Cognitive Decline In Elderly Individuals Research Articles

Viewpoint on the Benefit of Hearing Care on Cognitive Health.

The purpose of this article is to provide a viewpoint on the recently published results showing the positive effect hearing intervention can have on mitigating the risk of cognitive decline in elderly individuals with hearing impairment. We intend to trigger a broader discussion on the implications of these results from an implementation science perspective. Recently published results were reviewed and contextualized. In our view, these recent findings provide a great opportunity for hearing care professionals to change the perspective on hearing care being an essential service that contributes not only to managing challenges with audibility but to enabling healthy living and aging. As exciting as these findings are, from our perspective, they are also a call to action for the audiology field in terms of clinical implementation science. The findings guide us toward a more interprofessional approach in order to develop and test new, more holistic models of hearing care.

Abstract 20: Axonal Neuropathy and Inflammatory Response in Peripheral Nerves of a Murine Cerebral Amyloid Angiopathy Model

Introduction: Cerebral amyloid angiopathy (CAA) induces intracerebral hemorrhages, small vessel disease, and cognitive decline in elderly individuals. CAA is also associated with slower walking speed and abnormal gait rhythms compared to healthy controls. Little is known regarding the impact of peripheral nervous system abnormalities on CAA-associated gait disturbance. Furthermore, it is unknown whether peripheral nerves pose extracerebral targets of amyloid-related endoneurial inflammation. Hypothesis: Gait disturbance in a CAA model is associated with peripheral neuropathy through endoneurial inflammation related to amyloid accumulation. Methods: Aged (19-24 months) Tg-SwDI mice (CAA mice) of both sexes harboring mutations of human amyloid precursor protein (APP) were used as a CAA model. Age-matched C57BL/6 wild-type (WT) mice were used as controls (n=6-11/grp). Gait disturbance and sensorimotor function were assessed via DigiGait and grip strength testing. Flow cytometry was used to analyze immune cells in the sciatic nerve. Tibial nerve morphometry was performed to assess for neuropathy. Results: CAA mice had weaker grip strength ( CAA: 97.7 ± 17.6 g, WT 111.5 ± 8.1 g, p=0.039 ) and evidence of neuropathic gait disturbances, reflected by increased paw angles ( CAA: 21.1 ± 4.8°, WT 11.7 ± 3.4°, p=0.0002 ) and reduced paw areas ( CAA: 0.4 ± 0.05 cm 2 , WT 0.5 ± 0.06 cm 2 , p=0.013 ) impacting the ground when walking compared to WT mice. Tibial nerve morphometry showed a reduced number of myelinated nerve fibers ( CAA: 1023 ± 230.1, WT 1318 ± 45.8, p=0.0047 ) suggesting potential axonal degeneration in CAA mice. Flow cytometry showed an increase in the count of macrophage (both M1 and M2 subtypes) lineage cells ( M1 CAA: 102.3 ± 29.2, WT 57.9 ± 36.3, p=0.009 ) as well as M1 macrophage associated pro-inflammatory cytokine TNF-α ( CAA: 99.7 ± 28.3, WT 53.8 ± 12.2, p=0.009 ) in sciatic nerves of CAA mice compared to WT mice. Conclusions: CAA mice display an enhanced inflammatory response within the endoneurium which may contribute to observed axonal degeneration, ultimately impairing sensorimotor function and gait. Further studies are needed to unravel the mechanistic interplay between amyloid pathology, endoneurial inflammation, and axonal neuropathy in this CAA model.

Assessing the feasibility of a randomised controlled trial examining the effect of hearing aids on cognitive decline in elderly individuals: a study protocol

IntroductionHearing loss is one of the leading potentially modifiable risk factors for dementia. There is growing evidence suggesting that treating hearing loss with hearing aids could be a relatively low-cost...

Saccadic eye movement variables as biomarkers for cognitive decline in elderly individuals.

Alzheimer's disease (AD) is the leading cause of Dementia, and mild cognitive impairment (MCI) is often considered a precursor to the development of AD dementia and other types of Dementia. Biomarkers such as amyloid beta are specific and sensitive in identifying AD and can identify individuals who have biological evidence of the disease but have no symptoms, but clinicians and researchers may not easily use them on a large scale. Ocular biomarkers, such as those obtained through eye tracking (ET) technology, have the potential as a diagnostic tool due to their accuracy, affordability, and ease of use. In this study, we show that eye movement (EM) metrics from an interleaved Pro/Anti-saccade (PS/AS) ET task can differentiate between cognitively normal (CN) and MCI subjects and that the presence of Aβ brain deposits, a biomarker of AD, significantly affects performance on these tasks. Individuals with Aβ deposits (Aβ+) performed worse than those without (Aβ-). Our findings suggest that eye-tracking measurements may be a valuable tool for detecting amyloid brain pathology and monitoring changes in cognitive function in CN and MCI individuals over time.Clinical Relevance- The PS/AS paradigm, which measures saccadic eye movements, can accurately detect subtle cognitive impairments and changes in the brain associated with Alzheimer's disease in CN and MCI individuals. This makes it a valuable tool for identifying individuals at risk for cognitive decline and tracking changes in cognitive function over time.

The Need for Prospective Cohort Study of the Association between Lower Urinary Tract Symptoms and Cognitive Decline in Elderly Individuals.

The Need for Prospective Cohort Study of the Association between Lower Urinary Tract Symptoms and Cognitive Decline in Elderly Individuals.

The association of blood pressure variability with white matter integrity and cognitive impairment in cerebral amyloid angiopathy

AbstractBackgroundEmerging evidence suggests that blood pressure variability (BPV) may contribute to small vessel disease (SVD) progression and cognitive impairment beyond the deleterious effects of elevated blood pressure, but the mechanisms remain largely unknown. This study investigates if BPV is associated with white matter (WM) microstructural integrity and the slope of cognitive decline in elderly individuals with cerebral amyloid angiopathy (CAA), a well characterized type of SVD.MethodWe recruited 94 non‐demented individuals (73.3 ± 7.0 y, 40 F, MMSE 27.7 ± 1.5) from a memory‐clinic cohort with and without possible/probable CAA with available neuropsychological evaluation and 3.0 T research MRI. Visit‐to‐visit BPV was assessed using the coefficient of variation derived from the serial outpatient BP measures during a 5‐year interval. A novel diffusion tensor imaging marker – peak width of skeletonized mean diffusivity (PSMD) – was used to evaluate the WM integrity. Using linear regression models, we evaluated the association of PSMD with BPV, adjusted for standard cardiovascular risk factors.ResultWe found a significant association between loss of WM integrity and high systolic BPV (β = 0.37, P < 0.001), but not mean BP. The association remained significant after adjusting for age, antihypertensive medication usage, diabetes, smoking, and body mass index. Furthermore, the association of BPV with WM integrity was stronger when CAA was present (P for interaction = 0.018). Higher BPV at baseline was associated with worse executive function in CAA patients at 2‐year follow‐up (β = ‐0.53, P = 0.003), adjusted for baseline function.ConclusionOur findings show that visit‐to‐visit BP fluctuations are associated with loss of WM microstructural integrity and cognitive decline. The association between BP variability and WM integrity might in part be driven by CAA pathology. Further studies are warranted to disentangle the relationship between BP fluctuations, microvascular injury, and cognitive impairment in older adults.

Cognitive decline trajectories and influencing factors in China: A non-normal growth mixture model analysis

BackgroundWith the increase in the aging population worldwide, cognitive decline has become an important research topic. The purpose of this study is to examine the cognitive development trajectories and influencing factors of different latent classes of Chinese elderly people. This will provide us with effective guidance for prevention and intervention. MethodsFour waves of data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) were collected and included 2440 Chinese elderly individuals. The cognitive function of elderly individuals was measured using the Mini Mental State Examination (MMSE). A nonnormal Growth Mixture model (GMM) with five time-invariant covariates was used to identify the different trajectories of cognitive decline in elderly individuals. ResultsThree latent decline trajectory groups were identified: stable cognitive group (SCG), high initial level – cognitive decline group (HIL–CDG), and high initial level – cognitive decline group (LIL–CDG). Elderly women were more likely to be assigned to a lower level subgroup than men. People who smoked and played cards or mahjong were more likely to be assigned to a cognitively stable group. ConclusionEducation may help raise the upper limit of cognition. Smoking may impair cognitive upper limit. A small amount of alcohol intake and participation in cognitive and physical activities may help the elderly to delay cognitive decline in their later years.

Quantitative Immunoblotting Analyses Reveal that the Abundance of Actin, Tubulin, Synaptophysin and EEA1 Proteins is Altered in the Brains of Aged Mice

Optimal synaptic activity is essential for cognitive function, including memory and learning. Evidence indicates that cognitive decline in elderly individuals is associated with altered synaptic function. However, the impact of aging on the expression of neurotransmitter receptors and accessory proteins in brain synapses remains unclear. To fill this knowledge gap, we investigated the effect of aging on the mouse brain by utilizing a subcellular brain tissue fractionation procedure to measure protein abundance using quantitative Western Blotting. Comparing 7-month- (control) and 22-month- (aged) old mouse tissue, no significant differences were identified in the levels of AMPA receptor subunits between the experimental groups. The abundance of GluN2B NMDA receptor subunits decreased in aged mice, whereas the levels of GluN2A did not change. The analysis of cytoskeletal proteins showed an altered level of actin and tubulin in aged mice while PSD-95 protein did not change. Vesicle protein analysis revealed that synaptophysin abundance is decreased in older brains whereas EEA1 was significantly increased. Thus, our results suggest that physiological aging profoundly impacts the abundance of molecules associated with neurotransmitter release and vesicle cycling, proteins implicated in cognitive function.

Interaction Between Odor Identification Deficit and APOE4 Predicts 6-Year Cognitive Decline in Elderly Individuals

Olfactory identification impairment might indicate future cognitive decline in elderly individuals. An unresolved question is to what extent this effect is dependent on the ApoE-ε4, a genotype associated with risk of Alzheimer’s Disease (AD). Given the current concern about reproducibility in empirical research, we assessed this issue in a large sample (n = 1637) of older adults (60 – 96 years) from the population-based longitudinal Swedish National Study on Aging and Care in Kungsholmen (SNAC-K). A hierarchical regression analysis was carried out to determine if a low score on an odor identification test, and the presence of ApoE-ε4, would predict the magnitude of a prospective 6-year change in the Mini-Mental State Examination (MMSE) after controlling for demographic, health-related, and cognitive variables. We found that overall, lower odor identification performance was predictive of cognitive decline, and, as hypothesized, we found that the effect was most pronounced among ApoE-ε4 carriers. Our results from this high-powered sample suggest that in elderly carriers of the ApoE-ε4 allele, odor identification impairment provides an indication of future cognitive decline, which has relevance for the prognosis of AD.

Resting-state prefrontal EEG biomarkers in correlation with MMSE scores in elderly individuals

We investigated whether cognitive decline could be explained by resting-state electroencephalography (EEG) biomarkers measured in prefrontal regions that reflect the slowing of intrinsic EEG oscillations. In an aged population dwelling in a rural community (total = 496, males = 165, females = 331), we estimated the global cognitive decline using the Mini-Mental State Examination (MMSE) and measured resting-state EEG parameters at the prefrontal regions of Fp1 and Fp2 in an eyes-closed state. Using a tertile split method, the subjects were classified as T3 (MMSE 28–30, N = 162), T2 (MMSE 25–27, N = 179), or T1 (MMSE ≤ 24, N = 155). The EEG slowing biomarkers of the median frequency, peak frequency and alpha-to-theta ratio decreased as the MMSE scores decreased from T2 to T1 for both sexes (−5.19 ≤ t-value ≤ −3.41 for males and −7.24 ≤ t-value ≤ −4.43 for females) after adjusting for age and education level. Using a double cross-validation procedure, we developed a prediction model for the MMSE scores using the EEG slowing biomarkers and demographic covariates of sex, age and education level. The maximum intraclass correlation coefficient between the MMSE scores and model-predicted values was 0.757 with RMSE = 2.685. The resting-state EEG biomarkers showed significant changes in people with early cognitive decline and correlated well with the MMSE scores. Resting-state EEG slowing measured in the prefrontal regions may be useful for the screening and follow-up of global cognitive decline in elderly individuals.

Is cognitive status of the Cretan elderly aged ≥ 75 years associated with known behavioral and vascular risk factors?

Purpose This study aimed to examine the association of blood hypertension and certain behavioral risk factors with cognitive decline in elderly individuals.

Identifying elderly people at risk for cognitive decline by using the 2-step test.

[Purpose] The purpose is to verify the effectiveness of the 2-step test in predicting cognitive decline in elderly individuals. [Subjects and Methods] One hundred eighty-two participants aged over 65 years underwent the 2-step test, cognitive function tests and higher level competence testing. Participants were classified as Robust, <1.3, and <1.1 using criteria regarding the locomotive syndrome risk stage for the 2-step test, variables were compared between groups. In addition, ordered logistic analysis was used to analyze cognitive functions as independent variables in the three groups, using the 2-step test results as the dependent variable, with age, gender, etc. as adjustment factors. [Results] In the crude data, the <1.3 and <1.1 groups were older and displayed lower motor and cognitive functions than did the Robust group. Furthermore, the <1.3 group exhibited significantly lower memory retention than did the Robust group. The 2-step test was related to the Stroop test (β: 0.06, 95% confidence interval: 0.01–0.12). [Conclusion] The finding is that the risk stage of the 2-step test is related to cognitive functions, even at an initial risk stage. The 2-step test may help with earlier detection and implementation of prevention measures for locomotive syndrome and mild cognitive impairment.

Cognitive decline and slower reaction time in elderly individuals with mild cognitive impairment.

The relationship between declining performance, as measured by changes in reaction time, and declining cognitive function has not been critically studied. The aim of the present study was to investigate the association between reaction time during a task and cognitive ability in elderly Taiwanese individuals. Patients aged 65 years or older with mild cognitive impairment (MCI) (n = 33) and Alzheimer's disease (n = 26) were recruited from the neurology clinic of a regional hospital in southern Taiwan. In addition, 28 healthy controls aged 65 years or older were recruited from the community. The cognitive performance of the study participants was assessed using the Cognitive Abilities Screening Instrument (CASI). A computer-administered simple reaction time (SRT) task and a flanker reaction time (FRT) task were administered to assess participants' cognitive function. A non-parametric Kruskal-Wallis test was performed to compare CASI scores, SRT, and FRT among the three groups. anova was also used to compare CASI scores, inverse-transformed SRT, and inverse-transformed FRT among the three groups, with adjustment for age and years of education. Additionally, Pearson's partial correlation coefficients were used to assess the association of CASI scores with inverse-transformed SRT, and inverse-transformed FRT within each of the three groups. Significant differences in CASI scores, SRT, and FRT were found between the Alzheimer's disease group and the other two groups, either with or without adjustment for age or education. The reaction time of patients with Alzheimer's disease was significantly slower than the other two groups. Moreover, significant correlation between CASI and FRT was found in patients with MCI. Altered performance in a speed task was observed in patients with MCI. The FRT task should further be explored for its role as a marker for cognitive decline in elderly individuals, particularly in those with MCI.

Longitudinal association of hypertension and diabetes mellitus with cognitive functioning in a general 70-year-old population: the SONIC study.

Both hypertension and diabetes in middle-aged individuals have been suggested to be predictive indicators of cognitive decline. However, the association of hypertension, diabetes and their combination with cognitive functioning is still controversial in older people. The purpose of this study was to investigate the association between cognitive decline and hypertension, diabetes, and their combination in 70-year-old people based on a 3-year longitudinal analysis. Four hundred and fifty-four people aged 70 (±1) years who participated in the Japanese longitudinal cohort study of Septuagenarians, Octogenarians and Nonagenarians Investigation with Centenarians (SONIC) were recruited randomly from a general population and were monitored for 3 years. The data, including most of the demographics, cognitive functioning measured by the Montreal Cognitive Assessment Japanese version (MoCA-J), blood pressure, blood chemistry and other medical histories, were collected at baseline and during the follow-up. The prevalence of hypertension noted in the follow-up survey was significantly higher than than noted at baseline. The mean MoCA-J score at follow-up was not significantly different from the score obtained at baseline. However, the participants with diabetes, especially combined with hypertension at baseline, had significantly lower MoCA-J scores than those without lifestyle-related diseases. The combination of hypertension and diabetes was still a significant risk factor for cognitive decline, considering the MoCA-J scores obtained during the follow-up after adjustments at baseline, relative to sex, body mass index, dyslipidemia, smoking, excessive alcohol intake, antihypertensive treatment and education level (β=-0.14; P<0.01). Our findings indicate that diabetes and the combination of hypertension and diabetes are clear risk factors for future cognitive decline in elderly individuals who are 70 years of age.

Effect of Discontinuation of Antihypertensive Treatment in Elderly People on Cognitive Functioning--the DANTE Study Leiden: A Randomized Clinical Trial.

Observational studies indicate that lower blood pressure (BP) increases risk for cognitive decline in elderly individuals. Older persons are at risk for impaired cerebral autoregulation; lowering their BP may compromise cerebral blood flow and cognitive function. To assess whether discontinuation of antihypertensive treatment in older persons with mild cognitive deficits improves cognitive, psychological, and general daily functioning. A community-based randomized clinical trial with a blinded outcome assessment at the 16-week follow-up was performed at 128 general practices in the Netherlands. A total of 385 participants 75 years or older with mild cognitive deficits (Mini-Mental State Examination score, 21-27) without serious cardiovascular disease who received antihypertensive treatment were enrolled in the Discontinuation of Antihypertensive Treatment in Elderly People (DANTE) Study Leiden from June 26, 2011, through August 23, 2013 (follow-up, December 16, 2013). Intention-to-treat analyses were performed from January 20 through April 11, 2014. Discontinuation (n=199) vs continuation (n=186) of antihypertensive treatment (allocation ratio, 1:1). Change in the overall cognition compound score. Secondary outcomes included changes in scores on cognitive domains, the Geriatric Depression Scale-15, Apathy Scale, Groningen Activity Restriction Scale (functional status), and Cantril Ladder (quality of life). Compared with 176 participants undergoing analysis in the control (continuation) group, 180 in the intervention (discontinuation) group had a greater increase (95% CI) in systolic BP (difference, 7.36 [3.02 to 11.69] mm Hg; P=.001) and diastolic BP (difference, 2.63 [0.34 to 4.93] mm Hg; P=.03). The intervention group did not differ from the control group in change (95% CI) in overall cognition compound score (0.01 [-0.14 to 0.16] vs -0.01 [-0.16 to 0.14]; difference, 0.02 [-0.19 to 0.23]; P=.84). The intervention and control groups did not differ significantly in secondary outcomes, including differences (95% CIs) in change in compound scores of the 3 cognitive domains (executive function, -0.07 [-0.29 to 0.15; P=.52], memory, 0.08 [-0.12 to 0.29; P=.43], and psychomotor speed, -0.85 [-1.72 to 0.02; P=.06]), symptoms of apathy (0.17 [-0.65 to 0.99; P=.68]) and depression (0.14 [-0.20 to 0.48; P=.41]), functional status (-0.72 [-1.52 to 0.09; P=.08]), and quality-of-life score (-0.09 [-0.34 to 0.16; P=.46]). Adverse events were equally distributed. In older persons with mild cognitive deficits, discontinuation of antihypertensive treatment did not improve cognitive, psychological, or general daily functioning at the 16-week follow-up. trialregister.nl Identifier: NTR2829.

Vitamin D deficiency predicts cognitive decline in older men and women: The Pro.V.A. Study.

To test the hypothesis that hypovitaminosis D is associated with a higher risk of cognitive decline over a 4.4-year follow-up in a large sample of older adults. This research was part of the Progetto Veneto Anziani (Pro.V.A.), an Italian population-based cohort study of 1,927 elderly subjects. Serum 25-hydroxyvitamin D (25OHD) levels were measured at the baseline. Global cognitive function was measured with the Mini-Mental State Examination (MMSE); scores lower than 24 were indicative of cognitive dysfunction, and a decline of 3 or more points on the MMSE over the follow-up was considered as clinically significant. Analyses were adjusted for relevant confounders, including health and performance status. Participants with 25OHD deficiency (<50 nmol/L) or insufficiency (50-75 nmol/L) were more likely to have declining MMSE scores during the follow-up than those who were 25OHD sufficient (≥75 nmol/L). Among participants cognitively intact (baseline MMSE scores ≥24 and without diagnosis of dementia), the multivariate adjusted relative risk (95% confidence interval [CI]) of the onset of cognitive dysfunction was 1.36 (95% CI: 1.04-1.80; p = 0.02) for those with vitamin D deficiency and 1.29 (95% CI: 1.00-1.76; p = 0.05) for those with vitamin D insufficiency by comparison with individuals with normal 25OHD levels. The results of our study support an independent association between low 25OHD levels and cognitive decline in elderly individuals. In cognitively intact elderly subjects, 25OHD levels below 75 nmol/L are already predictive of global cognitive dysfunction at 4.4 years.

Influence of Alzheimer's disease genes on cognitive decline: the Guangzhou Biobank Cohort Study

Cognitive decline is a reduction in cognitive ability usually associated with aging, and those with more extreme cognitive decline either have or are at risk of progressing to mild cognitive impairment and dementia including Alzheimer's disease (AD). We hypothesized that genetic variants predisposing to AD should be predictive of cognitive decline in elderly individuals. We selected 1325 subjects with extreme cognitive decline and 1083 well-matched control subjects from the Guangzhou Biobank Cohort Study in which more than 30,000 southern Chinese older people have been recruited and followed up. Thirty single-nucleotide polymorphisms in 29 AD-associated genes were genotyped. No statistically significant allelic associations with cognitive decline were found by individual variant analysis. At the level of genotypic association, we confirmed that the APOE ε4 homozygote significantly accelerated cognitive decline and found that carriers of the ACE rs1800764_C allele were more likely to show cognitive decline than noncarriers, particularly in those without college education. However, these effects do not survive after multiple testing corrections, and together they only explain 1.7% of the phenotypic variance in cognitive score change. This study suggests that AD risk variants and/or genes are not powerful predictors of cognitive decline in our Chinese sample.

Intracranial pulsatility is associated with regional brain volume in elderly individuals

Excessive intracranial pulsatility is thought to damage the cerebral microcirculation, causing cognitive decline in elderly individuals. We investigated relationships between brain structure and measures related to intracranial pulsatility among healthy elderly. Thirty-seven stroke-free, non-demented individuals (62–82 years of age) were included. We assessed brain structure, invasively measured cerebrospinal fluid (CSF) pulse pressure, and magnetic resonance–quantified arterial and CSF flow pulsatility, as well as arterial pulse pressure. Using both multivariate partial least squares and ordinary regression analyses, we identified a significant pattern of negative relationships between the volume of several brain regions and measures of intracranial pulsatility. The strongest relationships concerned the temporal lobe cortex and hippocampus. These findings were also coherent with observations of positive relationships between intracranial pulsatility and ventricular volume. In conclusion, elderly subjects with high intracranial pulsatility display smaller brain volume and larger ventricles, supporting the notion that excessive cerebral arterial pulsatility harms the brain. This calls for research investigating altered intracranial cardiac-related pulsatile stress as a potential risk factor that may cause or worsen the prognosis in subjects developing cognitive impairment and dementia.

Cognitive Patterns of Normal Elderly Subjects Are Consistent With Frontal Cortico-Subcortical and Fronto-Parietal Neuropsychological Models of Brain Aging

Three neuropsychological theories have been developed according to a possible existence of a similar pattern of cognitive decline in elderly individuals and patients with brain damage. The respective neuropsychological theories attribute age-related deficits to: (a) dysfunction of the frontal lobes, (b) temporo-parietal dysfunction, or (c) decline of right-hemisphere functions. In the present study, we examined which of these theories best explains the cognitive patterns of normal elderly subjects older than 80 years of age (old elderly). Thirty normal old elderly subjects, 14 patients with subcortical vascular dementia, 14 with mild Alzheimer's disease, 15 with damage of the right hemisphere of the brain, and 20 young elderly controls participated. A test battery covering the main cognitive domains was administered to all participants. A hierarchical cluster analysis revealed five groups of individuals with different cognitive patterns across the whole sample. Old elderly subjects were assigned to four groups according to: (a) preserved overall cognitive performance, (b) processing speed decline, (c) attention decline, or (d) executive impairment. The results of the study are most congruent with models emphasizing frontal-lobe cortical–subcortical and fronto-parietal changes in old age. The results also indicate considerable heterogeneity in the cognitive patterns of normal old elderly adults.

Vascular risk factors: a ticking time bomb to Alzheimer's disease.

Evidence is growing that vascular risk factors (VRFs) for Alzheimer's disease (AD) affect cerebral hemodynamics to launch a cascade of cellular and molecular changes that initiate cognitive deficits and eventual progression of AD. Neuroimaging studies have reported VRFs for AD to be accurate predictors of cognitive decline and dementia. In regions that participate in higher cognitive function, middle temporal, posterior cingulate, inferior parietal and precuneus regions, and neuroimaging studies indicate an association involving VRFs, cerebral hypoperfusion, and cognitive decline in elderly individuals who develop AD. The VRF can be present in cognitively intact individuals for decades before mild cognitive deficits or neuropathological signs are manifested. In that sense, they may be "ticking time bombs" before cognitive function is demolished. Preventive intervention of modifiable VRF may delay or block progression of AD. Intervention could target cerebral blood flow (CBF), since most VRFs act to lower CBF in aging individuals by promoting cerebrovascular dysfunction.