decline or * Correspondence to: Lene Pålhaugen, P.B. 1000, N-1478 Lørenskog, Norway. Tel.: +47 95832775; E-mail: lene. palhaugen@gmail.com. 98 T. Fladby et al. / Detecting At-Risk AD Casesmild cognitive impairment. Subjects underwent a clinical and cognitive examination and MRI according to standardized protocols. Core biomarkers in CSF from 411 and APOE genotype from 445 subjects were obtained. Cases (both self-referrals (n = 180) and memory clinics referrals (n = 87)) had increased fractions of pA␤ and APOE ε4 frequency compared to NC. Also, NCFD had higher APOE ε4 frequencies without increased fraction of pA␤ compared to NC, and cases recruited from memory clinics had higher fractions of pA␤ and APOE ε4 frequency than self-referred. This study shows that memory clinic referrals are pA␤ enriched, whereas self-referred and NCFD cases more frequently are pA␤ negative but at risk (APOE ε4 positive), suitable for primary intervention.

SUMMARY We present associations between neuropsychiatric symptoms (NPS) and brain morphology in a large sample of patients with mild cognitive impairment (MCI) and Alzheimer’s disease with dementia (AD dementia). Several studies assessed NPS factor structure in MCI and AD dementia, but we know of no study that tested for associations between NPS factors and brain morphology. The use of factor scores increases parsimony and power. For transparency, we performed an additional analysis with selected Neuropsychiatric Inventory – Questionnaire (NPI-Q) items. Including regional cortical thickness, cortical and subcortical volumes, we examined associations between NPS and brain morphology across the whole brain in an unbiased fashion. We reported both statistical significance and effect sizes, using linear models adjusted for multiple comparisons by false discovery rate (FDR). Moreover, we included an interaction term for diagnosis and could thereby compare associations of NPS and brain morphology between MCI and AD dementia. We found an association between the factor elation and thicker right anterior cingulate cortex across MCI and AD dementia. Associations between the factors depression to thickness of the banks of the left superior temporal sulcus and psychosis to the left post-central volume depended on diagnosis: in MCI these associations were positive, in AD dementia negative. Our findings indicate that NPS in MCI and AD dementia are not exclusively associated with atrophy and support previous findings of associations between NPS and mainly frontotemporal brain structures.

To explore markers for synaptic function and Alzheimer disease (AD) pathology in late life depression (LLD), predementia AD and normal controls (NC). A cross-sectional study to compare cerebrospinal fluid (CSF) levels of neurogranin (Ng), Beta-site amyloid-precursor-protein cleaving enzyme1 (BACE1), Ng/BACE1 ratio and Amyloid-β 42/40 ratio, phosphorylated-tau and total-tau in LLD with (LLD AD) or without (LLD NoAD) AD pathology, predementia AD and normal controls (NC). We included 145 participants (NC = 41; predementia AD = 66 and LLD = 38). LLD comprised LLD AD (n = 16), LLD NoAD (n = 19), LLD with non-AD typical changes (n = 3, excluded). LLD AD (pADJ < 0.05) and predementia AD (pADJ < 0.0001) showed significantly higher Ng than NC. BACE1 and Ng/BACE1 ratio were altered similarly. Compared to LLD NoAD, LLD AD showed significantly higher Ng (pADJ < 0.001), BACE1 (pADJ < 0.05) and Ng/BACE1 ratio (pADJ < 0.01). All groups had significantly lower Aβ 42/40 ratio than NC (predementia AD and LLD AD, p < 0.0001; LLD NoAD, p < 0.05). Both LLD groups performed similarly on tests of memory and executive function, but significantly poorer than NC. Synaptic function in LLD depended on AD pathology. LLD showed an association to Amyloid dysmetabolism. The LLD groups performed poorer cognitively than NC. LLD AD may be conceptualized as “predementia AD with depression”.

Both depression and dementia occur by themselves or together in elderly subjects aged 65 and above. The aim of this review is to discuss several hypotheses which try to explain the frequent co-occurrence exceeding chance alone, based on a systematic literature search. A series of studies revealed potential biological similarities between both disorders which, however, were not found in all investigations. Lifetime history of depression can be considered as a distant risk factor for dementias. Depression occurs most frequently within one year before and after the onset of dementia, in which the association between both disorders is probably strongest. In a subgroup of subjects with more "cognitive reserve", depression was found to be a consequence of patient's realisation of beginning cognitive deficits. Several studies indicate that depression in Alzheimer and other dementia forms can be considered as a separate disease entity, as the clinical syndrome differs from depression in earlier periods of life. Studies on the therapy of depression in dementia have aroused increasing interest in recent years. Herewith, certain guidelines in the treatment of older patients with antidepressants must be followed.